Drugs for treating tumors

Abstract

This invention belongs to the field of biopharmaceuticals and relates to drugs for treating tumors, and provides the use of an anti-PD-L1 antibody or a pharmaceutical composition thereof in the manufacture of a medicament for treating endometrial cancer. It also provides the use of an anti-PD-L1 antibody or a pharmaceutical composition thereof in the manufacture of a medicament for treating MSI-H and / or dMMR tumors. It also provides the use of a therapeutic combination or pharmaceutical composition of an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating endometrial cancer.

Description

[Technical Field]

[0001] The present application is in the field of biopharmaceuticals, and specifically relates to drugs for treating tumors. [Background technology]

[0002] Endometrial cancer (EC), also known as uterine cancer, is a group of epithelial malignant tumors that originate in the uterine lining and is one of the three most common malignancies in the female reproductive tract. It is common in perimenopausal and postmenopausal women. As life expectancy increases and lifestyle changes occur, the incidence of endometrial cancer has continued to rise over the past 20 years, with a trend toward younger patients. In Western countries, endometrial cancer is the most common type of female reproductive system malignancy. In Japan, it is the second most common gynecological malignancy after cervical cancer, accounting for approximately 20–30% of all gynecological malignancies. In some developed cities, endometrial cancer is the most common type of gynecological malignancy. The postoperative recurrence rate for stage I and II patients is approximately 15%, with 50–70% of recurrences being symptomatic. Most recurrences occur within three years of treatment. Localized recurrences in the vagina or pelvic cavity are successfully treated. Isolated vaginal recurrence has a 50-70% 5-year survival rate after radiation therapy.

[0003] Treatment of endometrial cancer is primarily based on surgery, often combined with comprehensive treatments such as radiation therapy, drug therapy, and hormone therapy. Patients with estrogen-dependent, early-stage endometrial cancer who have not previously conceived typically receive conservative treatment with progesterone to preserve fertility. Patients with advanced-stage endometrial cancer require appropriate chemotherapy to reduce tumor volume before surgery, and rational selection of chemotherapy agents can significantly increase surgical resection rates. For metastatic and recurrent endometrial cancer, currently commonly used hormonal agents such as progesterone, gonadotropin-releasing hormone analogs, and aromatase inhibitors, as well as chemotherapy agents such as paclitaxel, carboplatin, and doxorubicin, are used. Due to the emergence of chemotherapy resistance, targeted drug therapies such as pembrolizumab, avelumab, bevacizumab, sorafenib, and sunitinib have significant potential for improving the efficacy and prognosis of endometrial cancer.

[0004] Microsatellites (MS), also known as short tandem repeats (STRs), are DNA sequences consisting of several nucleotides (usually 1–6) repeated in tandem in the cellular genome. When DNA mismatch repair (MMR) is impaired, replication errors in microsatellites accumulate uncorrected, resulting in changes in the length or base composition of microsatellites. This is called microsatellite instability (MSI), and leads to a hypermutable genomic phenotype. MSI can be divided into three categories based on the degree of MSI: microsatellite high instability (MSI-H), microsatellite low instability (MSI-L), and microsatellite stability (MSS).

[0005] Programmed cell death protein 1 and its ligand (PD-1 / PD-L1) are a pair of immune co-stimulatory factors. PD-1 normally exerts its immunomodulatory effects through its ligand PD-L1. Activation of the PD-1 / PD-L1 signaling pathway leads to the formation of an immunosuppressive tumor microenvironment that allows tumor cells to escape from the host's immune surveillance and killing. Blocking the PD-1 / PD-L1 signaling pathway reverses the tumor immune microenvironment and enhances the intrinsic antitumor immune effect. can be increased. Summary of the Invention

[0006] In one aspect of the application, there is provided the use of an anti-PD-L1 antibody in the manufacture of a medicament for treating MSI-H endometrial cancer and / or dMMR endometrial cancer.

[0007] In another aspect of the application, there is provided the use of a pharmaceutical composition comprising an anti-PD-L1 antibody in the manufacture of a medicament for treating MSI-H endometrial cancer and / or dMMR endometrial cancer.

[0008] In another aspect of the present application, there is further provided a use of an anti-PD-L1 antibody for treating MSI-H endometrial cancer and / or dMMR endometrial cancer.

[0009] In another aspect of the present application, there is further provided a use of a pharmaceutical composition comprising an anti-PD-L1 antibody for treating MSI-H endometrial cancer and / or dMMR endometrial cancer.

[0010] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0011] In one aspect of the present application, there is provided a therapeutic combination for treating endometrial cancer comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, there is provided a therapeutic combination for treating non-MSI-H and / or non-dMMR endometrial cancer comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof.

[0012] In another aspect of the application, there is provided the use of a therapeutic combination of an anti-PD-L1 antibody and anlotinib, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating endometrial cancer. In some embodiments, there is provided the use of a therapeutic combination comprising an anti-PD-L1 antibody and anlotinib, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating endometrial cancer. In some embodiments, there is provided the use of a therapeutic combination of an anti-PD-L1 antibody and anlotinib, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating non-MSI-H and / or non-dMMR endometrial cancer. In some embodiments, there is provided the use of a therapeutic combination comprising an anti-PD-L1 antibody and anlotinib, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating non-MSI-H and / or non-dMMR endometrial cancer.

[0013] In another aspect of the application, there is provided a use of a therapeutic combination of an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof for treating endometrial cancer. In some embodiments, there is provided a use of a therapeutic combination comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof for treating endometrial cancer. In some embodiments of the application, there is provided a use of a therapeutic combination of an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof for treating non-MSI-H and / or non-dMMR endometrial cancer. In some embodiments of the application, there is provided a use of a therapeutic combination comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof for treating non-MSI-H and / or non-dMMR endometrial cancer.

[0014] In some embodiments, the therapeutic combination further comprises a pharmaceutically acceptable carrier.

[0015] In one aspect of the present application, a method for the preparation of a medicament for treating MSI-H and / or dMMR tumors is provided. In some embodiments, there is provided the use of an anti-PD-L1 antibody in the manufacture of a medicament for treating MSI-H and / or dMMR malignancies. In some embodiments, there is provided the use of an anti-PD-L1 antibody in the manufacture of a medicament for treating MSI-H and / or dMMR solid tumors. In some embodiments, there is provided the use of an anti-PD-L1 antibody in the manufacture of a medicament for treating MSI-H and / or dMMR malignant solid tumors.

[0016] In another aspect of the application, there is provided use of a pharmaceutical composition comprising an anti-PD-L1 antibody in the manufacture of a medicament for treating MSI-H and / or dMMR tumors. In some embodiments, there is provided use of a pharmaceutical composition comprising an anti-PD-L1 antibody in the manufacture of a medicament for treating MSI-H and / or dMMR malignant tumors. In some embodiments, there is provided use of a pharmaceutical composition comprising an anti-PD-L1 antibody in the manufacture of a medicament for treating MSI-H and / or dMMR solid tumors. In some embodiments, there is provided use of a pharmaceutical composition comprising an anti-PD-L1 antibody in the manufacture of a medicament for treating MSI-H and / or dMMR malignant solid tumors.

[0017] In another aspect of the application, there is further provided a use of an anti-PD-L1 antibody for treating MSI-H and / or dMMR tumors. In some embodiments, there is provided a use of an anti-PD-L1 antibody for treating MSI-H and / or dMMR malignant tumors. In some embodiments, there is provided a use of an anti-PD-L1 antibody for treating MSI-H and / or dMMR solid tumors. In some embodiments, there is provided a use of an anti-PD-L1 antibody for treating MSI-H and / or dMMR malignant solid tumors.

[0018] In another aspect of the application, there is further provided a use of a pharmaceutical composition comprising an anti-PD-L1 antibody for treating MSI-H and / or dMMR tumors. In some embodiments, there is provided a use of a pharmaceutical composition comprising an anti-PD-L1 antibody for treating MSI-H and / or dMMR malignant tumors. In some embodiments, there is provided a use of a pharmaceutical composition comprising an anti-PD-L1 antibody for treating MSI-H and / or dMMR solid tumors. In some embodiments, there is provided a use of a pharmaceutical composition comprising an anti-PD-L1 antibody for treating MSI-H and / or dMMR malignant solid tumors.

[0019] In a further aspect, the present application further provides a method for treating MSI-H endometrial cancer and / or dMMR endometrial cancer, comprising administering to a patient in need thereof a therapeutically effective amount of an anti-PD-L1 antibody.

[0020] In a further aspect of the present application, there is provided a method for treating MSI-H endometrial cancer and / or dMMR endometrial cancer, comprising administering to a patient in need thereof a pharmaceutical composition comprising a therapeutically effective amount of an anti-PD-L1 antibody.

[0021] In a further aspect of the present application, there is provided a method for treating endometrial cancer, further comprising administering to a patient in need thereof therapeutically effective amounts of an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments of the present application, there is provided a method for treating non-MSI-H and / or non-dMMR endometrial cancer, further comprising administering to a patient in need thereof therapeutically effective amounts of an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof can be administered simultaneously, asynchronously, or sequentially. In some embodiments of the present application, there is provided a method for treating endometrial cancer, further comprising administering to a patient in need thereof a pharmaceutical composition comprising therapeutically effective amounts of an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, the present application provides a method for treating non-dMMR and / or non-MSI-H endometrial cancer, further comprising administering to a patient in need thereof a pharmaceutical composition comprising therapeutically effective amounts of an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of an anti-PD-L1 antibody and the pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof can be administered simultaneously, asynchronously, or sequentially. In some embodiments, the present application provides a method for treating non-dMMR and / or non-MSI-H endometrial cancer, further comprising administering to a patient in need thereof a pharmaceutical composition comprising therapeutically effective amounts of an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof.

[0023] In a further aspect of the present application, there is further provided a method for treating MSI-H and / or dMMR tumors, comprising administering to a patient in need thereof a therapeutically effective amount of an anti-PD-L1 antibody. In some embodiments, there is provided a method for treating MSI-H and / or dMMR malignant tumors, comprising administering to a patient in need thereof a therapeutically effective amount of an anti-PD-L1 antibody. In some embodiments, there is provided a method for treating MSI-H and / or dMMR malignant solid tumors, comprising administering to a patient in need thereof a therapeutically effective amount of an anti-PD-L1 antibody.

[0024] In a further aspect of the present application, there is further provided a method for treating MSI-H and / or dMMR tumors, comprising administering to a patient in need thereof a pharmaceutical composition comprising a therapeutically effective amount of an anti-PD-L1 antibody. In some embodiments, there is provided a method for treating MSI-H and / or dMMR malignant solid tumors, comprising administering to a patient in need thereof a pharmaceutical composition comprising a therapeutically effective amount of an anti-PD-L1 antibody. In some embodiments, there is provided a method for treating MSI-H and / or dMMR malignant solid tumors, comprising administering to a patient in need thereof a pharmaceutical composition comprising a therapeutically effective amount of an anti-PD-L1 antibody.

[0025] In yet another aspect of the present application, there is provided a kit for treating MSI-H endometrial cancer and / or dMMR endometrial cancer comprising an anti-PD-L1 antibody. In some embodiments, the kit further comprises instructions for treating endometrial cancer.

[0026] In a further aspect of the application, there is provided a kit for treating MSI-H endometrial cancer and / or dMMR endometrial cancer, comprising a pharmaceutical composition comprising an anti-PD-L1 antibody, and in some embodiments, the kit further comprises instructions for treating endometrial cancer.

[0027] In yet another aspect of the present application, there is provided a kit for treating endometrial cancer comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof; in some embodiments, the anti-PD-L1 antibody is contained in a first area and anlotinib or a pharmaceutically acceptable salt thereof is contained in a second area, and the two can be administered simultaneously, asynchronously, or sequentially to a patient in need thereof. In some embodiments, the kit further comprises instructions for treating endometrial cancer with the combination of the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the kit comprises a pharmaceutical composition of the anti-PD-L1 antibody and a pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof.

[0028] In some embodiments, the present application provides a kit for treating non-MSI-H endometrial cancer and / or non-dMMR endometrial cancer, comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof, wherein the anti-PD-L1 antibody is contained in a first area and anlotinib or a pharmaceutically acceptable salt thereof is contained in a second area, and the two can be administered simultaneously, asynchronously, or sequentially to a patient in need thereof. The kit further comprises instructions regarding treating non-MSI-H endometrial cancer and / or non-dMMR endometrial cancer with the combination of the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the kit comprises a pharmaceutical composition of the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof. and pharmaceutical compositions of pharmaceutically acceptable salts thereof.

