WO2022002153A1 - 用于治疗肿瘤的药物 - Google Patents

用于治疗肿瘤的药物 Download PDF

Info

Publication number
WO2022002153A1
WO2022002153A1 PCT/CN2021/103687 CN2021103687W WO2022002153A1 WO 2022002153 A1 WO2022002153 A1 WO 2022002153A1 CN 2021103687 W CN2021103687 W CN 2021103687W WO 2022002153 A1 WO2022002153 A1 WO 2022002153A1
Authority
WO
WIPO (PCT)
Prior art keywords
seq
antibody
amino acid
acid sequence
homology
Prior art date
Application number
PCT/CN2021/103687
Other languages
English (en)
French (fr)
Inventor
苏楠
张喜全
陈杰
王训强
李琨
于鼎
汪荣亮
Original Assignee
正大天晴药业集团股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 正大天晴药业集团股份有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to JP2022580273A priority Critical patent/JP2023531090A/ja
Priority to AU2021301947A priority patent/AU2021301947A1/en
Priority to EP21833511.5A priority patent/EP4174087A1/en
Priority to CA3188017A priority patent/CA3188017A1/en
Priority to US18/003,718 priority patent/US20230310596A1/en
Priority to CN202180041400.5A priority patent/CN115698076A/zh
Publication of WO2022002153A1 publication Critical patent/WO2022002153A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present application belongs to the field of biomedicine, and specifically relates to drugs for treating tumors.
  • Endometrial cancer is a group of epithelial malignant tumors that occur in the endometrium, also known as uterine body cancer, and is one of the three most common malignant tumors in the female reproductive tract. It mostly occurs in perimenopausal and postmenopausal women. With the increase of the average life expectancy of the population and the change of living habits, the incidence of endometrial cancer has continued to rise and become younger in the past 20 years. In western countries, endometrial cancer has occupied the first place in the incidence of malignant tumors of female reproductive system. In my country, as the second common gynecological malignant tumor after cervical cancer, it accounts for about 20%-30% of gynecological malignant tumors.
  • the incidence of endometrial cancer in some developed cities has reached the first place in gynecological malignant tumors.
  • the postoperative recurrence rate of patients with stage I and II is about 15%, and 50%-70% of the recurrences are symptomatic. Most relapses occurred within 3 years of treatment. Recurrences confined to the vagina or pelvis still have good results after treatment.
  • the 5-year survival rate after radiotherapy for isolated vaginal recurrence is 50%-70%.
  • endometrial cancer is mainly based on surgery, supplemented by radiotherapy, drug therapy and hormone therapy.
  • conservative treatment with progesterone is often used to preserve reproductive function;
  • advanced-stage patients appropriate chemotherapy should be taken before surgery to reduce tumor volume, and rational selection of chemotherapy drugs It can significantly improve the surgical resection rate;
  • hormone drugs such as progesterone, gonadotropin-releasing hormone analogs, aromatase inhibitors, etc. are commonly used.
  • chemotherapy drugs such as paclitaxel, carboplatin, and doxorubicin.
  • targeted drug therapy such as pembrolizumab, avelumab, bevacizumab, sorafenib, sunitinib, etc.
  • pembrolizumab avelumab
  • bevacizumab avelumab
  • sunitinib a sunitinib
  • Microsatellite refers to a DNA sequence that is repeated in tandem with a few nucleotides (mostly 1-6) in the cell genome, also known as short tandem repeat (STR).
  • MMR DNA mismatch repair
  • STR short tandem repeat
  • MSI DNA mismatch repair
  • MSI-high microsatellite high instability
  • MSI-low microsatellite low instability
  • MSS microsatellite stability
  • Programmed death factor 1 and its ligand are a pair of immune co-stimulatory factors.
  • PD-1 plays an immune regulatory role through its ligand PD-L1.
  • Activation of PD-1/PD-L1 signaling pathway can lead to the formation of an immunosuppressive tumor microenvironment, allowing tumor cells to evade immune surveillance and killing by the body, while blocking PD-1/PD-L1 signaling pathway can reverse the tumor immune microenvironment. Enhance endogenous anti-tumor immune effect.
  • the present application provides use of an anti-PD-L1 antibody in the manufacture of a medicament for the treatment of MSI-H endometrial cancer and/or dMMR endometrial cancer.
  • the present application provides the use of a pharmaceutical composition containing an anti-PD-L1 antibody in the preparation of a medicament for the treatment of MSI-H endometrial cancer and/or dMMR endometrial cancer.
  • the present application also provides the use of an anti-PD-L1 antibody for treating MSI-H endometrial cancer and/or dMMR endometrial cancer.
  • the present application also provides the use of a pharmaceutical composition containing an anti-PD-L1 antibody for the treatment of MSI-H endometrial cancer and/or dMMR endometrial cancer.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
  • the present application provides a pharmaceutical combination for treating endometrial cancer, comprising: an anti-PD-L1 antibody, and anlotinib or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical combination for the treatment of non-MSI-H and/or non-dMMR endometrial cancer comprising: an anti-PD-L1 antibody, and anlotinib or a pharmaceutically acceptable of salt.
  • the present application provides the use of a pharmaceutical combination of an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of endometrial cancer.
  • a pharmaceutical combination comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of endometrial cancer is provided.
  • a pharmaceutical combination comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical combination for the treatment of non-MSI-H and/or non-dMMR endometrial cancer Use of drugs.
  • the present application provides the use of a pharmaceutical combination of an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof for the treatment of endometrial cancer.
  • the use of a pharmaceutical combination comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof for the treatment of endometrial cancer is provided.
  • the application provides the use of a pharmaceutical combination of an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof for the treatment of non-MSI-H and/or non-dMMR endometrial cancer .
  • the present application provides a pharmaceutical combination comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof for the treatment of non-MSI-H and/or non-dMMR endometrial cancer use.
  • the pharmaceutical combination further comprises a pharmaceutically acceptable carrier.
  • the present application provides use of an anti-PD-L1 antibody in the manufacture of a medicament for the treatment of MSI-H and/or dMMR tumors.
  • use of an anti-PD-L1 antibody in the manufacture of a medicament for the treatment of MSI-H and/or dMMR malignancies is provided.
  • use of an anti-PD-L1 antibody in the manufacture of a medicament for the treatment of MSI-H and/or dMMR solid tumors is provided.
  • use of an anti-PD-L1 antibody in the manufacture of a medicament for the treatment of MSI-H and/or dMMR malignant solid tumors is provided.
  • the present application provides the use of a pharmaceutical composition containing an anti-PD-L1 antibody in the preparation of a medicament for the treatment of MSI-H and/or dMMR tumors.
  • a pharmaceutical composition comprising an anti-PD-L1 antibody in the manufacture of a medicament for the treatment of MSI-H and/or dMMR malignancies is provided.
  • the use of a pharmaceutical composition comprising an anti-PD-L1 antibody in the manufacture of a medicament for the treatment of MSI-H and/or dMMR solid tumors is provided.
  • the present application also provides the use of an anti-PD-L1 antibody for the treatment of MSI-H and/or dMMR tumors.
  • use of an anti-PD-L1 antibody for the treatment of MSI-H and/or dMMR malignancies is provided.
  • use of an anti-PD-L1 antibody for the treatment of MSI-H and/or dMMR solid tumors is provided.
  • use of an anti-PD-L1 antibody for the treatment of MSI-H and/or dMMR malignant solid tumors is provided.
  • the present application also provides the use of a pharmaceutical composition containing an anti-PD-L1 antibody for the treatment of MSI-H and/or dMMR tumors.
  • a pharmaceutical composition comprising an anti-PD-L1 antibody for the treatment of MSI-H and/or dMMR solid tumors is provided.
  • the present application also provides a method of 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.
  • the application 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 a drug combination comprising an anti-PD-L1 antibody thing.
  • the present application also provides a method for treating endometrial cancer, comprising administering a therapeutically effective amount of an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof to a patient in need thereof.
  • the present application also provides a method of treating non-MSI-H and/or non-dMMR endometrial cancer, comprising administering to a patient in need thereof a therapeutically effective amount of an anti-PD-L1 antibody and an anti-PD-L1 antibody Rotinib or a pharmaceutically acceptable salt thereof.
  • the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof may be administered simultaneously, sequentially or sequentially.
  • the application also provides a method of treatment of endometrial cancer, comprising administering to a patient in need thereof a therapeutically effective amount of an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable form thereof Pharmaceutical compositions of salts.
  • the present application also provides a method of treating non-dMMR and/or non-MSI-H endometrial cancer, comprising administering to a patient in need thereof a therapeutically effective amount of an anti-PD-L1 antibody drug Compositions and pharmaceutical compositions of Anlotinib or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the anti-PD-L1 antibody and the pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof may be administered simultaneously, sequentially or sequentially.
  • the present application also provides a method of treating non-dMMR and/or non-MSI-H endometrial cancer, comprising administering to a patient in need thereof a therapeutically effective amount of an anti-PD-L1-containing antibody and A pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof.
  • the present application also provides a method of 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.
  • methods of treating MSI-H and/or dMMR malignancies are provided, comprising administering to a patient in need thereof a therapeutically effective amount of an anti-PD-L1 antibody.
  • methods of treating MSI-H and/or dMMR malignant solid tumors are provided, comprising administering to a patient in need thereof a therapeutically effective amount of an anti-PD-L1 antibody.
  • the present application also provides a method for treating MSI-H and/or dMMR tumors, comprising administering a therapeutically effective amount of a pharmaceutical composition containing an anti-PD-L1 antibody to a patient in need thereof.
  • methods of treating MSI-H and/or dMMR malignancies comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising an anti-PD-L1 antibody.
  • methods of treating MSI-H and/or dMMR malignant solid tumors are provided, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising an anti-PD-L1 antibody.