[0029] In yet another aspect of the application, there is provided a kit for treating MSI-H and / or dMMR tumors comprising an anti-PD-L1 antibody, in some embodiments, the kit further comprising instructions for treating MSI-H and / or dMMR tumors. In some embodiments of the application, there is provided a kit for treating MSI-H and / or dMMR malignant tumors comprising an anti-PD-L1 antibody, in some embodiments, the kit further comprising instructions for treating MSI-H and / or dMMR malignant solid tumors. In some embodiments of the application, there is provided a kit for treating MSI-H and / or dMMR malignant solid tumors comprising an anti-PD-L1 antibody, in some embodiments, the kit further comprising instructions for treating MSI-H and / or dMMR malignant solid tumors.

[0030] In a further aspect of the application, there is provided a kit for treating MSI-H and / or dMMR tumors, comprising a pharmaceutical composition comprising an anti-PD-L1 antibody, and in some embodiments, the kit further comprises instructions for treating MSI-H and / or dMMR tumors. In some embodiments of the application, there is provided a kit for treating MSI-H and / or dMMR malignant tumors, comprising a pharmaceutical composition comprising an anti-PD-L1 antibody. In some embodiments, the kit further comprises instructions for treating MSI-H and / or dMMR malignant solid tumors. In some embodiments, the application provides a kit for treating MSI-H and / or dMMR malignant solid tumors, comprising a pharmaceutical composition comprising an anti-PD-L1 antibody. In some embodiments, the kit further comprises instructions for treating MSI-H and / or dMMR malignant solid tumors.

[0031] The dosage and administration schedule of the anti-PD-L1 antibody can be determined based on the severity of the disease, disease response, treatment-related toxicities, and the age and health of the patient. For example, in some embodiments, the daily dose of the anti-PD-L1 antibody may be 600-2400 mg, and in some embodiments, the daily dose of the anti-PD-L1 antibody may be 600 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, 1600 mg, 1800 mg, 2000 mg, 2200 mg, or 2400 mg. In some embodiments, the anti-PD-L1 antibody is administered parenterally. In some embodiments, the anti-PD-L1 antibody is administered intravenously. In some embodiments, the anti-PD-L1 antibody is administered at a concentration of 10-60 mg / mL. In some embodiments, the anti-PD-L1 antibody is administered at a concentration of 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, or 60 mg / mL. In some embodiments, a treatment cycle for the anti-PD-L1 antibody is 1 week, 2 weeks, 3 weeks, or 4 weeks apart. In some embodiments, the anti-PD-L1 antibody is administered once per treatment cycle. In some embodiments, the anti-PD-L1 antibody is administered once every week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, a treatment cycle for the anti-PD-L1 antibody is 3 weeks apart. In some embodiments, the anti-PD-L1 antibody is administered once every 3 weeks or every 4 weeks.

[0032] In some embodiments, 600 to 2400 mg of the anti-PD-L1 antibody is administered in each treatment cycle. In some embodiments, the administered dose of the anti-PD-L1 antibody in each treatment cycle is 600 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, 1600 mg, 1800 mg, 2000 mg, 2200 mg, or 2400 mg. In some specific embodiments, the administered dose of the anti-PD-L1 antibody in each treatment cycle is 1200 mg. In some embodiments, the anti-PD-L1 antibody is administered on the first day of each treatment cycle. In some specific embodiments, one treatment cycle is 3 weeks. In some specific embodiments, the anti-PD-L1 antibody is administered once every 3 weeks, at a dose of 600 to 2400 mg. In some embodiments, one treatment is 3 weeks (21 days). The treatment cycles are divided into three groups, with the anti-PD-L1 antibody administered to patients in need thereof on the first day of each treatment cycle. In some specific embodiments, the anti-PD-L1 antibody is administered once every three weeks on the first day, at a single dose of 600-2400 mg. In some specific embodiments, the anti-PD-L1 antibody is administered once every three weeks on the first day, at a single dose of 1200 mg.

[0033] In some embodiments, the therapeutic combination described herein comprises an anti-PD-L1 humanized monoclonal antibody and anlotinib, or a pharmaceutically acceptable salt thereof.

[0034] In some embodiments, a therapeutic combination comprising an anti-PD-L1 antibody described herein and anlotinib, or a pharmaceutically acceptable salt thereof, comprises a pharmaceutical composition of the anti-PD-L1 antibody and a pharmaceutical composition of anlotinib, or a pharmaceutically acceptable salt thereof, which in some embodiments further comprises a pharmaceutically acceptable carrier.

[0035] In some embodiments, a therapeutic combination comprising an anti-PD-L1 antibody described herein and anlotinib, or a pharmaceutically acceptable salt thereof, comprises a pharmaceutical composition comprising 600-2400 mg of the anti-PD-L1 antibody. In some embodiments, the therapeutic combination comprises a pharmaceutical composition comprising 600-2400 mg of the anti-PD-L1 antibody, where the pharmaceutical composition of the anti-PD-L1 antibody is a unit dose or multiple doses.

[0036] In some embodiments, a therapeutic combination comprising an anti-PD-L1 antibody described herein and anlotinib or a pharmaceutically acceptable salt thereof comprises a pharmaceutical composition of 6-12 mg of anlotinib or a pharmaceutically acceptable salt thereof, hi some embodiments, the therapeutic combination comprises a pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof in unit doses of 6 mg, 8 mg, 10 mg, and / or 12 mg.

[0037] In some embodiments, a therapeutic combination comprising an anti-PD-L1 antibody described herein and anlotinib or a pharmaceutically acceptable salt thereof comprises a pharmaceutical composition of 600-2400 mg of the anti-PD-L1 antibody and a pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof, wherein the unit dose is 6 mg, 8 mg, 10 mg, and / or 12 mg, where the pharmaceutical composition of the anti-PD-L1 antibody is a unit dose or a multiple dose. In some embodiments, the therapeutic combination comprises a pharmaceutical composition of 600-2400 mg of the anti-PD-L1 antibody provided in the form of a multiple dose, and a pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof, wherein the unit dose is 6 mg, 8 mg, 10 mg, and / or 12 mg. In some embodiments, the therapeutic combination is a formulation suitable for administration within a single treatment cycle (e.g., a 21-day treatment cycle) and comprises 600 to 2400 mg of a pharmaceutical composition of an anti-PD-L1 antibody and 84 to 168 mg of a pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof.

[0038] In some embodiments, a therapeutic combination comprising an anti-PD-L1 antibody described herein and anlotinib or a pharmaceutically acceptable salt thereof comprises the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof in a weight ratio of (0.35-29):1, (3.5-29):1, (3.5-14.5):1, or (7-14.5):1, with the proviso that the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof may be packaged separately or together, with the proviso that anlotinib may be packaged in multiple aliquots (e.g., 2 aliquots, 7 aliquots, 14 aliquots, 28 aliquots, or more), and the anti-PD-L1 antibody may be packaged in a single aliquot or multiple aliquots (e.g., 2 aliquots, 4 aliquots, or more).

[0039] In some embodiments, a therapeutic combination comprising an anti-PD-L1 antibody described herein and anlotinib, or a pharmaceutically acceptable salt thereof, Tinib or a pharmaceutically acceptable salt thereof, each in the form of a pharmaceutical composition, can be administered simultaneously, asynchronously or sequentially.

[0040] In some embodiments, the therapeutic combination of an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof described herein comprises a pharmaceutical composition of an anti-PD-L1 antibody and a pharmaceutical composition of anlotinib, wherein the anti-PD-L1 antibody is formulated to be suitable for administration to a patient at a unit dose or multiple doses of 600 to 2400 mg of the anti-PD-L1 antibody for a first administration, and the pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof is formulated to be suitable for administration to a patient at a unit dose of 6 mg, 8 mg, 10 mg, and / or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof daily for 14 consecutive days.

[0041] In some embodiments, the therapeutic combination of an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof described herein comprises a pharmaceutical composition of an anti-PD-L1 antibody, wherein the concentration of the anti-PD-L1 antibody is 10-60 mg / mL, and a pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof, wherein the unit dose is 6 mg, 8 mg, 10 mg, and / or 12 mg.

[0042] In some embodiments, the therapeutic combination of an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof described herein comprises a pharmaceutical composition providing 1200 mg of the anti-PD-L1 antibody in a multiple dose form, and a pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof in unit doses of 8 mg, 10 mg, and / or 12 mg.

[0043] In some embodiments, the kit is suitable for administration within a single treatment cycle (e.g., a 21-day treatment cycle) and comprises a pharmaceutical composition comprising 600 to 2400 mg of an anti-PD-L1 antibody, and a pharmaceutical composition comprising 84 to 168 mg of anlotinib or a pharmaceutically acceptable salt thereof.

[0044] In some embodiments, methods are provided for treating non-MSI-H and / or non-dMMR endometrial cancer, comprising administering therapeutically effective amounts of an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof to a patient in need thereof. In some embodiments, the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof are administered simultaneously, asynchronously, or sequentially. In some embodiments, the anti-PD-L1 antibody is administered once every week, every two weeks, every three weeks, or every four weeks. In some embodiments, the anti-PD-L1 antibody is administered at a single dose of 600 to 2400 mg. In some embodiments, the anti-PD-L1 antibody is administered at a single dose of 600 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, 1600 mg, 1800 mg, 2000 mg, 2200 mg, or 2400 mg. In some embodiments, anlotinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 6 to 12 mg. In some embodiments, anlotinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 8 to 12 mg. In some embodiments, anlotinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 6 mg, 8 mg, 10 mg, or 12 mg. In some embodiments, anlotinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of 6 mg, 8 mg, 10 mg, or 12 mg. In some embodiments, anlotinib or a pharmaceutically acceptable salt thereof is administered on a dosing regimen of two weeks on continuous therapy followed by one week off therapy. In some embodiments, a treatment cycle is three weeks long. In some embodiments, a treatment cycle is 21 days long, and the patient is administered an anti-PD-L1 antibody on the first day of each treatment cycle. In some embodiments, one treatment cycle is 3 weeks, the anti-PD-L1 antibody is administered on the first day of each cycle, and anlotinib or a pharmaceutically acceptable salt thereof is administered on days 1 to 14 of each cycle. In some embodiments, the anti-PD-L1 antibody is administered parenterally. In some embodiments, the concentration of the anti-PD-L1 antibody pharmaceutical composition is 10 to 60 mg / mL. In some embodiments, the concentration of the anti-PD-L1 antibody pharmaceutical composition is 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, or 60 mg / mL. In some embodiments, anlotinib or a pharmaceutically acceptable salt thereof is administered orally.

[0045] In a further aspect of the present application, there is provided a method for treating endometrial cancer, comprising: (1) obtaining or having obtained a biological sample from a patient; (2) detecting or having detected the biological sample to determine whether the sample is MSI-H and / or dMMR; (3) if the detection result is MSI-H and / or dMMR, administering to the patient a therapeutically effective amount of an anti-PD-L1 antibody or a pharmaceutical composition comprising an anti-PD-L1 antibody; and (4) if the detection result is non-MSI-H and / or non-dMMR, administering to the patient a therapeutically effective amount of an anti-PD-L1 antibody and anlotinib, or a pharmaceutically acceptable salt thereof.

[0046] In yet another aspect of the present application, there is provided a method for treating MSI-H and / or dMMR tumors, comprising: (1) obtaining or having obtained a biological sample from a patient; (2) detecting or having detected the biological sample to determine whether the sample is MSI-H or dMMR; and (3) if the detection result is MSI-H or dMMR, administering to the patient a therapeutically effective amount of an anti-PD-L1 antibody or a pharmaceutical composition comprising an anti-PD-L1 antibody.

[0047] Anlotinib or a pharmaceutically acceptable salt thereof: The chemical name of anlotinib is 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine and has the following structural formula:

[0048] [ka]

[0049] The pharmaceutically acceptable salts of anlotinib include, but are not limited to, salts formed by anlotinib with an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, caproic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, p-toluenesulfonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, and stearic acid. In some embodiments, the pharmaceutically acceptable salt is a hydrochloride, maleate, or dihydrochloride salt.

[0050] Unless otherwise specified, all dosages of anlotinib or a pharmaceutically acceptable salt thereof in this application are based on the molecular weight of anlotinib free base.

[0051] Anlotinib or a pharmaceutically acceptable salt thereof can be administered by multiple routes, including oral and parenteral administration, including, but not limited to, oral, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, subcutaneous, intraadipose, intraarticular, intraperitoneal, and intrathecal. In certain embodiments, anlotinib or a pharmaceutically acceptable salt thereof is administered orally. The dosage of anlotinib or a pharmaceutically acceptable salt thereof can be determined based on the severity of the disease, disease response, treatment-related toxicity, and the patient's age and health status. For example, the daily dosage of anlotinib or a pharmaceutically acceptable salt thereof may be 2 to 20 mg. In some embodiments, the daily dosage of anlotinib or a pharmaceutically acceptable salt thereof may be 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, or 16 mg. Anlotinib or a pharmaceutically acceptable salt thereof can be administered one or more times daily. In some embodiments, anlotinib or a pharmaceutically acceptable salt thereof is administered once daily as an oral solid formulation.