  • the application provides a kit for treating MSI-H endometrial cancer and/or dMMR endometrial cancer, comprising an anti-PD-L1 antibody.
  • the kit further comprises instructions for treating endometrial cancer.
  • the present application provides a kit for treating MSI-H endometrial cancer and/or dMMR endometrial cancer, comprising a pharmaceutical composition comprising an anti-PD-L1 antibody; in some embodiments, the The kit further includes instructions for treating endometrial cancer.
  • the application provides a kit for treating endometrial cancer, comprising: an anti-PD-L1 antibody; and anlotinib or a pharmaceutically acceptable salt thereof; in some embodiments, an anti-PD-L1 antibody
  • the -L1 antibody is contained in the first compartment
  • Anlotinib or a pharmaceutically acceptable salt thereof is contained in the second compartment, and can be administered to a patient in need thereof simultaneously, sequentially or sequentially.
  • the kit further comprises instructions for the combined use of an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof for the treatment of endometrial cancer.
  • the kit includes: a pharmaceutical composition of an anti-PD-L1 antibody; and a pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof.
  • the 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 its A pharmaceutically acceptable salt, wherein: an anti-PD-L1 antibody is contained in a first compartment, and Anlotinib or a pharmaceutically acceptable salt thereof is contained in a second compartment, simultaneously, sequentially or sequentially Give to patients in need.
  • the kit further comprises instructions for the combined use of an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof for the treatment of non-MSI-H endometrial cancer and/or non-dMMR endometrial cancer.
  • the kit includes: a pharmaceutical composition of an anti-PD-L1 antibody; and a pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof.
  • the application provides a kit for treating MSI-H and/or dMMR tumors, comprising an anti-PD-L1 antibody; in some embodiments, the kit further comprises treating MSI-H and/or dMMR Tumor description. In some embodiments, the application provides kits for treating MSI-H and/or dMMR malignancies, comprising an anti-PD-L1 antibody; in some embodiments, the kit further comprises treating MSI-H and /or dMMR malignancy description.
  • kits for treating MSI-H and/or dMMR malignant solid tumors comprising an anti-PD-L1 antibody; in some embodiments, the kit further comprises treating MSI-H and/or description of dMMR malignant solid tumors.
  • the present application provides a kit for treating MSI-H and/or dMMR tumors, comprising a pharmaceutical composition containing an anti-PD-L1 antibody; in some embodiments, the kit further comprises treating MSI-H and /or dMMR tumor description. In some embodiments, the present application provides kits for the treatment of MSI-H and/or dMMR malignancies 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 malignancies. In some embodiments, the present 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.
  • the amount of anti-PD-L1 antibody administered, and the dosing regimen can be determined according to the severity of the disease, the response of the disease, any treatment-related toxicity, and the age and health status of the patient.
  • the daily dose of anti-PD-L1 antibody administered may be 600-2400 mg, and in some embodiments, the daily dose of anti-PD-L1 antibody may be administered at 600, 800, 1000, 1200, 1400, 1600, 1800, 2000, 2200, 2400 mg.
  • the anti-PD-L1 antibody is administered parenterally.
  • the anti-PD-L1 antibody is administered intravenously.
  • the anti-PD-L1 antibody is administered at a concentration of 10-60 mg/mL.
  • the anti-PD-L1 antibody is administered at a concentration of 10, 20, 30, 40, 50, or 60 mg/mL. In some embodiments, for an anti-PD-L1 antibody, every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks is a treatment cycle. In some embodiments, the anti-PD-L1 antibody is administered once per treatment cycle. In some embodiments, the anti-PD-L1 antibody is administered weekly, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, for anti-PD-L1 antibodies, every 3 weeks is a treatment cycle. In some embodiments, the anti-PD-L1 antibody is administered every 3 weeks, or every 4 weeks.
  • 600-2400 mg of anti-PD-L1 antibody is administered per treatment cycle.
  • the anti-PD-L1 antibody is administered at a dose of 600, 800, 1000, 1200, 1400, 1600, 1800, 2000, 2200 or 2400 mg per treatment cycle.
  • the anti-PD-L1 antibody is administered at a dose of 1200 mg per treatment cycle.
  • the anti-PD-L1 antibody is administered on the first day of each treatment cycle.
  • every 3 weeks is a treatment cycle.
  • the anti-PD-L1 antibody is administered every three weeks at a dose of 600-2400 mg per administration.
  • 3 weeks (21 days) is a treatment cycle, and the anti-PD-L1 antibody is administered to a patient in need thereof on the first day of each treatment cycle.
  • the anti-PD-L1 antibody is administered on the first day of every three weeks at a dose of 600-2400 mg per administration.
  • the anti-PD-L1 antibody is administered at a dose of 1200 mg on the first day of every three weeks.
  • the pharmaceutical combination described herein comprises: an anti-PD-L1 humanized monoclonal antibody and anlotinib or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition further contains a pharmaceutically acceptable carrier.
  • the pharmaceutical combination comprises: a pharmaceutical composition containing 600-2400 mg of anti-PD-L1 antibody, wherein the pharmaceutical composition of anti-PD-L1 antibody is a unit dose or multiple doses.
  • the pharmaceutical combination comprises: a pharmaceutical composition with a unit dose of 6 mg, 8 mg, 10 mg, and/or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination comprises: 600-2400 mg of the anti-PD-L1 antibody provided in multiple doses of the pharmaceutical composition and unit doses of 6 mg, 8 mg, 10 mg and/or 12 mg of anlotinib or its pharmaceutically acceptable Pharmaceutical compositions of acceptable salts.
  • the pharmaceutical combination is a formulation suitable for administration in a single treatment cycle (eg, a treatment cycle of 21 days) comprising a pharmaceutical composition of 600-2400 mg of anti-PD-L1 antibody and 84-168 mg of Anro A pharmaceutical composition of tinib or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof described in the present application comprises: a weight ratio of (0.35-29): 1, (3.5-29 ):1, (3.5-14.5):1, or (7-14.5):1 anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof.
  • the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof may be packaged separately or together.
  • Anlotinib can be packaged in multiple aliquots (eg, 2 aliquots, 7 aliquots, 14 aliquots, 28 aliquots or more); anti-PD-L1 antibodies can be packaged in a single aliquot or multiple aliquots aliquots (eg, 2 aliquots, 4 aliquots, or more) are packaged.
  • the anti-PD-L1 antibody and anlotinib or its pharmacy each of the above acceptable salts is in the form of a pharmaceutical composition which can be administered simultaneously, sequentially or sequentially.
  • the pharmaceutical combination of an anti-PD-L1 antibody described herein and anlotinib or a pharmaceutically acceptable salt thereof includes a pharmaceutical composition of an anti-PD-L1 antibody and anlotinib A drug, wherein the anti-PD-L1 antibody is prepared as a unit dose or multiple doses of 600-2400 mg of the anti-PD-L1 antibody suitable for first administration to the patient, said anlotinib or a pharmaceutically acceptable form thereof
  • the pharmaceutical composition of the salt is prepared as a unit dose suitable for daily administration to a patient of 6 mg, 8 mg, 10 mg and/or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof for 14 consecutive days.
  • the pharmaceutical combination of an anti-PD-L1 antibody described herein and anlotinib or a pharmaceutically acceptable salt thereof comprises: an anti-PD-L1 antibody concentration of 10-60 mg/mL of an anti-PD-L1 antibody
  • the pharmaceutical composition of L1 antibody, and the pharmaceutical composition of the unit dose of 6 mg, 8 mg, 10 mg and/or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof comprises:
  • the pharmaceutical combination of the anti-PD-L1 antibody described herein and anlotinib or a pharmaceutically acceptable salt thereof comprises: a pharmaceutical composition in which 1200 mg of the anti-PD-L1 antibody is provided in multiple doses , and a pharmaceutical composition with a unit dose of 8 mg, 10 mg and/or 12 mg of Anlotinib or a pharmaceutically acceptable salt thereof.
  • the kit is a kit suitable for administration in a single treatment cycle (eg, a treatment cycle of 21 days), comprising a pharmaceutical composition comprising 600-2400 mg of an anti-PD-L1 antibody and a A pharmaceutical composition of 84-168 mg of anlotinib or a pharmaceutically acceptable salt thereof.
  • a method of treating non-MSI-H and/or non-dMMR endometrial cancer comprising: administering to a patient in need thereof a therapeutically effective amount of an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof.
  • the anti-PD-L1 antibody and anlotinib, or a pharmaceutically acceptable salt thereof are administered simultaneously, sequentially, or sequentially.
  • the anti-PD-L1 antibody is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks.
  • the anti-PD-L1 antibody is administered at a dose of 600-2400 mg per dose.
  • the single administered dose of the anti-PD-L1 antibody is 600, 800, 1000, 1200, 1400, 1600, 1800, 2000, 2200, or 2400 mg.
  • anlotinib or a pharmaceutically acceptable salt thereof is administered in a daily dose of 6 mg-12 mg.
  • anlotinib or a pharmaceutically acceptable salt thereof is administered in a daily dose of 8 mg-12 mg.
  • anlotinib or a pharmaceutically acceptable salt thereof is administered in a daily dose of 6 mg, 8 mg, 10 mg, or 12 mg.
  • anlotinib or a pharmaceutically acceptable salt thereof is administered at a dose of 6 mg, 8 mg, 10 mg, or 12 mg once daily.
  • anlotinib or a pharmaceutically acceptable salt thereof is administered in a dosing regimen of 2 weeks on and 1 week off. In some embodiments, every 3 weeks is a treatment cycle. In some embodiments, 21 days is a treatment cycle, and the anti-PD-L1 antibody is administered to the patient on the first day of each treatment cycle. In some embodiments, every 3 weeks is a treatment cycle, 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 the first-day of each cycle 14 days of dosing. In some embodiments, the anti-PD-L1 antibody is administered parenterally.