[0052] The dosing regimen for anlotinib or a pharmaceutically acceptable salt thereof can be comprehensively determined based on the activity, toxicity, patient tolerability, etc. of the drug. Preferably, anlotinib or a pharmaceutically acceptable salt thereof is administered in an interval dosing manner. The interval dosing includes an administration period and a withdrawal period, and anlotinib or a pharmaceutically acceptable salt thereof can be administered once or multiple times per day during the administration period. For example, the ratio of the number of days in the administration period to the withdrawal period is 2:(0.5-5), 2:(0.5-3), 2:(0.5-2), or 2:(0.5-1). In some embodiments, the regimen is 2 weeks of continuous administration followed by 2 weeks of withdrawal. In some embodiments, the regimen is 2 weeks of continuous administration followed by 1 week of withdrawal. In some embodiments, the regimen is 5 days of continuous administration followed by 2 days of withdrawal. For example, anlotinib or a pharmaceutically acceptable salt thereof can be orally administered once daily at a dose of 6 mg, 8 mg, 10 mg, or 12 mg, with a dosing regimen of two weeks of continuous administration followed by one week of rest.

[0053] Pharmaceutical compositions of anlotinib or a pharmaceutically acceptable salt thereof: In some embodiments of the present application, the unit dose of the pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof contains 6 mg, 8 mg, 10 mg, or 12 mg of anlotinib.

[0054] In some embodiments of the present application, the treatment cycle is two weeks on and one week off, and the total dose of the pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof administered in each cycle is 84 to 168 mg. In some embodiments, the total dose of the pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof is selected from the group consisting of 84 mg, 112 mg, 140 mg, and 168 mg, or a range formed using any of the foregoing values. In some embodiments, the total dose of the pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof is 112 to 168 mg.

[0055] In some embodiments, the pharmaceutical composition includes, but is not limited to, a formulation suitable for oral or parenteral administration. In some embodiments, the pharmaceutical composition is a formulation suitable for oral administration. In some embodiments, the pharmaceutical composition is a solid formulation suitable for oral administration. In some embodiments, the pharmaceutical composition includes, but is not limited to, a tablet or capsule.

[0056] Anti-PD-L1 antibody: In some embodiments, the anti-PD-L1 antibody is a humanized monoclonal anti-PD-L1 antibody. It is a clonal antibody.

[0057] In some embodiments of the present application, the anti-PD-L1 antibody is an antibody described in WO2016022630 or CN107001463A.

[0058] In some embodiments of the application, the anti-PD-L1 antibodies comprise a heavy chain CDR1 region that has at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence set forth in SEQ ID NO:1 or SEQ ID NO:4; a heavy chain CDR2 region having 1%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% homology to the amino acid sequence set forth in SEQ ID NO:3 or SEQ ID NO:6, or at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) a heavy chain CDR3 region having at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence set forth in SEQ ID NO:7 or SEQ ID NO:10; a light chain CDR1 region having at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence set forth in SEQ ID NO:8 or SEQ ID NO:11; 9, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence set forth in SEQ ID NO:9 or SEQ ID NO:12, and a light chain CDR3 region having at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence set forth in SEQ ID NO:9 or SEQ ID NO:12.

[0059] In some embodiments of the application, the anti-PD-L1 antibodies comprise the following amino acid sequences: a heavy chain CDR1 region selected from the group consisting of SEQ ID NO:1 and SEQ ID NO:4; a heavy chain CDR2 region selected from the group consisting of SEQ ID NO:2 and SEQ ID NO:5; a heavy chain CDR3 region selected from the group consisting of SEQ ID NO:3 and SEQ ID NO:6; a light chain CDR1 region selected from the group consisting of SEQ ID NO:7 and SEQ ID NO:10; a light chain CDR2 region selected from the group consisting of SEQ ID NO:8 and SEQ ID NO:11; and a light chain CDR3 region selected from the group consisting of SEQ ID NO:9 and SEQ ID NO:12.

[0060] In some embodiments of the application, the isolated anti-PD-L1 antibodies described herein comprise a heavy chain CDR1 region having the amino acid sequence set forth in SEQ ID NO: 1, a heavy chain CDR2 region having the amino acid sequence set forth in SEQ ID NO: 2, a heavy chain CDR3 region having the amino acid sequence set forth in SEQ ID NO: 3, a light chain CDR1 region having the amino acid sequence set forth in SEQ ID NO: 7, a light chain CDR2 region having the amino acid sequence set forth in SEQ ID NO: 8, and a light chain CDR3 region having the amino acid sequence set forth in SEQ ID NO: 9.

[0061] Each of the CDR regions described herein and their various variants described above can specifically recognize and bind to PD-L1, thereby effectively blocking signal transduction between PD-L1 and PD-1.

[0062] In some embodiments of the present application, the anti-PD-L1 antibody has a sequence identity that is at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 1109%, 1111, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 12 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence set forth in SEQ ID NO:15 or SEQ ID NO:16, and a light chain variable region having at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence set forth in SEQ ID NO:15 or SEQ ID NO:16.

[0063] In some embodiments of the present application, the anti-PD-L1 antibody comprises the following amino acid sequences: a heavy chain variable region set forth in SEQ ID NO: 13, and a light chain variable region set forth in SEQ ID NO: 15.

[0064] In some embodiments of the present application, the anti-PD-L1 antibody comprises the following amino acid sequences: a heavy chain variable region set forth in SEQ ID NO:14, and a light chain variable region set forth in SEQ ID NO:16.

[0065] In some embodiments of the present application, the anti-PD-L1 antibody comprises the following amino acid sequences: a heavy chain amino acid sequence set forth in SEQ ID NO: 17, and a light chain amino acid sequence set forth in SEQ ID NO: 18.

[0066] In some embodiments of the present application, the anti-PD-L1 antibody comprises the following amino acid sequences: a heavy chain amino acid sequence set forth in SEQ ID NO: 19, and a light chain amino acid sequence set forth in SEQ ID NO: 20.

[0067] In some embodiments of the present application, the anti-PD-L1 antibody comprises the following amino acid sequences: a heavy chain amino acid sequence set forth in SEQ ID NO:21, and a light chain amino acid sequence set forth in SEQ ID NO:18.

[0068] In a specific embodiment, the anti-PD-L1 humanized monoclonal antibodies provided herein contain one or more conservative substitution variants selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, and SEQ ID NO: 21. Anti-PD-L1 humanized monoclonal antibodies containing such conservative substitution variants retain the ability to specifically recognize and bind to PD-L1.

[0069] In some embodiments of the present application, the anti-PD-L1 antibody may be an IgG1 or IgG4 antibody.

[0070] In some embodiments of the present application, the anti-PD-L1 antibody is an IgG1 antibody, hi some embodiments, the anti-PD-L1 antibody is a glycosylated IgG1 antibody.

[0071] In some embodiments of the present application, the anti-PD-L1 antibody comprises a heavy chain complementarity determining region (CDR) selected from the group consisting of 13C5 and 5G11 antibodies, and a light chain complementarity determining region selected from the group consisting of 13C5 and 5G11 antibodies. In one embodiment, the anti-PD-L1 antibody described herein comprises a heavy chain variable region selected from the group consisting of heavy chain variable regions of ch5G11-hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, and ch13C5-hIgG4 chimeric antibodies, and a light chain variable region selected from the group consisting of light chain variable regions of ch5G11-hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, and ch13C5-hIgG4 chimeric antibodies. In one embodiment, the anti-PD-L1 antibody described herein comprises a heavy chain variable region selected from the group consisting of hu13C5-hIgG1, hu13C5-hIgG4, h It comprises a heavy chain variable region selected from the group consisting of the heavy chain variable regions of u5G11-hIgG1 and hu5G11-hIgG4 humanized antibodies, and a light chain variable region selected from the group consisting of the light chain variable regions of hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1, and hu5G11-hIgG4 humanized antibodies. With reference to the descriptions in Patent Documents WO2016022630 or CN107001463A, the HCDR1 sequence of 13C5, ch13C5-hIgG1, ch13C5-hIgG4, hu13C5-hIgG1 or hu13C5-hIgG4 is set to SYGMS (SEQ ID NO: 4), the HCDR2 sequence is set to SISSGGSTYYPDSVKG (SEQ ID NO: 5), the HCDR3 sequence is set to GYDSGFAY (SEQ ID NO: 6), the LCDR1 sequence is set to ASQSVSTSSSSFMH (SEQ ID NO: 10), the LCDR2 sequence is set to YASNLES (SEQ ID NO: 11), and the LCDR3 sequence is set to may be QHSWEIPYT (SEQ ID NO: 12), the HCDR1 sequence of 5G11, ch5G11-hIgG1, ch5G11-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4 may be TYGVH (SEQ ID NO: 1), the HCDR2 sequence may be VIWRGVTTDYNAAFMS (SEQ ID NO: 2), the HCDR3 sequence may be LGFYAMDY (SEQ ID NO: 3), the LCDR1 sequence may be KASQSVSNDVA (SEQ ID NO: 7), the LCDR2 sequence may be YAANRYT (SEQ ID NO: 8), and the LCDR3 sequence may be QQDYTSPYT (SEQ ID NO: 9).

[0072] In some embodiments of the application, the anti-PD-L1 antibodies in the therapeutic combination may be one or more. As used herein, the term "multiple" may mean one or more, such as two, three, four, five, or more. For example, in some embodiments of the application, the anti-PD-L1 antibodies are selected from the group consisting of antibodies comprising a heavy chain variable region set forth in SEQ ID NO: 13 and a light chain variable region set forth in SEQ ID NO: 15, or antibodies comprising a heavy chain variable region set forth in SEQ ID NO: 14 and a light chain variable region set forth in SEQ ID NO: 16, or combinations thereof. Alternatively, for example, the anti-PD-L1 antibody is selected from the group consisting of antibodies comprising a heavy chain amino acid sequence set forth in SEQ ID NO: 17 and a light chain amino acid sequence set forth in SEQ ID NO: 18, or selected from the group consisting of antibodies comprising a heavy chain amino acid sequence set forth in SEQ ID NO: 19 and a light chain amino acid sequence set forth in SEQ ID NO: 20, or selected from the group consisting of antibodies comprising a heavy chain amino acid sequence set forth in SEQ ID NO: 21 and a light chain amino acid sequence set forth in SEQ ID NO: 18, or a combination of any two or more thereof.

[0073] In some embodiments, the anti-PD-L1 antibody comprises the following amino acid sequences: a heavy chain CDR1 region that is at least 80% homologous to the amino acid sequence set forth in SEQ ID NO:1 or SEQ ID NO:4; a heavy chain CDR2 region that is at least 80% homologous to the amino acid sequence set forth in SEQ ID NO:2 or SEQ ID NO:5; a heavy chain CDR3 region that is at least 80% homologous to the amino acid sequence set forth in SEQ ID NO:3 or SEQ ID NO:6; a light chain CDR1 region that is at least 80% homologous to the amino acid sequence set forth in SEQ ID NO:7 or SEQ ID NO:10; a light chain CDR2 region that is at least 80% homologous to the amino acid sequence set forth in SEQ ID NO:8 or SEQ ID NO:11; and a light chain CDR3 region that is at least 80% homologous to the amino acid sequence set forth in SEQ ID NO:9 or SEQ ID NO:12.

[0074] Pharmaceutical compositions of anti-PD-L1 antibodies: In some embodiments of the present application, the anti-PD-L1 antibody pharmaceutical composition contains 600-2400 mg of anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody pharmaceutical composition contains an amount of anti-PD-L1 antibody selected from the group consisting of 600 mg, 900 mg, 1200 mg, 1500 mg, 1800 mg, 2100 mg, and 2400 mg, or an amount selected from a range formed by any of the foregoing values. In some embodiments, the anti-PD-L1 antibody pharmaceutical composition contains 600-2100 mg or 900-1500 mg of anti-PD-L1 antibody, provided that the anti-PD-L1 antibody pharmaceutical composition may be present in multiple-dose or unit-dose form.

[0075] In some embodiments of the present application, the anti-PD-L1 antibody pharmaceutical composition comprises 300 mg, 600 mg, or 1200 mg of anti-PD-L1 antibody.In some embodiments of the present application, there is provided an anti-PD-L1 antibody pharmaceutical composition manufactured as a unit dose containing 300 mg, 600 mg, or 1200 mg of anti-PD-L1 antibody.

[0076] In some embodiments, the anti-PD-L1 antibody pharmaceutical composition is an injectable solution. In some embodiments, the anti-PD-L1 antibody pharmaceutical composition is an injectable aqueous solution. In some embodiments herein, the anti-PD-L1 antibody pharmaceutical composition comprises one or more of a buffer, a tonicity adjusting agent, a stabilizer, and / or a surfactant. In particular, the anti-PD-L1 antibody pharmaceutical composition comprises 1-150 mg / mL of an anti-PD-L1 antibody (e.g., a monoclonal), 3-50 mM buffer, 2-150 mg / mL of a tonicity adjusting agent / stabilizer, 0.01-0.8 mg / mL of a surfactant, and has a pH of 4.5-6.8.

[0077] In some embodiments of the present application, the anti-PD-L1 antibody pharmaceutical composition has an anti-PD-L1 monoclonal concentration, calculated on a w / v basis, of 5-150 mg / mL, in some embodiments 10-60 mg / mL, and in some embodiments 10-30 mg / mL. In some specific embodiments, the anti-PD-L1 monoclonal mass-to-volume concentration is 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, or 120 mg / mL, in some embodiments 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, or 60 mg / mL, and in some embodiments 10 mg / mL, 20 mg / mL, or 30 mg / mL. In some embodiments, the mass volume concentration of the anti-PD-L1 monoclonal is 10 mg / mL, in some embodiments, the mass volume concentration of the anti-PD-L1 monoclonal is 30 mg / mL, and in some embodiments, the mass volume concentration of the anti-PD-L1 monoclonal is 60 mg / mL.

[0078] In some embodiments of the present application, the buffer is a histidine salt buffer. The concentration of the histidine salt buffer is 5 to 30 mM, in some embodiments, 10 to 25 mM, in some embodiments, 10 to 20 mM, and in some embodiments, 10 to 15 mM. In some specific embodiments, the concentration of the histidine salt buffer is 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, or 30 mM. In some embodiments, the concentration of the histidine salt buffer is 10 mM. In some embodiments, the concentration of the histidine salt buffer is 15 mM. In some embodiments, the concentration of the histidine salt buffer is 20 mM, provided that the histidine salt buffer contains histidine and hydrochloric acid.

[0079] In some embodiments of the present application, the tonicity adjusting / stabilizing agent is 20 to 150 mg / mL of sucrose, in some embodiments, 40 to 100 mg / mL of sucrose, and in some embodiments, 60 to 80 mg / mL of sucrose, calculated on a w / v basis. In some specific embodiments, the concentration of the sucrose is 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, or 100 mg / mL. In some specific embodiments, the concentration of the sucrose is 60 mg / mL. In some specific embodiments, the concentration of the sucrose is 70 mg / mL. In some specific embodiments, the concentration of the sucrose is 80 mg / mL. In some specific embodiments, the concentration of the sucrose is 90 mg / mL.

[0080] In some embodiments of the present application, the surfactant is selected from the group consisting of polysorbate 80, polysorbate 20, and poloxamer 188, in some embodiments, selected from the group consisting of polysorbate 80 and polysorbate 20, and in some embodiments, selected from the group consisting of polysorbate 80. In some embodiments, the concentration of the surfactant, calculated on a w / v basis, is 0.05 to 0.6 mg / mL, in some embodiments, 0.1 to 0.4 mg / mL, and in some embodiments, 0.2 to 0.3 mg / mL.

[0081] In some embodiments of the present application, the surfactant is 0.01 to 0.8 mg / mL of polysorbate 80 or polysorbate 20, calculated on a w / v basis. In some specific embodiments, the surfactant is 0.05 to 0.6 mg / mL of polysorbate 80, in some embodiments, 0.1 to 0.4 mg / mL of polysorbate 80, in some embodiments, 0.2 to 0.3 mg / mL of polysorbate 80, and in some embodiments, 0.2 mg / mL of polysorbate 80. In some embodiments, the content of polysorbate 80 in the pharmaceutical composition is 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, or 0.6 mg / mL. In some embodiments, the content of polysorbate 80 in the pharmaceutical composition is 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, or 0.5 mg / mL. In some embodiments, the pharmaceutical composition contains 0.2 mg / mL, 0.3 mg / mL, or 0.4 mg / mL of polysorbate 80. In some embodiments, the pharmaceutical composition contains 0.2 mg / mL of polysorbate 80. In some embodiments, the pharmaceutical composition contains 0.1 mg / mL of polysorbate 80. In some embodiments, the pharmaceutical composition contains 0.2 mg / mL of polysorbate 80. In some embodiments, the pharmaceutical composition contains 0.3 mg / mL of polysorbate 80. In some embodiments, the pharmaceutical composition contains 0.4 mg / mL of polysorbate 80. In some embodiments, the pharmaceutical composition contains 0.5 mg / mL of polysorbate 80.

[0082] In some embodiments of the present application, the pH of the aqueous solution of the pharmaceutical composition is selected from the range of 4.0 to 6.8, in some embodiments, 4.5 to 6.5, in some embodiments, 5.5 to 6.0, and in some embodiments, 5.5. In some embodiments, the pH of the aqueous solution of the pharmaceutical composition is 4.5, 4.8, 5.0, 5.2, 5.4, 5.5, 5.6, 5.8, or 6.0, in some embodiments, 5.0, 5.2, 5.4, 5.5, or 5.6, and in some embodiments, 5.5. In some embodiments, the pH of the aqueous solution of the pharmaceutical composition is 5.0. In some embodiments, the pH of the aqueous solution of the pharmaceutical composition is 5.2. In some embodiments, the pH of the aqueous solution of the pharmaceutical composition is 5.4. In some embodiments, the pH of the aqueous solution of the pharmaceutical composition is 5.5. In some embodiments, the pH of the aqueous solution of the pharmaceutical composition is 5.6. In some embodiments, the pH of the aqueous solution of the pharmaceutical composition is 5.8. In some embodiments, the aqueous solution of the pharmaceutical composition has a pH of 6.0.

[0083] In some specific embodiments of the present application, the pharmaceutical composition comprises (a) an anti-PD-L1 antibody at a mass-volume concentration of 20 mg / mL, (b) sucrose at a mass-volume concentration of 70 mg / mL, (c) polysorbate 80 at a mass-volume concentration of 0.1 mg / mL, (d) histidine at a molar concentration of 20 mM, and (e) optionally, an appropriate amount of hydrochloric acid, wherein the pH of the composition is adjusted to 5.0. In one specific embodiment of the present application, the pharmaceutical composition comprises (a) an anti-PD-L1 monoclonal antibody at a mass-volume concentration of 20 mg / mL, (b) sucrose at a mass-volume concentration of 70 mg / mL, and (c) polysorbate 80 at a mass-volume concentration of 0.1 mg / mL. (d) histidine having a molarity of 20 mM; and (e) optionally, an appropriate amount of hydrochloric acid, the pH of the composition being adjusted to 5.0.

[0084] In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) anti-PD-L1 antibody at a mass-volume concentration of 10 mg / mL; (b) sucrose at a mass-volume concentration of 80 mg / mL; (c) polysorbate 80 at a mass-volume concentration of 0.2 mg / mL; (d) histidine at a molarity of 10 mM; and (e) optionally, an appropriate amount of hydrochloric acid, wherein the pH of the composition is adjusted to 5.5.

[0085] In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) anti-PD-L1 antibody at a mass-volume concentration of 50 mg / mL; (b) sucrose at a mass-volume concentration of 80 mg / mL; (c) polysorbate 80 at a mass-volume concentration of 0.3 mg / mL; (d) histidine at a molarity of 10 mM; and (e) optionally, an appropriate amount of hydrochloric acid, wherein the pH of the composition is adjusted to 5.5.

[0086] In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody at a mass-volume concentration of 100 mg / mL; (b) sucrose at a mass-volume concentration of 80 mg / mL; (c) polysorbate 80 at a mass-volume concentration of 0.5 mg / mL; (d) histidine at a molar concentration of 10 mM; and (e) optionally, an appropriate amount of hydrochloric acid, wherein the pH of the composition is adjusted to 5.5.

[0087] In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) anti-PD-L1 antibody at a mass-volume concentration of 30 mg / mL; (b) sucrose at a mass-volume concentration of 80 mg / mL; (c) polysorbate 80 at a mass-volume concentration of 0.2 mg / mL; (d) histidine at a molarity of 10 mM; and (e) optionally, an appropriate amount of hydrochloric acid, wherein the pH of the composition is adjusted to 5.5.

[0088] In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) anti-PD-L1 antibody at a mass-volume concentration of 60 mg / mL; (b) sucrose at a mass-volume concentration of 80 mg / mL; (c) polysorbate 80 at a mass-volume concentration of 0.2 mg / mL; (d) histidine at a molarity of 10 mM; and (e) optionally, an appropriate amount of hydrochloric acid, wherein the pH of the composition is adjusted to 5.5.

[0089] In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) anti-PD-L1 antibody at a mass-volume concentration of 10 mg / mL; (b) sucrose at a mass-volume concentration of 70 mg / mL; (c) polysorbate 80 at a mass-volume concentration of 0.4 mg / mL; (d) histidine at a molar concentration of 20 mM; and (e) optionally, an appropriate amount of acetic acid, wherein the pH of the composition is adjusted to 6.5.

[0090] In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) the anti-PD-L1 monoclonal at a mass-volume concentration of 10 mg / mL; (b) sucrose at a mass-volume concentration of 80 mg / mL; (c) polysorbate 80 at a mass-volume concentration of 0.2 mg / mL; (d) histidine at a molar concentration of 20 mM; and (e) optionally, an appropriate amount of hydrochloric acid, wherein the pH of the composition is adjusted to 5.5.

[0091] In another specific embodiment of the present application, the pharmaceutical composition is an aqueous injectable solution. In some embodiments, the aqueous injectable solution includes, but is not limited to, a non-lyophilized aqueous formulation or an aqueous formulation reconstituted from a lyophilized powder. In some embodiments, the pharmaceutical composition is a lyophilized formulation. The lyophilized formulation refers to a formulation produced from an aqueous solution by a lyophilization process, in which the material is first frozen and then heated. The amount of solvent is reduced by evaporation (primary drying process), followed by desorption (secondary drying process) until the amount of solvent reaches a value that does not correspond to biological activity or chemical reaction. The lyophilized formulations of the present application can also be dried by other methods known in the art, for example, spray drying, bubble drying.

[0092] Endometrial cancer: In the present application, the endometrial cancer is defined as type I (estrogen-dependent) endometrial cancer or type II (non-estrogen-dependent) endometrial cancer. estrogen-dependent) endometrial cancer, but is not limited to

[0093] In some embodiments of the present application, the endometrial cancer is advanced endometrial cancer. In some embodiments of the present application, the endometrial cancer is refractory endometrial cancer.

[0094] In some embodiments of the present application, the endometrial cancer is recurrent and / or metastatic endometrial cancer.

[0095] In some embodiments of the present application, the endometrial cancer is recurrent and / or metastatic advanced endometrial cancer.

[0096] In some embodiments of the present application, the non-microsatellite instability-high (non-MSI-H) endometrial cancer includes microsatellite instability-low (MSI-L) endometrial cancer and microsatellite stable (MSS) endometrial cancer.

[0097] In some embodiments of the present application, the non-mismatch repair deficient (non-dMMR) endometrial cancer includes non-mismatch repair deficient (pMMR) endometrial cancer.

[0098] In some embodiments of the present application, the patient with endometrial cancer has already received one or more drug therapies. In some embodiments of the present application, the endometrial cancer is endometrial cancer for which at least one drug treatment has failed. In some embodiments, the treatment failure includes disease progression during treatment and disease progression and / or recurrence after treatment has ended.

[0099] In some embodiments of the present application, the endometrial cancer patient has already received one or more chemotherapy regimens. In some embodiments of the present application, the endometrial cancer is endometrial cancer that has failed treatment with at least one chemotherapy regimen. In some embodiments, the treatment failure includes disease progression or no objective response during treatment, and disease progression and / or recurrence after treatment has ended. In some embodiments of the present application, the endometrial cancer patient has previously received first-line or second-line standard systemic chemotherapy and has experienced treatment failure or intolerance.

[0100] As used herein, said drug therapy includes, but is not limited to, chemotherapy, targeted drug therapy, and hormone therapy.

[0101] In some embodiments of the present application, the chemotherapy includes one or more of, but is not limited to, taxanes, vinblastine-based antineoplastic agents, platinum complexes, fluorouracil and its derivatives, camptothecin and its derivatives, anthracyclines, and podophyllum-based compounds, wherein the taxanes include, but are not limited to, one or more of paclitaxel, albumin-bound paclitaxel, and taxoids (docetaxel), and the vinblastine-based antineoplastic agents include vinblastine, vincristine, vindesine, vinorelbine, vinflunine, and vinorelbine base. The platinum complexes include one or more selected from miriplatin, cisplatin, carboplatin, dicycloplatin, nedaplatin, oxaliplatin, lobaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, and satraplatin, but are not limited thereto, and the fluorouracil and its derivatives include one or more selected from cytarabine, azacitidine, ancitabine, capecitabine, gemcitabine, fluorouracil, tegadifur, doxifluridine, trifluridine, tegafur, carmofur, and tegafur-uracil, but are not limited thereto. The camptothecin and its derivatives include, but are not limited to, one or more of camptothecin, hydroxycamptothecin, irinotecan, and topotecan; the anthracycline compounds include, but are not limited to, one or more of epirubicin (EPI), adriamycin, daunorubicin, pirarubicin, amrubicin, idarubicin, mitoxantrone, aclarubicin, valrubicin, zorubicin, pixantrone, THP-ADM, and doxorubicin liposome; and the podophyllum compounds include, but are not limited to, one or more of etoposide (lastet), teniposide, and VP-16.