  • the concentration of the pharmaceutical composition of anti-PD-L1 antibody is 10-60 mg/mL; in some embodiments, the concentration of the pharmaceutical composition of anti-PD-L1 antibody is 10, 20, 30, 40, 50 or 60 mg/mL. In some embodiments, anlotinib or a pharmaceutically acceptable salt thereof is administered orally.
  • the present application provides a method for treating endometrial cancer, comprising: (1) obtaining or having obtained a biological sample of a patient; (2) detecting or having detected the biological sample, Determine whether the sample is MSI-H and/or dMMR; (3) If the test result is MSI-H and/or dMMR, administer a therapeutically effective amount of anti-PD-L1 antibody or a drug combination containing anti-PD-L1 antibody to the patient and (4) if the test result is non-MSI-H and/or non-dMMR, then administer a therapeutically effective amount of anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof to the patient.
  • the present application provides a method for treating MSI-H and/or dMMR tumors, comprising: (1) obtaining or having obtained a biological sample of a patient; (2) testing the biological sample or having performed a biological sample on the biological sample Tested to determine whether the sample is MSI-H or dMMR; and (3) if the test results are MSI-H or dMMR, administer a therapeutically effective amount of anti-PD-L1 antibody or a drug containing anti-PD-L1 antibody to the patient combination.
  • Anlotinib 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy base]methyl]cyclopropylamine, which has the following structural formula:
  • the pharmaceutically acceptable salts of Anlotinib include but are not limited to salts of Anlotinib and 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, cyclopentane propionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamon 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 , Tri
  • anlotinib or a pharmaceutically acceptable salt thereof referred to in this application are based on the molecular weight of the anlotinib free base.
  • Anlotinib or a pharmaceutically acceptable salt thereof can be administered by a variety of routes including parenteral as well as parenteral routes, including but not limited to oral, intravenous, intraarterial, transdermal , sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vaginal, intraocular, subcutaneous, intrafat, intraarticular, intraperitoneal and intrathecal. In some specific embodiments, administration is by oral route.
  • the amount of anlotinib, or a pharmaceutically acceptable salt thereof, to be administered can be determined based on the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health status of the patient.
  • a daily dose of anlotinib or a pharmaceutically acceptable salt thereof may be administered from 2 mg to 20 mg.
  • the daily dose of anlotinib or a pharmaceutically acceptable salt thereof administered may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16 mg.
  • Anlotinib or a pharmaceutically acceptable salt thereof may be administered one or more times daily.
  • anlotinib or a pharmaceutically acceptable salt thereof is administered once daily in an oral solid formulation.
  • the dosage regimen of anlotinib or a pharmaceutically acceptable salt thereof can be comprehensively determined according to the activity of the drug, the toxicity, and the patient's tolerance.
  • anlotinib or a pharmaceutically acceptable salt thereof is administered in spaced dosing.
  • the said interval administration includes a dosing period and a withdrawal period, during which anlotinib or a pharmaceutically acceptable salt thereof can be administered once or more times per day.
  • the ratio in days of the dosing period and the dosing period is 2:(0.5-5), 2:(0.5-3), 2:(0.5-2), or 2:(0.5-1).
  • the dosing is for 2 consecutive weeks and the drug is off for 2 weeks.
  • 2 consecutive weeks of dosing are administered for 1 week off.
  • 5 consecutive days of administration are administered for 2 days off.
  • anlotinib or a pharmaceutically acceptable salt thereof can be administered orally at a dose of 6 mg, 8 mg, 10 mg, or 12 mg once a day, continuously for 2 weeks, and then for 1 week off.
  • the unit dose of the pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof comprises 6 mg, 8 mg, 10 mg, or 12 mg of anlotinib.
  • the total dose of the pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof administered in each cycle comprises 84-168 mg according to a treatment cycle of 2 weeks of administration and 1 week of rest .
  • the total dose of the pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof comprises a range selected from the group consisting of 84 mg, 112 mg, 140 mg, 168 mg or any of the above values.
  • the total dose of the pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof comprises 112 mg-168 mg.
  • the pharmaceutical compositions include, but are not limited to, formulations suitable for oral, 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, tablets, capsules.
  • the anti-PD-L1 antibody is an anti-PD-L1 humanized monoclonal antibody.
  • the anti-PD-L1 antibody is an antibody in WO2016022630 or CN107001463A.
  • the anti-PD-L1 antibody comprises an amino acid sequence that is at least 80% (eg, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the heavy chain CDR1 region; at least 80% (eg 81%, 82%, 83%, 84%, 85%) with the amino acid sequence shown in SEQ ID NO: 2 or SEQ ID NO: 5 , 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology Heavy chain CDR2 region; at least 80% (e.g.
  • amino acid sequence shown in SEQ ID NO:3 or SEQ ID NO:6 % 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the heavy chain CDR3 region; with SEQ ID
  • the amino acid sequence shown in NO:7 or SEQ ID NO:10 has at least 80% (e.g.
  • the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain CDR1 region selected from SEQ ID NO:1 or SEQ ID NO:4; selected from SEQ ID NO:2 or SEQ ID The heavy chain CDR2 region of NO:5; selected from the heavy chain CDR3 region of SEQ ID NO:3 or SEQ ID NO:6; selected from the light chain CDR1 region of SEQ ID NO:7 or SEQ ID NO:10; selected from SEQ ID NO:10 The light chain CDR2 region of ID NO: 8 or SEQ ID NO: 11; selected from the light chain CDR3 region of SEQ ID NO: 9 or SEQ ID NO: 12.
  • 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, having the region set forth in SEQ ID NO:2
  • the heavy chain CDR2 region of the amino acid sequence has the heavy chain CDR3 region of the amino acid sequence shown in SEQ ID NO: 3
  • the light chain CDR1 region with the amino acid sequence shown in SEQ ID NO: 7 has the amino acid sequence shown in SEQ ID NO: 7.
  • the light chain CDR2 region of the amino acid sequence shown in SEQ ID NO: 8 has the light chain CDR3 region of the amino acid sequence shown in SEQ ID NO: 9.
  • Each of the CDR regions described herein and the various variants described above can specifically recognize and bind to PD-L1, thereby effectively blocking the signaling between PD-L1 and PD-1.
  • the anti-PD-L1 antibody comprises an amino acid sequence that is at least 80% (eg, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the heavy chain variable region; 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 heavy chain variable region; at least 80% (e.g.
  • the anti-PD-L1 antibody comprises the following amino acid sequences: heavy chain variable region shown in SEQ ID NO:13; light chain variable region shown in SEQ ID NO:15 .
  • the anti-PD-L1 antibody comprises the following amino acid sequences: heavy chain variable region shown in SEQ ID NO: 14; light chain variable region shown in SEQ ID NO: 16 .
  • the anti-PD-L1 antibody comprises the following amino acid sequences: the heavy chain amino acid sequence shown in SEQ ID NO: 17; the light chain amino acid sequence shown in SEQ ID NO: 18.
  • the anti-PD-L1 antibody comprises the following amino acid sequences: heavy chain amino acid sequence as shown in SEQ ID NO: 19; light chain amino acid sequence as shown in SEQ ID NO: 20.
  • the anti-PD-L1 antibody comprises the following amino acid sequences: the heavy chain amino acid sequence shown in SEQ ID NO:21; the light chain amino acid sequence shown in SEQ ID NO:18.
  • the anti-PD-L1 humanized monoclonal antibody provided in this application comprises a monoclonal antibody 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, SEQID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, one of 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, SEQ ID NO:21 or more conservative substitution variants.
  • the anti-PD-L1 humanized monoclonal antibody comprising the conservative substitution variant retains the ability to specifically recognize and bind to PD-L1.
  • the anti-PD-L1 antibody may be an IgG1 or IgG4 antibody.
  • the anti-PD-L1 antibody is an IgG1 antibody. In some embodiments, the anti-PD-L1 antibody is a glycosylated IgG1 antibody.
  • the anti-PD-L1 antibody comprises a heavy chain complementarity determining region (CDR) selected from a 13C5 or 5G11 antibody, and a light chain complementarity determining region selected from a 13C5 or 5G11 antibody.
  • CDR heavy chain complementarity determining region
  • the anti-PD-L1 antibody described herein comprises a variable heavy chain selected from the group consisting of ch5G11-hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, ch13C5-hIgG4 chimeric antibodies, and is selected from the group consisting of ch5G11-hIgG1, Variable light chains of ch5G11-hlgG4, ch13C5-hlgG1, ch13C5-hlgg4 chimeric antibodies.
  • the anti-PD-L1 antibody described herein comprises a variable heavy chain selected from the group consisting of hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4 humanized antibody, and is selected from hu13C5-hIgG1 , hu13C5-hlgg4, hu5G11-hlgG1 or hu5G11-hlgg4 humanized antibody variable light chain.
  • the HCDR1 sequence of 13C5, ch13C5-hIgG1, ch13C5-hIgG4, hu13C5-hIgG1 or hu13C5-hIgG4 is SYGMS (SEQ ID NO: 4), and the HCDR2 sequence is SISSGGSTYYPDSVKG (SEQ ID NO: 5 ), the HCDR3 sequence is GYDSGFAY (SEQ ID NO: 6), the LCDR1 sequence is ASQSVSTSSSSFMH (SEQ ID NO: 10), the LCDR2 sequence is YASNLES (SEQ ID NO: 11), and the LCDR3 sequence is QHSWEIPYT (SEQ ID NO: 12);
  • the anti-PD-L1 antibodies in the pharmaceutical combination may be selected from one or more.
  • the term "plurality" can be more than one, eg, two, three, four, five or more.