[0102] In some embodiments of the present application, the targeted drug includes, but is not limited to, one or more of an EGFR antagonist, a VEGF inhibitor, a HER2 inhibitor, a PARP inhibitor, a PI3K / Akt / mTOR pathway inhibitor, a PD-1 / PD-L1 inhibitor, or an FGFR inhibitor.

[0103] In some embodiments of the present application, the EGFR antagonist includes, but is not limited to, one or more of trastuzumab, cetuximab, icotinib, gefitinib, erlotinib, and lapatinib. In some embodiments of the present application, the VEGF inhibitor includes, but is not limited to, bevacizumab, ranibizumab, axitinib, motesanib, aflibercept, cediranib, nintedanib, sorafenib, or sunitinib. In some embodiments of the present application, the PARP inhibitor includes, but is not limited to, one or more of olaparib, niraparib, or rucaparib. In some embodiments of the present application, the PI3K / Akt / mTOR pathway inhibitor includes, but is not limited to, one or more of NVP-BKM120, XL147, perifosine, rapamycin, temsirolimus, everolimus, sirolimus, or ridaforolimus. In some embodiments of the present application, the PD-1 / PD-L1 inhibitor includes, but is not limited to, one or more of atezolizumab, nivolumab, or pembrolizumab. In some embodiments of the present application, the FGFR inhibitor includes, but is not limited to, dovitinib or NVP-BGJ398.

[0104] In some embodiments of the present application, the hormone therapy agent includes, but is not limited to, one or more of a progesterone, an anti-estrogen, and an aromatase inhibitor. In some embodiments of the present application, the progesterone drug includes, but is not limited to, progesterone, megestrol acetate, chlormadinone, medroxyprogesterone acetate, hydroxyprogesterone acetate, hydroxyprogesterone caproate, cyproterone acetate, dydrogesterone, demegestone, promegestone, lynestrenol, norethisterone, levonolamine ... In some embodiments, the anti-estrogen drug may be one or more of, but is not limited to, lugestrel, desogestrel, dienogest, or drospirenone. In some embodiments, the anti-estrogen drug may be one or more of, but is not limited to, clomiphene, tamoxifen, toremifene, raloxifene, triptorelin, leuprorelin, or goserelin. In some embodiments, the aromatase inhibitor may be one or more of, but is not limited to, DL-aminoglutethimide, formestane, exemestane, letrozole, anastrozole, rogletimide, or fadrozole.

[0105] MSI-H and / or dMMR tumors: In some embodiments, the tumor is a solid tumor, in some embodiments, the tumor is a malignant tumor, in some embodiments, the tumor is a malignant solid tumor.

[0106] The MSI-H and / or dMMR tumors described herein are those indicated as MSI-H and / or dMMR in the biomarker detection results, for example, but the type of tumor is not limited.

[0107] As used herein, the solid tumor does not include hematologic / blood tumors.

[0108] In some embodiments, the tumor is selected from the group consisting of breast cancer (e.g., hormone receptor-positive breast cancer, triple-negative breast cancer, HER2 / neu-positive or -negative breast cancer), gastrointestinal / gastrointestinal tumors (e.g., anal cancer, appendix cancer, bile duct cancer, gastrointestinal stromal tumor, gastrointestinal carcinoid, colorectal cancer, gastric cancer, esophageal cancer, gallbladder cancer, bile duct cancer, liver cancer, pancreatic cancer, pancreatic islet cell tumor, pancreatic neuroendocrine tumor), endocrine and neuroendocrine cancers (e.g., adrenocortical carcinoma, thyroid cancer, neuroendocrine tumors of the skin, parathyroid cancer), eye cancer, genitourinary system cancer (e.g., bladder cancer, kidney cancer, prostate cancer, testicular cancer, urethral cancer, urothelial cancer), gynecological cancer (e.g., endometrial cancer, ovarian cancer, cervical cancer, fallopian tube cancer, primary peritoneal carcinoma, cancer, vaginal cancer, vulvar cancer), head and neck cancer (e.g., hypopharyngeal cancer, laryngeal cancer, lip cancer, oral cavity cancer, nasopharyngeal cancer, oropharyngeal cancer, paranasal sinus and nasal cavity cancer, pharyngeal cancer, salivary gland cancer, pharyngeal cancer), respiratory system cancer (e.g., lung cancer (including but not limited to non-small cell lung cancer, small cell lung cancer), malignant mesothelioma, thymic carcinoma), skin cancer (e.g., Merkel cell carcinoma, squamous cell carcinoma of the skin, melanoma), nervous system tumors (e.g., brain cancer, glioma, neuroblastoma, pituitary tumor, primary central nervous system lymphoma), bone cancer, soft tissue sarcoma, hematologic / blood tumors (e.g., leukemia, lymphoma).

[0109] In some embodiments, the malignant tumor is breast cancer (e.g., hormone receptor-positive breast cancer, triple-negative breast cancer, HER2 / neu-positive or HER2 / neu-negative breast cancer), digestive system / gastrointestinal cancer (e.g., anal cancer, appendix cancer, bile duct cancer, gastrointestinal stromal tumor, gastrointestinal carcinoid, colorectal cancer, gastric cancer, esophageal cancer, gallbladder cancer, bile duct cancer, liver cancer, pancreatic cancer), endocrine system and neuroendocrine cancer (e.g., adrenocortical carcinoma, thyroid cancer, neuroendocrine tumors of the skin, parathyroid cancer), eye cancer, genitourinary system cancer (e.g., bladder cancer, kidney cancer, prostate cancer, testicular cancer, urethral cancer, urothelial cancer), gynecological cancer (e.g., endometrial cancer, ovarian cancer, cervical cancer, fallopian tube cancer, primary peritoneal cancer, vaginal cancer, vulvar cancer), head and neck cancer (e.g., hypopharyngeal cancer, laryngeal cancer, lip cancer, oral cavity cancer, nasopharyngeal cancer, oropharynx cancer, paranasal sinus and nasal cavity cancer, pharyngeal cancer, salivary gland cancer, pharyngeal cancer), respiratory system cancer (including, but not limited to, lung cancer (non-small cell lung cancer, small cell lung cancer), malignant mesothelioma, thymic carcinoma), skin cancer (e.g., Merkel cell carcinoma, cutaneous squamous cell carcinoma, Cancers that may be present include, but are not limited to, one or more of: cancers of the nervous system (e.g., brain cancer, glioma, neuroblastoma, primary central nervous system lymphoma), bone cancer, soft tissue sarcoma, and hematologic / blood cancer (e.g., leukemia, lymphoma).

[0110] In some embodiments of the present application, the MSI-H and / or dMMR tumor is cervical cancer (including, but not limited to, cervical squamous cell carcinoma and cervical adenocarcinoma). In some embodiments of the present application, the MSI-H and / or dMMR tumor is hepato-biliary cancer (including, but not limited to, liver cancer, gallbladder cancer, and cholangiocarcinoma). In some embodiments of the present application, the MSI-H and / or dMMR tumor is liver cancer (including, but not limited to, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma). In some embodiments of the present application, the MSI-H and / or dMMR tumor is urothelial cancer (including, but not limited to, bladder cancer and urethral cancer). In some embodiments of the present application, the MSI-H and / or dMMR tumor is lung cancer (e.g., small cell lung cancer, non-small cell lung cancer (including, but not limited to, lung squamous cell carcinoma, and lung adenocarcinoma)). In some embodiments, the MSI-H and / or dMMR tumor is a leukemia (including, but not limited to, acute myeloid leukemia, chronic myeloid leukemia, and chronic lymphocytic leukemia). In some embodiments, the MSI-H and / or dMMR tumor is a lymphoma (including, but not limited to, Hodgkin's lymphoma and primary mediastinal large B-cell lymphoma). In some embodiments, the MSI-H and / or dMMR tumor is colorectal cancer.

[0111] In some embodiments of the present application, the tumor is an advanced and / or metastatic tumor. In some embodiments of the present application, the tumor is a refractory and / or recurrent tumor.

[0112] In some embodiments of the present application, the MSI-H and / or dMMR malignancy is an aggressive MSI-H and / or dMMR malignancy. In some embodiments of the present application, the MSI-H and / or dMMR malignancy is a refractory MSI-H and / or dMMR malignancy.

[0113] In some embodiments of the present application, the MSI-H and / or dMMR malignancy is a recurrent and / or metastatic MSI-H and / or dMMR malignancy.

[0114] In some embodiments of the present application, the MSI-H and / or dMMR malignancy is a recurrent and / or metastatic, aggressive MSI-H and / or dMMR malignancy.

[0115] In some embodiments of the present application, the MSI-H and / or dMMR solid tumor is breast cancer (e.g., hormone receptor-positive breast cancer, triple-negative breast cancer, HER2 / neu-positive or -negative breast cancer), digestive system / gastrointestinal tumor (e.g., anal cancer, appendix cancer, bile duct cancer, gastrointestinal stromal tumor, gastrointestinal carcinoid, colorectal cancer, gastric cancer, esophageal cancer, gallbladder cancer, bile duct cancer, liver cancer, pancreatic cancer, pancreatic islet cell tumor, pancreatic neuroendocrine tumor), endocrine tumor and neuroendocrine cancer (e.g., adrenocortical carcinoma, thyroid cancer, neuroendocrine tumor of the skin, parathyroid cancer), eye cancer, genitourinary system cancer. (e.g., bladder cancer, kidney cancer, prostate cancer, testicular cancer, urethral cancer, urothelial cancer), gynecological cancer (e.g., endometrial cancer, ovarian cancer, cervical cancer, fallopian tube cancer, primary peritoneal cancer, vaginal cancer, vulvar cancer), head and neck cancer (e.g., hypopharyngeal cancer, laryngeal cancer, lip cancer, oral cavity cancer, nasopharyngeal cancer, oropharynx cancer, paranasal sinus and nasal cavity cancer, pharyngeal cancer, salivary gland cancer, pharyngeal cancer), respiratory system cancer (e.g., lung cancer (including, but not limited to, non-small cell lung cancer, small cell lung cancer), malignant mesothelioma, thymic carcinoma), skin cancer (e.g., Merkel cell carcinoma, squamous cell carcinoma of the skin, melanoma), nervous system tumors (e.g., Cancers include, but are not limited to, one or more of: brain cancer, glioma, neuroblastoma, pituitary tumor, primary central nervous system lymphoma), bone cancer, and soft tissue sarcoma.

[0116] In some embodiments of the present application, the MSI-H and / or dMMR solid tumor is a malignant solid tumor.

[0117] In some embodiments of the present application, the MSI-H and / or dMMR malignant solid tumor is an aggressive malignant solid tumor. In some embodiments of the present application, the MSI-H and / or dMMR malignant solid tumor is a refractory malignant solid tumor.

[0118] In some embodiments of the present application, the MSI-H and / or dMMR malignant solid tumor is a recurrent and / or metastatic malignant solid tumor.

[0119] In some embodiments of the present application, the MSI-H and / or dMMR malignant solid tumor is a recurrent and / or metastatic advanced malignant solid tumor.

[0120] In some embodiments of the present application, the patient with the MSI-H and / or dMMR tumor has already received one or more prior therapies, hi some embodiments of the present application, the MSI-H and / or dMMR tumor is an MSI-H and / or dMMR tumor that has received prior therapies and has progressed and / or has no satisfactory alternative treatment.

[0121] In some embodiments, the patient with the MSI-H and / or dMMR tumor has already received one or more drug treatments. In some embodiments, the MSI-H and / or dMMR tumor is an MSI-H and / or dMMR tumor for which at least one drug treatment has failed. In some embodiments, the treatment failure includes disease progression during treatment and disease progression and / or recurrence after treatment has ended.

[0122] In some embodiments of the present application, the patient with MSI-H and / or dMMR tumor has previously received one or more chemotherapy regimens. In some embodiments of the present application, the MSI-H and / or dMMR tumor is an MSI-H and / or dMMR tumor that has failed at least one chemotherapy treatment. In some embodiments, the treatment failure includes disease progression during treatment and disease progression and / or recurrence after treatment has ended. In some embodiments of the present application, the patient with MSI-H and / or dMMR tumor has previously received first-line or second-line standard systemic chemotherapy and has experienced treatment failure or intolerance.