  • the anti-PD-L1 antibody is selected from a group comprising a heavy chain variable region as set forth in SEQ ID NO:13 and a light chain variable region as set forth in SEQ ID NO:15 , or selected from the group comprising a heavy chain variable region as shown in SEQ ID NO: 14 and a light chain variable region as shown in SEQ ID NO: 16, or selected from a combination of the above.
  • the anti-PD-L1 antibody is selected from the heavy chain amino acid sequence shown in SEQ ID NO: 17 and the light chain amino acid sequence shown in SEQ ID NO: 18, or is selected from the amino acid sequence shown in SEQ ID NO: 19
  • the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain CDR1 region having at least 80% homology to the amino acid sequence set forth in SEQ ID NO:1 or SEQ ID NO:4; Heavy chain CDR2 region with at least 80% homology to the amino acid sequence shown in SEQ ID NO: 2 or SEQ ID NO: 5; at least 80% homology with the amino acid sequence shown in SEQ ID NO: 3 or SEQ ID NO: 6
  • the heavy chain CDR3 region; the light chain CDR1 region with at least 80% homology with the amino acid sequence shown in SEQ ID NO: 7 or SEQ ID NO: 10; shown in SEQ ID NO: 8 or SEQ ID NO: 11 The amino acid sequence has at least 80% homology in the light chain CDR2 region; and the amino acid sequence shown in SEQ ID NO: 9 or SEQ ID NO: 12 has at least 80% homology in the light chain CDR3 region.
  • the pharmaceutical composition of the anti-PD-L1 antibody contains 600-2400 mg of the anti-PD-L1 antibody.
  • the pharmaceutical composition of the anti-PD-L1 antibody contains an anti-PD-L1 antibody selected from the range of 600 mg, 900 mg, 1200 mg, 1500 mg, 1800 mg, 2100 mg, 2400 mg, or any of the above values.
  • the pharmaceutical composition of the anti-PD-L1 antibody contains 600-2100 mg, or 900 mg-1500 mg of the anti-PD-L1 antibody; wherein the pharmaceutical composition of the anti-PD-L1 antibody can be multiple doses or unit doses form exists.
  • the pharmaceutical composition of the anti-PD-L1 antibody contains 300 mg, 600 mg or 1200 mg of the anti-PD-L1 antibody. In some embodiments of the present application, there is provided a pharmaceutical composition formulated as a unit dose of an anti-PD-L1 antibody containing 300 mg, 600 mg, or 1200 mg of an anti-PD-L1 antibody.
  • the pharmaceutical composition of the anti-PD-L1 antibody is a solution for injection. In some embodiments, the pharmaceutical composition of the anti-PD-L1 antibody is an aqueous solution for injection. In some embodiments of the present application, the pharmaceutical composition of the anti-PD-L1 antibody comprises one or more of buffers, isotonicity modifiers, stabilizers and/or surfactants. In particular, the pharmaceutical composition of the anti-PD-L1 antibody comprises 1-150 mg/mL anti-PD-L1 antibody (eg monoclonal antibody), 3-50 mM buffer, 2-150 mg/mL isotonicity modifier/stabilizer and 0.01-0.8 mg/mL surfactant and pH 4.5-6.8.
  • the pharmaceutical composition of the anti-PD-L1 antibody is calculated on a w/v basis, and the concentration of the anti-PD-L1 monoclonal antibody is 5-150 mg/mL; in some embodiments, it is 10-60 mg/mL mL; in some embodiments 10-30 mg/mL.
  • the mass volume concentration of anti-PD-L1 monoclonal antibody is 10mg/mL, 20mg/mL, 30mg/mL, 40mg/mL, 50mg/mL, 60mg/mL, 70mg/mL, 80mg/mL, 90mg/mL 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; in some embodiments , at 10 mg/mL, 20 mg/mL or 30 mg/mL.
  • the mass volume concentration of the anti-PD-L1 mAb is 10 mg/mL. In other embodiments, the mass volume concentration of anti-PD-L1 monoclonal antibody is 30 mg/mL. In other embodiments, the mass volume concentration of anti-PD-L1 monoclonal antibody is 60 mg/mL.
  • the buffer is a histidine buffer.
  • the histidine buffer concentration is 5-30 mM; in some embodiments, 10-25 mM; in some embodiments, 10-20 mM; in some embodiments, 10-15 mM.
  • the histidine buffer concentration is 5 mM, 10 mM, 15 mM, 20 mM, 25 mM or 30 mM.
  • the histidine buffer concentration is 10 mM.
  • the histidine buffer concentration is 15 mM.
  • the histidine buffer concentration is 20 mM.
  • the histidine buffer contains histidine and hydrochloric acid.
  • the isotonicity modifier/stabilizer is 20-150 mg/mL sucrose; in some embodiments, 40-100 mg/mL sucrose; in some In embodiments, 60-80 mg/mL of sucrose.
  • the concentration of sucrose is 40 mg/mL, 50 mg/mL, 60 mg/mL, 70 mg/mL, 80 mg/mL, 90 mg/mL, or 100 mg/mL.
  • the concentration of sucrose is 60 mg/mL.
  • the concentration of sucrose is 70 mg/mL.
  • the concentration of sucrose is 80 mg/mL.
  • the concentration of sucrose is 90 mg/mL.
  • the surfactant is selected from polysorbate 80, polysorbate 20, poloxamer 188; in some embodiments, from polysorbate 80 or polysorbate 20; In some embodiments, selected from polysorbate 80.
  • the concentration of the surfactant is 0.05-0.6 mg/mL on a w/v basis; in some embodiments, 0.1-0.4 mg/mL; in some embodiments, 0.2-0.3 mg/mL.
  • the surfactant is 0.01-0.8 mg/mL polysorbate 80 or polysorbate 20 on a w/v basis.
  • the surfactant is 0.05-0.6 mg/mL polysorbate 80; in some embodiments, 0.1-0.4 mg/mL polysorbate 80; in some embodiments, is 0.2-0.3 mg/mL polysorbate 80; in some embodiments, 0.2 mg/mL polysorbate 80.
  • the amount 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.
  • the amount 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 amount of polysorbate 80 in the pharmaceutical composition is 0.2 mg/mL, 0.3 mg/mL, or 0.4 mg/mL. In some embodiments, the polysorbate 80 content in the pharmaceutical composition is 0.2 mg/mL. In some embodiments, the polysorbate 80 content in the pharmaceutical composition is 0.1 mg/mL. In other embodiments, the polysorbate 80 content in the pharmaceutical composition is 0.2 mg/mL. In some embodiments, the polysorbate 80 content in the pharmaceutical composition is 0.3 mg/mL. In other embodiments, the polysorbate 80 content in the pharmaceutical composition is 0.4 mg/mL. In some embodiments, the polysorbate 80 content in the pharmaceutical composition is 0.5 mg/mL.
  • the pH of the aqueous solution of the pharmaceutical composition is selected from the group consisting of 4.0-6.8; in some embodiments, 4.5-6.5; in some embodiments, 5.5-6.0; in some embodiments medium, 5.5.
  • the pH of the aqueous 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; in In some embodiments, it is 5.5.
  • the pH of the aqueous pharmaceutical composition is 5.0.
  • the pH of the aqueous pharmaceutical composition is 5.2.
  • the pH of the aqueous pharmaceutical composition is 5.4. In some embodiments, the pH of the aqueous pharmaceutical composition is 5.5. In some embodiments, the pH of the aqueous pharmaceutical composition is 5.6. In some embodiments, the pH of the aqueous pharmaceutical composition is 5.8. In some embodiments, the pH of the aqueous pharmaceutical composition is 6.0.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody at a concentration of 20 mg/mL by volume, (b) sucrose at a concentration of 70 mg/mL by volume, (c) Polysorbate 80 with a mass volume concentration of 0.1 mg/mL, (d) histidine with a molar concentration of 20 mM, and (e) optionally an appropriate amount of hydrochloric acid, to adjust the pH of the composition to 5.0.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 monoclonal antibody with a mass/volume concentration of 20 mg/mL, (b) sucrose with a mass/volume concentration of 70 mg/mL, (c) Polysorbate 80 with a mass volume concentration of 0.1 mg/mL, (d) histidine with a molar concentration of 20 mM, and (e) optionally an appropriate amount of hydrochloric acid, to adjust the pH of the composition to 5.0.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody at a concentration of 10 mg/mL by volume, (b) sucrose at a concentration of 80 mg/mL by volume, (c) ) polysorbate 80 with a mass volume concentration of 0.2 mg/mL, (d) histidine with a molar concentration of 10 mM, (e) optionally an appropriate amount of hydrochloric acid, and adjusting the pH of the composition to 5.5.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody at a concentration of 50 mg/mL by volume, (b) sucrose at a concentration of 80 mg/mL by volume, (c) ) polysorbate 80 with a mass volume concentration of 0.3 mg/ml, (d) histidine with a molar concentration of 10 mM, (e) optionally an appropriate amount of hydrochloric acid, and adjusting the pH of the composition to 5.5.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody at a concentration of 100 mg/mL by volume, (b) sucrose at a concentration of 80 mg/mL by volume, (c) ) polysorbate 80 with a mass volume concentration of 0.5 mg/mL, (d) histidine with a molar concentration of 10 mM, (e) optionally an appropriate amount of hydrochloric acid, and adjusting the pH of the composition to 5.5.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody at a concentration of 30 mg/mL by volume, (b) sucrose at a concentration of 80 mg/mL by volume, (c) ) polysorbate 80 with a mass volume concentration of 0.2 mg/mL, (d) histidine with a molar concentration of 10 mM, (e) optionally an appropriate amount of hydrochloric acid, and adjusting the pH of the composition to 5.5.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody at a concentration of 60 mg/mL by volume, (b) sucrose at a concentration of 80 mg/mL by volume, (c) ) polysorbate 80 with a mass volume concentration of 0.2 mg/mL, (d) histidine with a molar concentration of 10 mM, (e) optionally an appropriate amount of hydrochloric acid, and adjusting the pH of the composition to 5.5.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody at a concentration of 10 mg/mL by volume, (b) sucrose at a concentration of 70 mg/mL by volume, (c) ) polysorbate 80 with a mass volume concentration of 0.4 mg/mL, (d) histidine with a molar concentration of 20 mM, (e) optionally an appropriate amount of acetic acid, and adjusting the pH of the composition to 6.5.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 monoclonal antibody with a mass/volume concentration of 10 mg/mL, (b) sucrose with a mass/volume concentration of 80 mg/mL, ( c) polysorbate 80 with a mass volume concentration of 0.2 mg/mL, (d) histidine with a molar concentration of 20 mM, (e) optionally an appropriate amount of hydrochloric acid, and adjusting the pH of the composition to 5.5.