[0123] Dosage regimen for anti-PD-L1 antibodies or pharmaceutical compositions thereof: In some embodiments of the present application, the uses or methods of treatment include administering the anti-PD-L1 antibody once every week (q1w), every two weeks (q2w), every three weeks (q3w), or every four weeks (q4w). In a specific embodiment, the anti-PD-L1 antibody is administered once every three weeks. In some embodiments, the anti-PD-L1 antibody is administered at a single dose of 600 to 2400 mg.

[0124] In some embodiments of the application, the uses or methods of treatment comprise administering the PD-L1 antibody on the first day of each 21-day treatment cycle.

[0125] In some embodiments of the application, in the use or method of treatment, the anti-PD-L1 antibody is administered at a dose of 0.01 to 40 mg / kg, 0.1 to 30 mg / kg, 0.1 to 20 mg / kg, 0.1 to 15 mg / kg, 0.1 to 10 mg / kg, 1 to 15 mg / kg, 1 to 20 mg / kg, 1 to 3 mg / kg, 3 to 10 mg / kg, 3 to 15 mg / kg, 3 to 20 mg / kg The compound can be administered to a subject at a dose selected from the group consisting of 60 to 2400 mg, 90 to about 1800 mg, 120 to 1500 mg, 300 to 900 mg, 600 to 900 mg, 300 to 1200 mg, 600 to 1200 mg, or 900 to 1200 mg.

[0126] In some embodiments of the above-described uses or methods of treatment, 1200 mg of the PD-L1 antibody is administered on the first day of each 21-day treatment cycle.

[0127] Administration of anti-PD-L1 antibodies or pharmaceutical compositions thereof: The following is not intended to limit the administration method of the antibody or pharmaceutical composition thereof according to the present application.

[0128] The anti-PD-L1 antibodies and pharmaceutical compositions thereof of the present application may be administered by any suitable route, including, but not limited to, oral or parenteral (e.g., intravenous, intramuscular, topical, or subcutaneous) or, in some embodiments, by injection (e.g., intravenous or intraperitoneal injection).

[0129] The pharmaceutical compositions of the present application include, but are not limited to, dosage forms that are tablets, troches, pills, capsules (e.g., hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions, and sustained-release formulations for oral or parenteral administration.

[0130] The pharmaceutical compositions of the present application may further comprise pharmaceutically acceptable carriers and / or excipients.

[0131] Therapeutic combination dosing regimen: In some embodiments of the application, in the uses or methods of treatment, the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof are each in the form of a pharmaceutical composition and may be administered simultaneously, asynchronously, or sequentially.

[0132] In some embodiments of the present application, the uses or methods of treatment comprise administering the anti-PD-L1 antibody and anlotinib, respectively, in an interval dosing regimen. In some embodiments, the antibody and anlotinib, respectively, are administered in the same or different dosing regimens. In some embodiments, they are administered in different dosing regimens.

[0133] In some embodiments of the present application, the uses or methods of treatment include administering the anti-PD-L1 antibody once every week (q1w), every two weeks (q2w), every three weeks (q3w), or every four weeks (q4w). In a specific embodiment, the anti-PD-L1 antibody is administered once every three weeks. In some embodiments, the anti-PD-L1 antibody is administered at a single dose of 600 to 2400 mg.

[0134] The anlotinib or a pharmaceutically acceptable salt thereof can be administered at a dose of 6 mg, 8 mg, 10 mg, or 12 mg once daily in a regimen of two weeks of continuous administration followed by one week of rest.

[0135] In some embodiments, the anti-PD-L1 antibody and anlotinib, or a pharmaceutically acceptable salt thereof, each have the same or different treatment cycles. In some particular embodiments, the anti-PD-L1 antibody and anlotinib have the same treatment cycle, e.g., , 1, 2, 3 or 4 weeks is one treatment cycle.

[0136] In some embodiments of the application, the use or method of treatment comprises administering the PD-L1 antibody on the first day of each treatment cycle and administering anlotinib or a pharmaceutically acceptable salt thereof daily on days 1 to 14 of each cycle, with each treatment cycle lasting 21 days. In one particular embodiment, the PD-L1 antibody is administered once on the first day of each treatment cycle and administering anlotinib or a pharmaceutically acceptable salt thereof once daily on days 1 to 14 of each cycle.

[0137] In some embodiments of the application, in the use or method of treatment, the anti-PD-L1 antibody is administered to a subject at a dose selected from the group consisting of 0.01 to 40 mg / kg, 0.1 to 30 mg / kg, 0.1 to 20 mg / kg, 0.1 to 15 mg / kg, 0.1 to 10 mg / kg, 1 to 15 mg / kg, 1 to 20 mg / kg, 1 to 3 mg / kg, 3 to 10 mg / kg, 3 to 15 mg / kg, 3 to 20 mg / kg, 3 to 30 mg / kg, 10 to 20 mg / kg, or 15 to 20 mg / kg, or may be administered to a subject at a dose of 60 to 2400 mg, 90 to 1800 mg, 120 to 1500 mg, 300 to 900 mg, 600 to 900 mg, 300 to 1200 mg, 600 to 1200 mg, or 900 to 1200 mg.

[0138] In some embodiments of the above-described uses or methods of treatment, 1200 mg of the PD-L1 antibody is administered on the first day of each treatment cycle, and 6 mg, 8 mg, 10 mg, and / or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof are administered daily on days 1-14 of each cycle, with each treatment cycle lasting 21 days.

[0139] In some embodiments of the present application, the anti-PD-L1 antibody and anlotinib, or a pharmaceutically acceptable salt thereof, are administered to a subject in a weight ratio of (0.35-29):1, (3.5-29):1, (3.5-14.5):1, or (7-14.5):1 over a 3-week treatment cycle, where the anti-PD-L1 antibody and anlotinib, or a pharmaceutically acceptable salt thereof, are administered in a unit dose and multiple doses, respectively.

[0140] Therapeutic combination administration regimen: The following is not intended to limit the administration regimen of the therapeutic combination of this application.

[0141] The components of the therapeutic combinations herein, individually or in part or in whole, can be administered by a variety of suitable routes, including, but not limited to, oral or parenteral (intravenous, intramuscular, topical, or subcutaneous) administration. In some embodiments of the present application, the components of the therapeutic combinations herein, individually or in part or in whole, can be administered orally or by injection (e.g., intravenous or intraperitoneal injection).

[0142] The components of the therapeutic combinations herein may each, independently, or some or all of them, be in any suitable dosage form, including, but not limited to, dosage forms that are tablets, troches, pills, capsules (e.g., hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions, sustained release formulations for oral or parenteral administration.

[0143] The components of the therapeutic combination of the present application may each, independently, or in part or in whole, contain a pharmaceutically acceptable carrier and / or excipient.

[0144] The present anti-PD-L1 antibody can safely and effectively treat endometrial cancer.

[0145] In some embodiments, the anti-PD-L1 antibodies of the present application are highly sensitive to MSI-H or dMMR endometrial cancer, and after treatment with the anti-PD-L1 antibody, patients with MSI-H or dMMR endometrial cancer experience an objective response rate (ORR) of well over 15%, and in certain embodiments, an ORR of 30% or greater. In some embodiments, after treatment with the anti-PD-L1 antibody, patients experience a disease control rate (DCR) of 50% or greater. In certain embodiments, a DCR of 80% or greater.

[0146] In a specific embodiment, treating MSI-H or dMMR endometrial cancer with the anti-PD-L1 antibodies described herein can significantly reduce the incidence and severity of treatment-related adverse events (TRAEs), with the incidence of treatment-related adverse events being less than 80% and the incidence of Grade 3 or higher being less than 20%. In some embodiments, treating MSI-H or dMMR endometrial cancer with the anti-PD-L1 antibodies described herein can significantly reduce the incidence and severity of treatment-related adverse events, with the incidence of treatment-related adverse events being less than 70% and the incidence of Grade 3 or higher being no more than 16%.

[0147] The anti-PD-L1 antibodies of the present application are highly sensitive to MSI-H and / or dMMR tumors (e.g., MSI-H and / or dMMR malignancies) and can safely and effectively treat MSI-H and / or dMMR tumors, with patient objective response rates (ORR) of well over 15%. In certain embodiments, in the case of MSI-H and / or dMMR tumors (e.g., MSI-H or dMMR endometrial cancer), after treatment with the anti-PD-L1 antibody, the patient objective response rate (ORR) is well over 15%. In certain embodiments, the ORR reaches or exceeds 30%. In some embodiments, after treatment with the anti-PD-L1 antibody, the patient's disease control rate (DCR) reaches or exceeds 50%. In certain embodiments, the DCR reaches or exceeds 80%.

[0148] In some embodiments, treatment of MSI-H or dMMR tumors with the anti-PD-L1 antibodies disclosed herein can significantly reduce the incidence and severity of treatment-related adverse events (TRAEs), with the incidence of treatment-related adverse events being less than 80% and the incidence of Grade 3 or higher being less than 20%. In some embodiments, treatment of MSI-H or dMMR malignancies with the anti-PD-L1 antibodies disclosed herein can significantly reduce the incidence and severity of treatment-related adverse events, with the incidence of treatment-related adverse events being less than 70% and the incidence of Grade 3 or higher being no more than 16%.

[0149] In some embodiments, a therapeutic combination comprising an anti-PD-L1 antibody of the present application and anlotinib, or a pharmaceutically acceptable salt thereof, can safely and effectively treat endometrial cancer.

[0150] In some embodiments, a therapeutic combination comprising an anti-PD-L1 antibody of the present application and anlotinib or a pharmaceutically acceptable salt thereof can safely and effectively treat non-MSI-H and / or non-dMMR endometrial cancer. In some embodiments, a therapeutic combination comprising an anti-PD-L1 antibody of the present application and anlotinib or a pharmaceutically acceptable salt thereof results in an ORR (objective response rate) of greater than 15% in patients with non-MSI-H and / or non-dMMR endometrial cancer. In certain embodiments, the ORR reaches or exceeds 25%. In certain embodiments, the ORR reaches or exceeds 30%. The disease control rate (DCR) reaches or exceeds 80%. In some specific embodiments, the DCR reaches or exceeds 90%.

[0151] In some embodiments, there is a synergistic effect when treating endometrial cancer with the anti-PD-L1 antibodies of the present application and anlotinib or a pharmaceutically acceptable salt thereof. In some particular embodiments, there is a significant synergistic effect when treating non-MSI-H and / or non-dMMR endometrial cancer with the anti-PD-L1 antibodies of the present application and anlotinib or a pharmaceutically acceptable salt thereof.

[0152] In some embodiments, when treating endometrial cancer, particularly non-MSI-H and / or non-dMMR endometrial cancer, with an anti-PD-L1 antibody described herein and anlotinib or a pharmaceutically acceptable salt thereof, the incidence and severity of treatment-related adverse events (TRAEs) can be significantly reduced, with the incidence of treatment-related adverse events being less than 80% and the incidence of Grade 3 or higher treatment-related adverse events being less than 10%. In some embodiments, when treating non-MSI-H and / or non-dMMR endometrial cancer with an anti-PD-L1 antibody described herein and anlotinib or a pharmaceutically acceptable salt thereof, the incidence of treatment-related adverse events does not exceed 75% and the incidence of Grade 3 or higher treatment-related adverse events does not exceed 7%.

[0153] In some embodiments, ORR is calculated from the proportion of objective responses (PR+CR) determined by calculating the IRC to the total number of cases and the 95% CI.

[0154] In some embodiments of the present application, a patient's immunogenicity is studied, and the immunogenicity study includes a study of anti-drug antibodies (ADA) and neutralizing antibodies (Nab), and if a patient's anti-drug antibodies (ADA) are detected as positive, neutralizing antibody (Nab) detection is added. In some embodiments, the timing of immunogenicity monitoring is based on the time of administration of the antibody injection, and if the administration of the antibody is delayed, the immunogenicity blood sampling is correspondingly delayed.

[0155] In the present application, the MSI (microsatellite instability) is caused by a functional defect in a DNA mismatch repair (MMR) protein. In the present application, the MSI status can be detected by methods well known in the art, including, but not limited to, immunohistochemistry-based detection of MMR proteins, multiplex fluorescent PCR (polymerase chain reaction)-based detection of microsatellite locations, and next-generation sequencing (NGS)-based MSI detection. In a specific embodiment, MSI is detected using multiplex fluorescent PCR (polymerase chain reaction). For example, MSI status is detected using commercially available kit products. In some embodiments, multiplex fluorescent PCR (polymerase chain reaction) is used to detect microsatellite locations, and interpretation criteria vary depending on the number of loci in the kit. The MSI status (e.g., MSI-H (microsatellite high instability), MSI-L (microsatellite low instability), or MSS (microsatellite stable)) is determined based on the criteria of commercially available qualified kit products.

[0156] In the present application, MMR status (e.g., dMMR) can be detected by methods well known in the art, such as immunohistochemistry (IHC) to detect MMR proteins. For example, four MMR proteins (MLH1, MSH2, MSH6, and PMS2) are primarily detected in tumor samples from patients. If any of the MMR proteins is absent, the patient is classified as dMMR, and if no MMR protein is absent, the patient is classified as non-dMMR. The absence of MMR protein expression can be determined according to the criteria of the College of American Pathologists (CAP), for example, by detecting the location of microsatellites using PCR.

[0157] In some embodiments, detection by PCR (polymerase chain reaction) and / or ICH (immunohistochemistry) determines whether the endometrial cancer is MSI-H or dMMR, or whether the endometrial cancer is non-MSI-H or non-dMMR.

[0158] "Definitions and Explanations" Unless otherwise specified, the following terms used in this application have the meanings set forth below. Certain terms are to be understood in their ordinary sense in the art, and not as being indefinite or unclear, unless otherwise defined. When trade names are mentioned in this application, they refer to the corresponding product or its active ingredient.

[0159] Unless otherwise specified, all references herein to the amount of anlotinib or a pharmaceutically acceptable salt thereof refer to the amount of anlotinib free base, which is the active ingredient.

[0160] Unless otherwise specified, the term "dose" refers to the dose administered to a patient without regard to the patient's weight or body surface area (BSA). For example, a 60 kg human and a 100 kg human would receive the same dose of antibody (e.g., 240 mg of an anti-PD-1 antibody).

[0161] The term "MSI" refers to microsatellite instability.

[0162] The term "MSI-H" refers to high microsatellite instability or microsatellite instability-high (MSI-high).

[0163] The term "MSI-L" refers to microsatellite instability low (MSI-low).

[0164] The term "MSS" refers to microsatellite stability.

[0165] The term "MMR" refers to mismatch repair.

[0166] The term "dMMR" refers to deficient mismatch repair.

[0167] The term "pMMR" refers to proficient mismatch repair.

[0168] As used herein, the term "therapeutic combination" refers to a combination of two or more active ingredients (each active ingredient may be administered by itself or in the form of a derivative, prodrug, or composition, such as a pharmaceutically acceptable salt or ester thereof) administered simultaneously or sequentially to a subject, either simultaneously as a separate formulation or sequentially in any order as separate formulations.

[0169] As used herein, the term "antibody" refers to a binding protein having at least one antigen-binding domain. The antibodies and fragments thereof of the present application may be whole antibodies or any fragments thereof. Thus, the antibodies and fragments of the present application include monoclonal antibodies or fragments thereof, antibody variants or fragments thereof, and immunoconjugates. Examples of antibody fragments include Fab fragments, Fab' fragments, F(ab)'2 fragments, Fv fragments, isolated CDR regions, single-chain Fv molecules (scFv), Fd fragments, and other antibody fragments known in the art. Antibodies and fragments thereof also include recombinant polypeptides, fusion proteins, and bispecific antibodies. The anti-PD-L1 antibodies and fragments thereof described herein may be of the IgG1, IgG2, IgG3, or IgG4 isotype. The term "isotype" refers to the antibody species encoded by the heavy chain constant region genes. In one embodiment, The anti-PD-L1 antibodies and fragments thereof described herein are of the IgG1 or IgG4 isotype. The PD-L1 antibodies and fragments thereof of the present application may be derived from any species, including, but not limited to, mouse, rat, rabbit, primate, llama, and human. The PD-L1 antibodies and fragments thereof may be chimeric, humanized, or fully human. In one embodiment, the anti-PD-L1 antibody is an antibody produced from a hybridoma cell line derived from a mouse. Thus, in one embodiment, the anti-PD-L1 antibody is a murine antibody. In another embodiment, the anti-PD-L1 antibody is a chimeric antibody. In another embodiment, the chimeric antibody is a mouse-human chimeric antibody. In another embodiment, the antibody is a humanized antibody. In another embodiment, the antibody is derived from a murine antibody and humanized.

[0170] A "humanized antibody" is an antibody that contains complementarity-determining regions (CDRs) derived from a non-human antibody and framework and constant regions derived from a human antibody. For example, an anti-PD-L1 antibody described herein may contain CDRs derived from one or more murine antibodies and human framework and constant regions. Thus, in one embodiment, a humanized antibody described herein and the murine antibody from which the CDRs of the antibody are derived bind to the same epitope of PD-L1. In some embodiments, the anti-PD-L1 antibody is humanized. Other anti-PD-L1 antibodies or variants thereof comprising the heavy chain and light chain CDRs described herein can be produced using any human framework sequences and are included herein. In one embodiment, framework sequences suitable for use herein include framework sequences that are structurally similar to the framework sequences described herein. Other modifications in the framework regions can be made to improve the properties of the antibodies described herein. Such other framework modifications include chemical modifications, point mutations to reduce immunogenicity or eliminate T-cell epitopes, and backmutations to residues in the original germline sequence. In some embodiments, such modifications include those corresponding to the exemplary mutations described herein, including backmutations to germline sequences. For example, in one embodiment, one or more amino acids in the human framework regions of the VH and / or VL of a humanized antibody described herein are backmutated to the corresponding amino acid in the parent mouse antibody. For example, in the case of the VH and VL of humanized 5G11 and humanized 13C5, several amino acid positions in the framework of the template human antibody are backmutated to the corresponding amino acid sequences in the mouse 5G11 and 13C5 antibodies. In one embodiment, amino acids at positions 53, 60, and / or 67 in the light chain variable region are backmutated to the corresponding amino acids found at those positions in the mouse 5G11 or 13C5 light chain variable region. In another embodiment, amino acids at positions 24, 28, 30, 49, 73, 83, and / or 94 in the heavy chain variable region are backmutated to the corresponding amino acids found at those positions in the mouse 5G11 or 13C5 heavy chain variable region.In one embodiment, the humanized 5G11 antibody comprises a light chain variable region in which the amino acid at position 60 is mutated from Ser (S) to Asp (D) and the amino acid at position 67 is mutated from Ser (S) to Tyr (Y), and a heavy chain variable region in which the amino acid at position 24 is mutated from Phe (F) to Val (V), the amino acid at position 49 is mutated from Ala (A) to Gly (G), the amino acid at position 73 is mutated from Thr (T) to Asn (N), and the amino acid at position 83 is mutated from Thr (T) to Asn (N). In one embodiment, the humanized 13C5 antibody comprises a light chain variable region in which the amino acid at position 53 has been mutated from Tyr (Y) to Lys (K); and a heavy chain variable region in which the amino acid at position 28 has been mutated from Thr (T) to Ile (I), the amino acid at position 30 has been mutated from Ser (S) to Arg (R), the amino acid at position 49 has been mutated from Ser (S) to Ala (A), and the amino acid at position 94 has been mutated from Tyr (Y) to Asp (D). The framework regions of the humanized antibodies described herein may also contain other or optional back-mutations to improve the antibody's properties. The present application further includes humanized antibodies that bind to PD-L1 and have framework modifications that correspond to any of the exemplary modifications of suitable framework sequences described herein, as well as other framework modifications to improve antibody properties in other ways.

[0171] The present application provides an isolated antibody or fragment thereof that binds to PD-L1, wherein the antibody may be produced by a hybridoma, the hybridoma being selected from the group consisting of the hybridomas designated herein as 13C5 and 5G11. The present application further provides isolated polynucleotides encoding the antibodies and fragments thereof described herein. The present application further includes expression vectors comprising the isolated polynucleotides, and host cells comprising the expression vectors.

[0172] An "isolated antibody" is an antibody that is substantially free of other antibodies with different antigenic specificities (e.g., an isolated antibody that specifically binds PD-1 is substantially free of antibodies that specifically bind to antigens other than PD-1). However, an isolated antibody that specifically binds PD-1 may have cross-reactivity with other antigens (e.g., PD-1 molecules from different species). An isolated antibody may also be substantially free of other cellular material and / or chemicals.

[0173] The term "monoclonal antibody (mAb)" refers to a non-naturally occurring composition of antibody molecules consisting of a single molecule (i.e., antibody molecules having substantially the same basic sequence and displaying a single binding specificity and affinity for a particular epitope). mAbs are an example of an isolated antibody. mAbs can be produced by hybridoma, recombinant, genetic engineering, or other techniques known to those skilled in the art.

[0174] The antibodies and antigen-binding fragments thereof described herein are specific for PD-L1. In one embodiment, the antibodies and / or fragments thereof are specific for PD-L1. In one embodiment, the antibodies and fragments thereof described herein bind to human or primate PD-L1 but do not bind to PD-L1 from other mammals. In another embodiment, the antibodies and / or fragments thereof do not bind to murine PD-L1. The terms "human PD-L1," "hPD-L1," "huPD-L1," etc. are used interchangeably herein to refer to human PD-L1 and variants or isotypes of human PD-L1. "Specificity" means that the antibodies and fragments thereof bind to PD-L1 with greater affinity than to other targets.

[0175] The term "treatment" generally refers to obtaining a desired pharmacological and / or physiological effect. Such effect is therapeutic if it partially or completely stabilizes or cures a disease and / or its associated side effects. As used herein, the term "treatment" includes any treatment of a patient's disease, either (a) inhibiting the symptoms of the disease, i.e., preventing its progression, or (b) ameliorating the symptoms of the disease, i.e., eliminating the disease or symptoms.

[0176] The term "effective amount" refers to a dose of a compound of the present application that (i) treats a particular disease, condition, or disorder, (ii) alleviates, improves, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. A "therapeutically effective amount" of an active agent (e.g., an antibody or compound of the present application) will vary depending on several factors, such as the individual's condition, age, sex, and weight, and the ability of the therapeutic agent or combination of therapeutic agents to elicit a desired response in the individual. An effective amount can generally be determined by one of ordinary skill in the art based on their knowledge or the present disclosure.

[0177] The term "administration" refers to the physical introduction of a composition containing 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 immune checkpoint inhibitors (e.g., anti-PD-1 antibodies or anti-PD-L1 antibodies) include parenteral routes of administration (intravenous, intramuscular, subcutaneous, intraperitoneal, intrathecal, or other parenteral routes of administration (e.g., injection or infusion)). In some embodiments, the term "parenteral administration" as used herein refers to administration of an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody or an anti-PD-L1 antibody) by parenteral administration (e.g., intravenous, intramuscular, subcutaneous, intraperitoneal, intrathecal, or other parenteral routes of administration (e.g., injection or infusion)). " refers to routes of administration other than enteral and topical administration, which are typically performed by injection, and includes, but is not limited to, intravenous, intramuscular, intra-arterial, 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. In some embodiments, the immune checkpoint inhibitor (e.g., an anti-PD-1 antibody or anti-PD-L1 antibody) is administered parenterally, and in some embodiments, orally. Other parenteral routes include topical, epidermal, or mucosal administration routes, such as intranasal, intravaginal, rectal, sublingual, and topical. Administration may be single or multiple times and / or over one or more extended periods.

[0178] The term "pharmaceutically acceptable" is used to refer to compounds, materials, compositions and / or dosage forms that are suitable for use in contact with the tissues of human beings or animals without toxicity, irritation, allergic response or other problem or complication.

[0179] The term "pharmaceutically acceptable salt" includes salts formed between a free base and an acid, and salts formed between an acid and a free base, such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, fumarate, oxalate, maleate, citrate, succinate, methanesulfonate, benzenesulfonate, and p-toluenesulfonate, and in some embodiments, hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, methanesulfonate, p-toluenesulfonate, sodium salt, potassium salt, ammonium salt, amino acid salt, etc. In the present application, when forming a pharmaceutically acceptable salt, the molar ratio of the acid to the free base is 1:0.2 to 1:5, and in some embodiments, is 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, or 1:8.

[0180] As used herein, the terms "subject" and "patient" are used interchangeably. In some embodiments, the term "subject" or "patient" is a mammal. In some embodiments, the subject or patient is a mouse. In some embodiments, the subject or patient is a human.

[0181] The term "unit dose" refers to an indivisible packaged unit containing a predetermined amount of drug; for example, if a medicine box contains seven capsules, each capsule is a unit dose, or a bottle of injection solution is a unit dose.

[0182] The term "multi-dose" consists of a plurality of unit doses.

[0183] The term "pharmaceutical composition" refers to a mixture of one or more of the active ingredients of the present application or therapeutic combinations thereof with pharmaceutically acceptable excipients to facilitate administration of the compounds of the present application or therapeutic combinations thereof to a subject.

[0184] In this specification, unless otherwise stated, singular terms cover plural referents and vice versa.