  • the pharmaceutical composition is a water-soluble injection.
  • the water-soluble injections include, but are not limited to, water-soluble formulations without lyophilization or water-soluble formulations reconstituted with lyophilized powder.
  • the pharmaceutical composition is a lyophilized formulation.
  • the lyophilized formulation refers to a formulation in which an aqueous solution undergoes a lyophilization process, in which the substance is first frozen, then the amount of solvent is reduced first by sublimation (primary drying process), and then the amount of solvent is reduced by desorption (secondary drying). process) until the amount of solvent is at a value that no longer supports biological activity or chemical reaction.
  • the lyophilized formulations of the present application can also be dried by other methods known in the art, such as spray drying and bubble drying.
  • the endometrial cancer includes, but is not limited to, type I (estrogen-dependent) endometrial cancer or type II (estrogen-independent) endometrial cancer.
  • the endometrial cancer is advanced endometrial cancer. In some embodiments of the present application, the endometrial cancer is refractory endometrial cancer.
  • the endometrial cancer is recurrent and/or metastatic endometrial cancer.
  • the endometrial cancer is recurrent and/or metastatic advanced endometrial cancer.
  • the non-microsatellite unstable hypermutant (non-MSI-H) endometrial cancer comprises microsatellite low-grade instability (MSI-L) endometrial cancer and microsatellite stable type (MSS) endometrial cancer.
  • the non-mismatch repair deficient (non-dMMR) endometrial cancer comprises mismatch repair intact (pMMR) endometrial cancer.
  • the patient with endometrial cancer has been treated with one or more drugs.
  • the endometrial cancer is endometrial cancer that has failed at least one drug therapy.
  • the treatment failure includes disease progression during treatment, and disease progression and/or relapse after treatment ends.
  • the patient with endometrial cancer has received one or more chemotherapy treatments.
  • the endometrial cancer is endometrial cancer that has failed at least one chemotherapy treatment.
  • the treatment failure includes disease progression or no objective response during treatment, and disease progression and/or relapse after treatment ends.
  • the patient with endometrial cancer has previously received 1-2 lines of standard systemic chemotherapy regimens, and the treatment has failed or cannot be tolerated.
  • the drug therapy includes but is not limited to chemotherapy, targeted drug therapy and hormone therapy.
  • the chemotherapy includes but is not limited to taxanes, vinblastine antineoplastics, platinum complexes, fluorouracil and its derivatives, camptothecin and its derivatives, anthracyclines , one or more of the podophyllotoxins.
  • the taxanes include but are not limited to one or more of paclitaxel, albumin-bound paclitaxel and docetaxel (docetaxel);
  • the vinblastine antitumor drugs include but are not limited to One or more selected from vinblastine, vincristine, vindesine, vinorelbine, vinflunine, norvinblastine;
  • the platinum complexes include but are not limited to selected from meplatin , one or more of cisplatin, carboplatin, bicycloplatin, nedaplatin, oxaliplatin, Lobaplatin, triplatinum tetranitrate, phenanthroplatin, picoplatin, satraplatin;
  • the fluorouracil and Its derivatives include, but are not limited to, cytarabine, azacitidine, amcitabine, capecitabine, gemcitabine, fluorouracil, difurfluorouracil, deoxyfluridine, trifluridine, t
  • the targeted drugs include but are not limited to EGFR antagonists, VEGF inhibitors, HER2 inhibitors, PARP inhibitors, PI3K/Akt/mTOR pathway inhibitors, PD-1/PD-L1 Inhibitors, or one or more of FGFR inhibitors.
  • the EGFR antagonists include, but are not limited to, trastuzumab, cetuximab, icotinib, gefitinib ), one or more of erlotinib and lapatinib.
  • the VEGF inhibitor includes, but is not limited to, bevacizumab, ranibizumab, axitinib, motesanib , aflibercept, cediranib, nintedanib, sorafenib, or sunitinib.
  • the PARP inhibitor includes, but is not limited to, one or more of olaparib, niraparib, or rucaparib.
  • the PI3K/Akt/mTOR pathway inhibitors include but are not limited to NVP-BKM120, XL147, perifosine, rapamycin, temsirolimus ( temsirolimus), everolimus, sirolimus, or one or more of ridaforolimus.
  • the PD-1/PD-L1 inhibitor includes, but is not limited to, atezolizumab, nivolumab, or pembrolizumab ) one or more of.
  • the FGFR inhibitor includes, but is not limited to, dovitinib, or NVP-BGJ398.
  • the hormone therapy drugs include, but are not limited to, one or more of progestins, antiestrogens, aromatase inhibitors.
  • the progestin drugs include, but are not limited to, progesterone, megestrol acetate, clodrogesterone, medroxyprogesterone acetate, hydroxyprogesterone acetate, hydroxyprogesterone caproate, of cyproterone acetate, dydrogesterone, demegesterone, primegestrel, linegestrol, norethisterone, levonorgestrel, desogestrel, dienogest, or drospirenone one or more.
  • the anti-estrogen drugs include, but are not limited to, clomiphene, tamoxifen, toremifene, raloxifene, triptorelin, leuprolide, or One or more of goserelin.
  • the aromatase inhibitors include, but are not limited to, aminoglutamine, formestane, exemestane, letrozole, anastrozole, loglutimide ( Rogletimide), or one or more of Fadrozole.
  • 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.
  • MSI-H and/or dMMR tumors described in this application are based on the detection results of biomarkers, such as shown as MSI-H and/or dMMR, without limiting the type of tumor.
  • the solid tumors do not include hematologic/blood tumors.
  • the tumor includes, but is not limited to, breast cancer (eg, hormone receptor positive breast cancer, triple negative breast cancer, HER2/neu positive or negative breast cancer), digestive system/gastrointestinal tumors (for example, anal cancer, appendix cancer, cholangiocarcinoma, gastrointestinal stromal tumor, gastrointestinal carcinoid, colorectal cancer, gastric cancer, esophageal cancer, gallbladder cancer, bile duct cancer, liver cancer, pancreatic cancer, islet cell tumor, pancreatic neuroendocrine tumor ), endocrine and neuroendocrine cancers (e.g. adrenocortical, thyroid, skin neuroendocrine, parathyroid), eye, genitourinary (e.g.
  • breast cancer eg, hormone receptor positive breast cancer, triple negative breast cancer, HER2/neu positive or negative breast cancer
  • digestive system/gastrointestinal tumors for example, anal cancer, appendix cancer, cholangiocarcinoma, gastrointestinal stromal tumor, gastrointestinal carcinoid,
  • gynecological cancer eg endometrial cancer, ovarian cancer, cervical cancer, fallopian tube cancer, primary peritoneal cancer, vaginal cancer, vulvar cancer
  • head and neck cancer eg hypopharyngeal cancer, laryngeal cancer
  • lip and oral cavity cancer oral cavity cancer, nasopharyngeal cancer, oropharyngeal cancer, paranasal sinus and nasal cavity cancer, pharyngeal cancer, salivary gland cancer, throat cancer
  • respiratory system cancer such as 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 cutaneous squamous cell carcinoma, melanoma
  • nervous system tumors e.g. brain cancer, glioblastoma, neuroblastoma
  • the malignancy includes, but is not limited to, breast cancer (eg, hormone receptor positive breast cancer, triple negative breast cancer, HER2/neu positive or HER2/neu negative breast cancer), digestive system cancer/ Gastrointestinal cancer (eg, 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 Carcinomas and neuroendocrine cancers (e.g. adrenal cortex, thyroid, skin neuroendocrine tumors, parathyroid glands), eye cancers, genitourinary cancers (e.g.
  • breast cancer eg, hormone receptor positive breast cancer, triple negative breast cancer, HER2/neu positive or HER2/neu negative breast cancer
  • Gastrointestinal cancer eg, anal cancer, appendix cancer, bile duct cancer, gastrointestinal stromal tumor, gastrointestinal carcinoid,
  • gynecological cancers e.g. endometrial, ovarian, cervical, fallopian tube, primary peritoneal, vaginal, vulvar
  • head and neck cancers e.g.
  • hypopharyngeal, laryngeal, lip and oral cavity cancer cancer, oral cancer, nasopharyngeal cancer, oropharyngeal cancer, paranasal sinus cancer and nasal cavity cancer, pharyngeal cancer, salivary gland cancer, throat cancer), respiratory system cancer (such as 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, cutaneous squamous cell carcinoma, melanoma), nervous system malignancies (e.g.
  • brain cancer glioblastoma, neuroblastoma, One or more of primary central nervous system lymphoma), bone cancer, soft tissue sarcoma, Hematologic/Blood cancer (eg, Leukemia, Lymphoma).
  • the MSI-H and/or dMMR tumor is cervical cancer (including but not limited to cervical squamous cell carcinoma, cervical adenocarcinoma). In some embodiments of the present application, the MSI-H and/or dMMR tumor is hepatobiliary cancer (including but not limited to liver cancer, gallbladder cancer, 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).
  • the MSI-H and/or dMMR tumor is urothelial cancer (including but not limited to bladder cancer, urethral cancer).
  • the MSI-H and/or dMMR tumor is lung cancer (eg, small cell lung cancer, non-small cell lung cancer (including but not limited to lung squamous cell carcinoma, lung adenocarcinoma)).
  • the MSI-H and/or dMMR tumor is leukemia (including but not limited to acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia).
  • the MSI-H and/or dMMR tumor is a lymphoma (including but not limited to Hodgkin's lymphoma, primary mediastinal large B-cell lymphoma). In some embodiments of the present application, the MSI-H and/or dMMR tumor is colorectal cancer.
  • the tumor is an advanced and/or metastatic tumor. In some embodiments of the present application, the tumor is a refractory and/or relapsed tumor.
  • the MSI-H and/or dMMR malignancy is an advanced 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.
  • the MSI-H and/or dMMR malignancy is a recurrent and/or metastatic MSI-H and/or dMMR malignancy.
  • the MSI-H and/or dMMR malignancy is a recurrent and/or metastatic advanced MSI-H and/or dMMR malignancy.
  • the solid tumors of MSI-H and/or dMMR include but are not limited to breast cancer (eg, hormone receptor positive breast cancer, triple negative breast cancer, HER2/neu positive or negative breast cancer) breast cancer), digestive system/gastrointestinal tumors (e.g. anal cancer, appendix cancer, cholangiocarcinoma, gastrointestinal stromal tumor, gastrointestinal carcinoid, colorectal cancer, gastric cancer, esophagus cancer, gallbladder cancer, bile duct cancer, liver cancer , pancreatic cancer, islet cell tumors, pancreatic neuroendocrine tumors), endocrine system tumors and neuroendocrine cancers (e.g.
  • breast cancer eg, hormone receptor positive breast cancer, triple negative breast cancer, HER2/neu positive or negative breast cancer
  • digestive system/gastrointestinal tumors e.g. anal cancer, appendix cancer, cholangiocarcinoma, gastrointestinal stromal tumor, gastrointestinal carcinoid, colorectal cancer, gastric cancer,
  • adrenocortical carcinoma thyroid cancer, skin neuroendocrine tumor, 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 cancers (e.g.
  • 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 cancers e.g.
  • lung cancer including but not limited to non-small cell lung cancer, small cell lung cancer), malignant mesothelioma, thymic carcinoma), skin cancer (eg Merkel cell carcinoma, cutaneous squamous cell carcinoma, melanoma), tumors of the nervous system ( For example, one or more of brain cancer, glioblastoma, neuroblastoma, pituitary tumor, primary central nervous system lymphoma), bone cancer, soft tissue sarcoma.
  • lung cancer including but not limited to non-small cell lung cancer, small cell lung cancer
  • skin cancer eg Merkel cell carcinoma, cutaneous squamous cell carcinoma, melanoma
  • tumors of the nervous system For example, one or more of brain cancer, glioblastoma, neuroblastoma, pituitary tumor, primary central nervous system lymphoma), bone cancer, soft tissue sarcoma.
  • the MSI-H and/or dMMR solid tumor is a malignant solid tumor.
  • the MSI-H and/or dMMR malignant solid tumor is an advanced 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.
  • the MSI-H and/or dMMR malignant solid tumor is a recurrent and/or metastatic malignant solid tumor.
  • the MSI-H and/or dMMR malignant solid tumor is a recurrent and/or metastatic advanced malignant solid tumor.
  • the patient with the MSI-H and/or dMMR tumor has received one or more prior therapies.
  • the MSI-H and/or dMMR tumor is an MSI-H and/or dMMR tumor with disease progression after prior therapy and/or without satisfactory replacement therapy.
  • the patient with the MSI-H and/or dMMR tumor has been treated with one or more drugs.
  • the MSI-H and/or dMMR tumor is an MSI-H and/or dMMR tumor that has failed treatment with at least one drug.
  • the treatment failure includes disease progression during treatment, and disease progression and/or relapse after treatment ends.
  • the patient with MSI-H and/or dMMR tumor has received one or more chemotherapy.
  • the MSI-H and/or dMMR tumor is an MSI-H and/or dMMR tumor that has failed at least one chemotherapy treatment.
  • the treatment failure includes disease progression during treatment, and disease progression and/or relapse after treatment ends.
  • the patient with MSI-H and/or dMMR tumor has previously received 1-2 lines of systemic standard chemotherapy regimens, and the treatment has failed or cannot be tolerated.
  • the anti-PD-L1 antibody in the use or method of treatment, may be weekly (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks ( q4w) once administered. In a specific embodiment, the anti-PD-L1 antibody is administered every 3 weeks. In some embodiments, the anti-PD-L1 antibody is administered at a dose of 600-2400 mg per administration.
  • 21 days is a treatment cycle, and the PD-L1 antibody is administered on the first day of each cycle.
  • the anti-PD-L1 antibody may comprise a compound 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 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 a dose of 900 mg to 1200 mg is administered to the subject.
  • 21 days is a treatment cycle, and 1200 mg of PD-L1 antibody is administered on the first day of each cycle.
  • the anti-PD-L1 antibodies of the present application and pharmaceutical compositions thereof can be administered by suitable routes, including but not limited to, oral or parenteral (eg, by intravenous, intramuscular, topical or subcutaneous routes).
  • suitable routes including but not limited to, oral or parenteral (eg, by intravenous, intramuscular, topical or subcutaneous routes).
  • the administration may be by injection, such as intravenous injection or intraperitoneal injection.
  • compositions of the present application include, but are not limited to, tablets, troches, pills, capsules (such as 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.
  • compositions of the present application may further contain pharmaceutically acceptable carriers and/or excipients.
  • the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof are each in the form of a pharmaceutical composition, which can be simultaneously, sequentially or sequentially Dosing.
  • the anti-PD-L1 antibody and anlotinib are each administered in a spaced-apart manner.
  • the antibody and anlotinib are administered on the same or different dosing regimens, respectively.
  • the administrations are administered in separate dosing regimens.
  • the anti-PD-L1 antibody in the use or method of treatment, may be every 1 week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w) administered once. In a specific embodiment, the anti-PD-L1 antibody is administered every 3 weeks. In some embodiments, the anti-PD-L1 antibody is administered at a dose of 600-2400 mg per administration.
  • 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 a day, continuously for 2 weeks, and 1 week off.
  • the anti-PD-L1 antibody and anlotinib, or a pharmaceutically acceptable salt thereof have the same or different treatment cycles, respectively.
  • the anti-PD-L1 antibody and anlotinib have the same treatment cycle, eg, every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks as a treatment cycle.
  • 21 days is a treatment cycle
  • the PD-L1 antibody is administered on the first day of each cycle
  • the PD-L1 antibody is administered daily on days 1-14 of each cycle
  • Anlotinib or a pharmaceutically acceptable salt thereof is administered once daily on days 1-14 of each cycle.
  • the anti-PD-L1 antibody may comprise 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 a dose of 900 mg to 1200 mg is administered to the subject.
  • 21 days is a treatment cycle, and 1200 mg of PD-L1 antibody is administered on the first day of each cycle, and 6 mg, 8 mg, 10 mg and/or 12 mg of Anlotinib or a pharmaceutically acceptable salt thereof.
  • every three weeks is a treatment cycle at (0.35-29):1, (3.5-29):1, (3.5-14.5):1, or (7-14.5):1
  • the components of the pharmaceutical combinations of the present application may be administered individually, or some or all of them together, by various routes as appropriate, including, but not limited to, oral or parenteral (by intravenous, intramuscular, topical or subcutaneous routes). ).
  • the components of the pharmaceutical combinations of the present application may each be administered independently, or some or all of them may be administered orally or by injection, eg, intravenously or intraperitoneally.
  • the components of the pharmaceutical combinations of the present application may each independently, or some or all of them together be in a suitable dosage form, including, but not limited to, tablets, troches, pills, capsules (eg, hard capsules, soft capsules, enteric capsules) capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and for oral or non-oral administration
  • a suitable dosage form including, but not limited to, tablets, troches, pills, capsules (eg, hard capsules, soft capsules, enteric capsules) capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and for oral or non-oral administration
  • a suitable dosage form including, but not limited to,
  • the components of the pharmaceutical combination of the present application may each independently, or some or all of them together contain a pharmaceutically acceptable carrier and/or excipient.
  • the anti-PD-L1 antibody of the present application can safely and effectively treat endometrial cancer.
  • the anti-PD-L1 antibodies of the present application show a higher sensitivity to MSI-H or dMMR endometrial cancer in patients with MSI-H or dMMR endometrial cancer who are receiving anti-PD-L1 antibody therapy Afterwards, the patient's objective response rate (ORR) is well above 15%; in specific embodiments, the ORR is at or above 30%.
  • the patient has a disease control rate (DCR) of 50% or more following treatment with an anti-PD-L1 antibody. In specific embodiments, the DCR is at or above 80%.
  • the anti-PD-L1 antibody provided in this application can significantly reduce the incidence and severity of adverse reactions (TRAE) in the treatment of MSI-H or dMMR endometrial cancer, and the incidence of adverse reactions is less than 80% , the incidence of adverse reactions of grade 3 or above is less than 20%.
  • the anti-PD-L1 antibody provided in this application is used to treat MSI-H or dMMR endometrial cancer, and the incidence of adverse reactions is less than 70%, and the incidence of adverse reactions of grade 3 or above is not more than 16%.
  • the anti-PD-L1 antibody of the present application shows high sensitivity to MSI-H and/or dMMR tumors, such as MSI-H and/or dMMR malignancies, and can be safely and effectively treated for MSI-H and/or dMMR tumors , the objective response rate (ORR) of patients was well over 15%.