[0185] In this specification, unless otherwise stated, the terms "comprise," "comprises," "comprising," or equivalent terms are open-ended and mean that the invention may include unspecified elements, ingredients, or steps in addition to the listed elements, ingredients, or steps.

[0186] All patents, patent applications, and other publications are expressly incorporated herein by reference for purposes of explanation and disclosure. Such publications are provided because they were published prior to the filing date of the present application. Any statement as to the disclosure date of any such document or representation of its contents is based on the information available to applicant. The disclosure of such documents is not intended to constitute an admission as to the accuracy of the disclosure dates or contents thereof, nor is the incorporation of such publications into this specification an admission that such publications constitute common general knowledge in the art in all jurisdictions. DETAILED DESCRIPTION OF THE INVENTION

[0187] The present application is further illustrated by the following examples, but the scope of the present application is not limited to these examples. All reagents used in the present application are commercially available products and can be used without purification. In the examples, anti-PD-L1 antibodies are produced according to the method described in WO2016022630, and after affinity chromatography, an eluate containing the antibody is obtained using conventional antibody purification methods.

[0188] Example 1: Phase II clinical trial for endometrial cancer Patients with endometrial cancer who met the inclusion criteria were initially assessed for MMR / MSI status by immunohistochemistry or PCR. Enrollment was based on MSI-H / dMMR detection. Non-MSI-H / non-dMMR patients received an anti-PD-L1 antibody and anlotinib hydrochloride (Cohort 1), while MSI-H or dMMR patients received an anti-PD-L1 antibody (Cohort 2). Patients achieving disease control (CR+PR+SD) and tolerable treatment-related adverse events were able to continue treatment. The study was terminated when clinical benefit was lost, toxicity was unacceptable, efficacy was assessed as PD / iCPD, and the investigator deemed the patient unsuitable for further treatment. Efficacy assessments were conducted every 6 weeks (42 days) ± 3 days from the first day of the first treatment cycle, and again every 12 weeks (84 days) ± 3 days after 54 weeks. Patients were followed until tumor imaging-based disease progression.

[0189] 1.1 Main recruitment criteria: 1) Histologically or cytologically confirmed unresectable recurrent or metastatic advanced endometrial cancer (previously treated with first- or second-line standard systemic chemotherapy with treatment failure or intolerance. Previous neoadjuvant or adjuvant chemotherapy may also be administered).

[0190] 2) evidence of at least one measurable site of disease by Response Evaluation Criteria in Solid Tumors (RECIST 1.1);

[0191] 3) Age: 18 years or older, ECOG PS score: 0-1 point, expected survival time: 3 months or longer.

[0192] 1.2 Test drug Anti-PD-L1 antibody injection hu5G11-hIgG1: 1200 mg of anti-PD-L1 antibody injection (specification: 600 mg / 20 mL) was diluted to 250 mL with normal saline, and the infusion time was 60 ± 10 minutes (the starting point for the infusion of the anti-PD-L1 antibody injection was the start point, and the end point was the completion of the anti-PD-L1 antibody injection infusion and the completion of flushing with normal saline (recommended 20 mL)). The anti-PD-L1 antibody injection was administered on the first day and once every 21 days, i.e., 21 days constituted one treatment cycle (d1 / q3w).

[0193] Anlotinib hydrochloride capsules (active ingredient: anlotinib dihydrochloride): Take one capsule (12 mg) once daily (orally before breakfast on an empty stomach). This consists of two consecutive weeks of oral administration followed by one week of rest, making a 21-day treatment cycle. Administration is on days 1-14 of each cycle. Unless otherwise specified, it is recommended to take the medication at the same time each day (i.e., anlotinib hydrochloride capsules: 12 mg / qd, days 1-14 / q3w). The investigator may adjust the dose of anlotinib hydrochloride capsules, for example, to 12 mg, 10 mg, or 8 mg, based on disease status and safety.

[0194] 1.3 Evaluation Criteria Safety evaluation criteria: The NCI-CTC AE 5.0 criteria will be adopted to judge the severity of adverse events.

[0195] Efficacy evaluation criteria: RECIST 1.1 and iRECIST criteria are used to determine the disease status. Evaluation is primarily based on RECIST 1.1 criteria, and efficacy is also confirmed using iRECIST criteria. That is, subjects who are determined to have progressive disease (PD) according to RECIST 1.1 criteria are further confirmed using iRECIST criteria to determine whether further treatment and observation are necessary.

[0196] 1.4 Endpoint Indicators Primary endpoint: objective response rate (ORR) assessed by IRC. Secondary endpoints: (1) Investigator-assessed objective response rate (ORR), disease control rate (DCR), duration of remission (DOR), progression-free survival (PFS), overall survival (OS), and DOR rate (≥6 months), etc.; (2) incidence and severity of adverse events (AEs) and serious adverse events (SAEs), and abnormal clinical laboratory indicators.

[0197] 1.5 Results Preliminary studies have shown that the combination of anlotinib hydrochloride and anti-PD-L1 antibodies can safely and effectively treat non-MSI-H and / or non-dMMR endometrial cancer, demonstrating clinical benefit in patients. As of the data collection date, 22 patients in Cohort 1 (anlotinib hydrochloride and anti-PD-L1 antibody combination group) had completed at least two treatment cycles. Of these, 14 patients (14 / 22) achieved stable disease (SD), 5 patients (5 / 22) achieved partial response (PR), and 1 patient (1 / 22) achieved complete response (CR). The objective response rate (ORR) was 27.27%, the disease control rate (DCR) was 90.91%, the incidence of treatment-related adverse events was 75%, and the incidence of grade 3 or higher treatment-related adverse events was 7%. See Table 1 for details.

[0198] Preliminary studies have shown that anti-PD-L1 antibodies can safely and effectively treat MSI-H and / or dMMR tumors, particularly MSI-H and / or dMMR endometrial cancer, and provide clinical benefit to patients. As of the data collection date, six patients in Cohort 2 (anti-PD-L1 antibody group) had completed at least two treatment cycles. Two patients (2 / 6) achieved stable disease (SD) and one patient (1 / 6) achieved partial remission (PR). The objective response rate reached 16.67%, the disease control rate reached 50.00%, the incidence of treatment-related adverse events (AEs) was 67%, and the incidence of grade 3 or higher AEs was 16%. See Table 1 for details.

[0199] [Table 1] *: For one of the subjects, the best immediate response was iUPD (iRECIST criteria), and further efficacy evaluation is required. **: Three of these patients currently have the best response according to iUPD (iRECIST criteria), and further evaluation of the response is required.

Claims

1. A drug combination for use in the treatment of endometrial cancer, comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof; The anti-PD-L1 antibody A combination drug comprising a heavy chain CDR1 region having the amino acid sequence set forth in SEQ ID NO: 1; a heavy chain CDR2 region having the amino acid sequence set forth in SEQ ID NO: 2; a heavy chain CDR3 region having the amino acid sequence set forth in SEQ ID NO: 3; a light chain CDR1 region having the amino acid sequence set forth in SEQ ID NO: 7; a light chain CDR2 region having the amino acid sequence set forth in SEQ ID NO: 8; and a light chain CDR3 region having the amino acid sequence set forth in SEQ ID NO:

9.

2. 2. The combination drug of claim 1, comprising a pharmaceutical composition comprising 600 to 2400 mg of an anti-PD-L1 antibody provided in the form of multiple doses, and a pharmaceutical composition comprising 6 mg, 8 mg, 10 mg, and / or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof in a unit dose.

3. Use of an anti-PD-L1 antibody in the manufacture of a medicament for treating endometrial cancer in combination with anlotinib or a pharmaceutically acceptable salt thereof, comprising: The anti-PD-L1 antibody Uses comprising: a heavy chain CDR1 region having the amino acid sequence set forth in SEQ ID NO: 1; a heavy chain CDR2 region having the amino acid sequence set forth in SEQ ID NO: 2; a heavy chain CDR3 region having the amino acid sequence set forth in SEQ ID NO: 3; a light chain CDR1 region having the amino acid sequence set forth in SEQ ID NO: 7; a light chain CDR2 region having the amino acid sequence set forth in SEQ ID NO: 8; and a light chain CDR3 region having the amino acid sequence set forth in SEQ ID NO:

9.

4. Use of an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating endometrial cancer by combining the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof, comprising: The anti-PD-L1 antibody a heavy chain CDR1 region having the amino acid sequence shown in SEQ ID NO:1; a heavy chain CDR2 region having the amino acid sequence shown in SEQ ID NO:2; a heavy chain CDR3 region having the amino acid sequence shown in SEQ ID NO:3; a light chain CDR1 region having the amino acid sequence set forth in SEQ ID NO:7; a light chain CDR2 region having the amino acid sequence set forth in SEQ ID NO:8; and a light chain CDR3 region having the amino acid sequence set forth in SEQ ID NO:

9.

5. The combination drug described in claim 1 or 2, wherein the endometrial cancer is non-MSI-H and / or non-dMMR endometrial cancer.

6. The combination drug according to claim 1 or 2, wherein the endometrial cancer is advanced endometrial cancer and / or refractory and / or recurrent and / or metastatic endometrial cancer.

7. The combination drug described in claim 1 or 2, wherein the endometrial cancer is recurrent and / or metastatic, non-MSI-H and / or non-dMMR endometrial cancer.

8. The combination drug described in claim 1 or 2, wherein the endometrial cancer is endometrial cancer that has failed treatment with at least one chemotherapy regimen.

9. The drug combination of claim 1 or 2, wherein the patient with endometrial cancer has previously received first- or second-line standard systemic chemotherapy with treatment failure or intolerance.

10. The anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof are packaged separately, or The combination drug according to claim 1 or 2, wherein the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof are each in the form of a pharmaceutical composition and can be administered simultaneously, sequentially, or sequentially.

11. The combination drug of claim 10, wherein 1200 mg of the PD-L1 antibody is administered on the first day of each treatment cycle, each treatment cycle being 3 weeks long, and 6 mg, 8 mg, 10 mg, and / or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof is administered daily on days 1 to 14 of each cycle.

12. The use described in claim 3 or 4, wherein the endometrial cancer is non-MSI-H and / or non-dMMR endometrial cancer.

13. The use described in claim 3 or 4, wherein the endometrial cancer is advanced endometrial cancer and / or refractory and / or recurrent and / or metastatic endometrial cancer.

14. The use described in claim 3 or 4, wherein the endometrial cancer is recurrent and / or metastatic, non-MSI-H and / or non-dMMR endometrial cancer.

15. The use described in claim 3 or 4, wherein the endometrial cancer is endometrial cancer that has failed treatment with at least one chemotherapy regimen.

16. The use of claim 3 or 4, wherein the patient with endometrial cancer has previously received first- or second-line standard systemic chemotherapy with treatment failure or intolerance.

17. The use according to claim 3 or 4, wherein the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof are each in the form of a pharmaceutical composition and can be administered simultaneously, sequentially, or sequentially.

18. The use according to claim 17, wherein 1200 mg of the PD-L1 antibody is administered on the first day of each treatment cycle, with one treatment cycle being three weeks, and 6 mg, 8 mg, 10 mg, and / or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof is administered daily on days 1 to 14 of each cycle.

19. The combination drug of claim 1 or 2, wherein the anti-PD-L1 antibody comprises a heavy chain variable region having at least 80% homology to the amino acid sequence shown in SEQ ID NO: 13; and a light chain variable region having at least 80% homology to the amino acid sequence shown in SEQ ID NO:

15.

20. The combination drug of claim 1 or 2, wherein the anti-PD-L1 antibody comprises a heavy chain variable region shown in SEQ ID NO: 13 and a light chain variable region shown in SEQ ID NO:

15.

21. The anti-PD-L1 antibody a heavy chain amino acid sequence set forth in SEQ ID NO: 17 and a light chain amino acid sequence set forth in SEQ ID NO: 18; or The combination drug of claim 1 or 2, comprising a heavy chain amino acid sequence shown in SEQ ID NO: 21 and a light chain amino acid sequence shown in SEQ ID NO:

18.

22. The use of claim 3 or 4, wherein the anti-PD-L1 antibody comprises a heavy chain variable region having at least 80% homology to the amino acid sequence shown in SEQ ID NO: 13; and a light chain variable region having at least 80% homology to the amino acid sequence shown in SEQ ID NO:

15.

23. The use of claim 3 or 4, wherein the anti-PD-L1 antibody comprises a heavy chain variable region shown in SEQ ID NO: 13 and a light chain variable region shown in SEQ ID NO:

15.

24. The anti-PD-L1 antibody a heavy chain amino acid sequence set forth in SEQ ID NO: 17 and a light chain amino acid sequence set forth in SEQ ID NO: 18; or The use according to claim 3 or 4, comprising a heavy chain amino acid sequence shown in SEQ ID NO: 21 and a light chain amino acid sequence shown in SEQ ID NO: 18.

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