  • the objective response rate (ORR) of patients following anti-PD-L1 antibody treatment is well above 15% .
  • the ORR is at or above 30%.
  • the patient has a disease control rate (DCR) of 50% or more following anti-PD-L1 antibody treatment.
  • the DCR is at or above 80%.
  • the anti-PD-L1 antibody provided in this application can significantly reduce the incidence and severity of adverse reactions (TRAEs) in the treatment of MSI-H or dMMR tumors, and the incidence of adverse reactions is less than 80%, grade 3 or above The incidence of adverse reactions is less than 20%.
  • the anti-PD-L1 antibody provided in this application is used to treat MSI-H or dMMR malignant tumors, and the incidence of adverse reactions is less than 70%, and the incidence of adverse reactions of grade 3 or above does not exceed 16%.
  • the pharmaceutical combination of the present application comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof can safely and effectively treat endometrial cancer.
  • the pharmaceutical combination of the present application comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof can safely and effectively treat non-MSI-H and/or non-dMMR endometrial cancer .
  • the pharmaceutical combination of the present application comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof is in non-MSI-H and/or non-dMMR endometrial cancer patients, ORR ( Objective response rate) was more than 15%.
  • the ORR is at or above 25%.
  • the ORR is at or above 30%.
  • Disease control rate (DCR) at or above 80%.
  • the DCR is at or above 90%.
  • the anti-PD-L1 antibodies of the present application and anlotinib or a pharmaceutically acceptable salt thereof have a synergistic effect in the treatment of endometrial cancer.
  • the anti-PD-L1 antibodies of the present application and anlotinib or a pharmaceutically acceptable salt thereof have a significant synergistic effect in the treatment of non-MSI-H and/or non-dMMR endometrial cancer.
  • the anti-PD-L1 antibodies provided herein and anlotinib or a pharmaceutically acceptable salt thereof for the treatment of endometrial cancer, especially non-MSI-H and/or non-dMMR endometrial cancer can Significantly reduce the incidence and severity of adverse reactions (TRAE), the incidence of adverse reactions is less than 80%, and the incidence of adverse reactions above grade 3 is less than 10%.
  • the anti-PD-L1 antibody provided herein and anlotinib or a pharmaceutically acceptable salt thereof for the treatment of non-MSI-H and/or non-dMMR endometrial cancer the incidence of adverse reactions does not exceed 75% %, and the incidence of adverse reactions of grade 3 or above does not exceed 7%.
  • ORR is calculated by calculating the ratio of IRC-assessed objective responses (PR+CR) to total cases and 95% CI.
  • the immunogenicity of the patient is studied; the immunogenicity study includes the study of anti-drug antibody ADA and neutralizing antibody Nab, if the anti-drug antibody (ADA) expression of the patient is detected When positive, neutralizing antibody (Nab) was added.
  • the time point of immunogenicity monitoring is based on the administration time of the antibody injection; when the administration of the antibody is delayed, the immunogenic blood collection is correspondingly delayed.
  • the MSI is caused by the loss of DNA mismatch repair (mismatch repair, MMR) protein function.
  • MMR DNA mismatch repair
  • the status of MSI can be detected according to methods known in the art. Methods for detecting MSI status include, but are not limited to, immunohistochemical detection of MMR protein, multiplex fluorescence polymerase chain reaction PCR detection of microsatellite sites, and next-generation sequencing-based detection. (NGS) platform for the detection of MSI.
  • MSI is detected using multiplex fluorescent polymerase chain reaction PCR.
  • commercially available kits are used to detect the status of MSI.
  • the microsatellite loci are detected according to multiplex fluorescent polymerase chain reaction PCR, and the interpretation standard changes with the number of loci in the kit. Status such as MSI-H (Microsatellite High Instability), MSI-L (Microsatellite Low Instability), and MSS (Microsatellite Stable).
  • the status of MMR can be detected according to methods known in the art, eg, immunohistochemistry (IHC) can be used to detect MMR proteins, eg, four MMR proteins (MLH1) can be detected mainly in tumor samples of patients , MSH2, MSH6 and PMS2), any MMR protein deletion is dMMR, and no MMR protein deletion is non-dMMR; the interpretation method can use the college of American Pathologists (CAP) standard to judge the expression of MMR protein Whether it is deleted; for example, microsatellite loci can also be detected using PCR methods.
  • IHC immunohistochemistry
  • MMR proteins eg, four MMR proteins (MLH1) can be detected mainly in tumor samples of patients , MSH2, MSH6 and PMS2), any MMR protein deletion is dMMR, and no MMR protein deletion is non-dMMR
  • the interpretation method can use the college of American Pathologists (CAP) standard to judge the expression of MMR protein Whether it is deleted; for example, microsatellite
  • PCR polymerase chain reaction
  • ICH immunohistochemistry
  • anlotinib or its pharmaceutically acceptable salt refers to the amount in which the active ingredient, anlotinib free base, is used.
  • dose refers to a dose administered to a patient regardless of the patient's weight or body surface area (BSA).
  • BSA body surface area
  • a 60kg person and a 100kg person will receive the same dose of antibody (eg, 240mg anti-PD-1 antibody).
  • MSI microsatellite instability
  • MSI-H refers to microsatellite high instability or microsatellite instability hypermutant (MSI-high).
  • MSI-L refers to Microsatellite Instability Low (MSI-low).
  • MSS microsatellite stability
  • MMR mismatch repair
  • dMMR defective mismatch repair
  • pMMR mismatch repair functionally complete (proficient mismatch repair).
  • the term "pharmaceutical combination” refers to the simultaneous or sequential administration of two or more active ingredients (either as the respective active ingredients themselves, or their respective derivatives such as pharmaceutically acceptable salts or esters) , prodrugs or compositions).
  • the actives may each be administered to a subject simultaneously as a single formulation, or each may be administered sequentially to a subject in any order as a single formulation.
  • 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. Accordingly, the antibodies and fragments of the present application include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof, as well as 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 can also include recombinant polypeptides, fusion proteins, and bispecific antibodies.
  • the anti-PD-L1 antibodies and fragments thereof described herein can be of the IgG1, IgG2, IgG3, or IgG4 isotype.
  • the term "isotype" refers to the species of antibody encoded by the heavy chain constant region genes.
  • 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 can be derived from any species including, but not limited to, mouse, rat, rabbit, primate, llama, and human.
  • PD-L1 antibodies and fragments thereof can be chimeric antibodies, humanized antibodies, or fully human antibodies.
  • the anti-PD-L1 antibody is an antibody produced by a mouse-derived hybridoma cell line.
  • the anti-PD-L1 antibody is a murine antibody.
  • the anti-PD-L1 antibody is a chimeric antibody.
  • the chimeric antibody is a mouse-human chimeric antibody.
  • the antibody is a humanized antibody.
  • the antibody is derived from a murine antibody and is humanized.
  • 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.
  • CDRs complementarity determining regions
  • an anti-PD-L1 antibody described herein can comprise CDRs derived from one or more murine antibodies as well as human framework and constant regions.
  • the humanized antibody described herein binds the same epitope on PD-L1 as the murine antibody from which the CDRs of the antibody are derived.
  • the anti-PD-L1 antibody is a humanized antibody. Additional anti-PD-L1 antibodies or variants thereof comprising the heavy and light chain CDRs provided herein can be generated using any human framework sequences and are also included in this application.
  • framework sequences suitable for use in this application include those that are structurally similar to those provided herein. Additional modifications can be made in the framework regions to improve the properties of the antibodies provided herein. Such additional framework modifications may include chemical modifications; point mutations to reduce immunogenicity or to remove T cell epitopes; or reversion of mutations to residues in the original germline sequence. In some embodiments, such modifications include those corresponding to the mutations exemplified herein, including 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 the humanized antibodies described herein are backmutated to the corresponding amino acids in the parental murine antibody.
  • the amino acids at positions 53 and/or 60 and/or 67 of the light chain variable region are backmutated to the corresponding ones found at said positions in the mouse 5G11 or 13C5 light chain variable region amino acid.
  • the amino acids at positions 24 and/or 28 and/or 30 and/or 49 and/or 73 and/or 83 and/or 94 of the heavy chain variable region are backmutated to be in mouse 5G11 or the corresponding amino acid found at said position in the 13C5 heavy chain variable region.
  • 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) is Tyr(Y); and the heavy chain variable region, wherein the amino acid at position 24 is mutated from Phe(F) to Val(V) and the amino acid at position 49 is mutated from Ala(A) to Gly(G), The amino acid at position 73 was mutated from Thr(T) to Asn(N), and the amino acid at position 83 was mutated from Thr(T) to Asn(N).
  • the humanized 13C5 antibody comprises a light chain variable region in which the amino acid at position 53 is mutated from Tyr(Y) to Lys(K); and a heavy chain variable region in which the amino acid at position 28 is mutated from Tyr(Y) to Lys(K);
  • the amino acid is mutated from Thr(T) to Ile(I)
  • the amino acid at position 30 is mutated from Ser(S) to Arg(R)
  • the amino acid at position 49 is mutated from Ser(S) to Ala(A)
  • the amino acid at position 94 was mutated from Tyr (Y) to Asp (D). Additional or alternative backmutations can be made in the framework regions of the humanized antibodies provided herein to improve the properties of the antibodies.
  • the present application also includes humanized antibodies that bind PD-L1 and comprise framework modifications corresponding to the exemplary modifications described herein with respect to any suitable framework sequences, and otherwise improve the antibody Additional framework modifications for properties.
  • the present application describes isolated antibodies or fragments thereof that bind PD-L1, wherein the antibodies can be produced by hybridomas selected from the hybridomas referred to herein as 13C5, 5G11.
  • the application also provides isolated polynucleotides encoding the antibodies and fragments thereof provided herein.
  • the application also includes expression vectors comprising the isolated polynucleotides, and host cells comprising the expression vectors.
  • isolated antibody means an antibody that is substantially free of other antibodies with different antigenic specificities (eg, an isolated antibody that specifically binds PD-1 is substantially free of antibodies that specifically bind to anything other than PD-1 antibody to the antigen).
  • isolated antibodies that specifically bind PD-1 may have cross-reactivity with other antigens, such as PD-1 molecules from different species.
  • the isolated antibody may be substantially free of other cellular material and/or chemicals.
  • mAb refers to an antibody molecule of single molecular composition (ie, an antibody molecule whose basic sequence is substantially identical and which exhibits a single binding specificity and affinity for a particular epitope) ) non-naturally occurring preparations.
  • a mAb is an example of an isolated antibody.
  • mAbs can be produced by hybridoma, recombinant, transgenic or other techniques known to those skilled in the art.
  • the antibodies and antigen-binding fragments thereof described herein are specific for PD-L1. In one embodiment, the antibody or/and fragment thereof is specific for PD-L1. In one embodiment, the antibodies and fragments described herein bind human or primate PD-L1, but do not bind PD-L1 from any other mammal. In another embodiment, the antibody or/and fragment thereof does not bind mouse PD-L1.
  • the terms "human PD-L1”, “hPD-L1”, and “huPD-L1” and the like are used interchangeably herein and refer to human PD-L1 and variants or isoforms of human PD-L1. "Specific" means that antibodies and fragments thereof bind PD-L1 with greater affinity than any other target.
  • treating generally refers to obtaining a desired pharmacological and/or physiological effect.
  • the effect may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease.
  • Treatment encompasses any treatment of a disease in a patient, including: (a) inhibiting the symptoms of the disease, ie, preventing its progression; or (b) alleviating the symptoms of the disease, ie, causing regression of the disease or symptoms.
  • the term "effective amount” means (i) treating a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying the symptoms described herein. amount of a compound of the present application for the onset of one or more symptoms of the particular disease, condition or disorder described.
  • amount of an active substance eg, an antibody or compound of the present application
  • the amount of an active substance that constitutes a "therapeutically effective amount” may vary depending on factors such as the disease state, age, sex, and weight of the individual, and the elicitation of the therapeutic agent or combination of therapeutic agents in the individual. ability to respond. Effective amounts can also be routinely determined by those skilled in the art based on their own knowledge and this disclosure.
  • administering means physically introducing a composition comprising a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those skilled in the art.
  • Routes of administration of immune checkpoint inhibitors include parenteral routes of administration (including but not limited to intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other gastrointestinal external route of administration), such as by injection or infusion.
  • parenteral administration or “parenteral administration” as used herein are used interchangeably and generally refer to modes of administration other than enteral and topical administration by injection, and include but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intraarticular, subcapsular , subarachnoid, intraspinal, epidural and intrasternal injection and infusion, and in vivo electroporation.
  • the immune checkpoint inhibitor (eg, anti-PD-1 antibody or anti-PD-L1 antibody) is administered by a non-parenteral route; in certain embodiments, orally.
  • non-parenteral routes include topical, epidermal or mucosal administration, eg, intranasal, intravaginal, intrarectal, sublingual or topical administration. Administration can also be performed, eg, once, multiple times, and/or over one or more extended periods of time.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic response or other problems or complications.
  • salts includes salts of free bases with acids or salts of acids with free bases, including, for example, hydrochloride, hydrobromide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, fumarate, oxalate, maleate, citrate, succinate, mesylate, benzenesulfonate or p-toluenesulfonate;
  • the molar ratio of the acid to the free base is 1:0.2-1:5; in some embodiments, 1:0.5, 1:1, 1 :2, 1:3, 1:4, 1:5, 1:6, 1:7 or 1:8.
  • the terms “subject” or “patient” are used interchangeably.
  • the term “subject” or “patient” is a mammal.
  • the subject or patient is a mouse.
  • the subject or patient is a human.
  • unit dose refers to the smallest packaging unit containing a certain amount of medicine, for example, a box of medicine has seven capsules, and each capsule is a unit dose; or each bottle of injection is a unit dose.
  • multi-dose consists of a plurality of unit doses.
  • pharmaceutical composition refers to a mixture of one or more of the active ingredients of the present application or a pharmaceutical combination thereof and pharmaceutically acceptable excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application or a pharmaceutical combination thereof to a subject.
  • the present application is further illustrated with examples, but the examples do not limit the scope of the present application. All reagents used in this application were commercially available and used without further purification.
  • the anti-PD-L1 antibody was prepared according to the method described in WO2016022630. After affinity chromatography, an eluate containing the antibody was obtained according to a conventional antibody purification method.
  • Subjects with endometrial cancer who meet the inclusion criteria firstly detect MMR/MSI status by immunohistochemistry or PCR, and enter the group according to the test results of MSI-H/dMMR.
  • MSI-H/dMMR For non-MSI-H/non-dMMR subjects , given anti-PD-L1 antibody and anlotinib hydrochloride (cohort one), for subjects with MSI-H or dMMR, given anti-PD-L1 antibody (cohort two), disease control (CR+PR+SD) and Subjects with tolerable adverse reactions can continue to use the drug until the clinical benefit is lost, the toxicity is intolerable, the efficacy evaluation is PD/iCPD, and the investigator considers that it is not suitable to continue the drug.
  • the efficacy evaluation will be conducted every 6 weeks (42 days) ⁇ 3 days, and after 54 weeks, the efficacy evaluation will be conducted every 12 weeks (84 days) ⁇ 3 days until the subject develops tumor imaging Scientifically proven disease progression.
  • Age ⁇ 18 years old; ECOG PS score: 0-1; the expected survival time is more than 3 months.
  • Anti-PD-L1 antibody injection hu5G11-hIgG1 1200mg anti-PD-L1 antibody injection (specification: 600mg/20mL) diluted with normal saline to 250mL, the infusion time is 60 ⁇ 10min (the infusion time is to start the infusion of anti-PD-L1
  • the antibody injection is the starting point, and the end of the anti-PD-L1 antibody injection is the end of the infusion and the end of the normal saline (recommended 20mL) flushing tube).
  • Anti-PD-L1 antibody injections were administered on the first day and administered once every 21 days, that is, 21 days as a treatment cycle (d1/q3w).
  • Anlotinib hydrochloride capsules active ingredient is anlotinib dihydrochloride: 1 capsule (12 mg) each time (orally on an empty stomach before breakfast). Continuous oral administration for 2 weeks and 1 week off, that is, a 21-day treatment cycle, administered on the 1-14th day of each cycle. Without special circumstances, it is recommended to take it at a fixed time every day. (ie, Anlotinib hydrochloride capsules: 12mg/qd, d1-14/q3w)
  • Anlotinib hydrochloride capsules such as 12mg, 10mg, and 8mg, according to the disease status and safety.
  • RECIST 1.1 and iRECIST criteria were used to determine disease status.
  • the RECIST 1.1 standard was mainly used for evaluation, and the iRECIST standard was used to confirm the efficacy. That is, subjects who are judged as disease progression (PD) according to the RECIST 1.1 standard will be further confirmed according to the iRECIST standard, so as to decide whether to further observe the medication.
  • PD disease progression
  • IRC-assessed objective response rate ORR

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Endocrinology (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Mycology (AREA)
  • Reproductive Health (AREA)
  • Microbiology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

属于生物医药领域，涉及用于治疗肿瘤的药物，提供了抗PD-L1抗体或其药物组合物在制备用于治疗子宫内膜癌的药物中的用途。还提供了抗PD-L1抗体或其药物组合物在制备用于治疗MSI-H和/或dMMR肿瘤的药物中的用途。另外，还提供了抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合或药物组合物在制备用于治疗子宫内膜癌的药物中的用途。

Description

用于治疗肿瘤的药物 技术领域
本申请属于生物医药领域，具体涉及用于治疗肿瘤的药物。
背景技术
子宫内膜癌(Endometrial cancer，EC)是发生于子宫内膜的一组上皮性恶性肿瘤，又称子宫体癌，是女性生殖道三大常见恶性肿瘤之一。其多发生于围绝经期及绝经后妇女。随着人口平均寿命的增加以及生活习惯的改变，子宫内膜癌的发病率近20年呈持续上升和年轻化趋势。在西方国家，子宫内膜癌已经占据女性生殖系统恶性肿瘤发病率首位，在我国，作为继宫颈癌之后第二个常见的妇科恶性肿瘤，约占妇科恶性肿瘤的20％-30％。部分发达城市的子宫内膜癌发病率已达妇科恶性肿瘤第一位。I期和II期患者术后复发率约15％，其中50％-70％的复发有症状。大多数复发发生在治疗后3年内。局限于阴道或盆腔的复发经过治疗后仍有较好的效果。孤立的阴道复发经放疗后5年生存率达50％-70％。
子宫内膜癌的治疗原则上以手术治疗为主，辅以放疗、药物治疗和激素等综合治疗。对于雌激素依赖型且未生育的早期子宫内膜癌患者，常采用孕激素进行保守治疗以保留生育功能；对于晚期患者，手术前要采取合适的化疗以缩小肿瘤体积，合理的化疗药物的选择能显著提高手术切除率；对于转移性子宫内膜癌以及术后复发的子宫内膜癌，目前常用的是孕激素、促性腺激素释放激素类似物、芳香化酶抑制剂等激素类药物，还有紫杉醇(paclitaxel)、卡铂(carboplatin)、多柔比星(doxorubicin)等化疗药物。而随着化疗耐药性的出现，靶向药物治疗如帕博利珠单抗、阿维单抗、贝伐单抗、索拉非尼、舒尼替尼等对改善子宫内膜癌的疗效和预后具有重要意义。
微卫星(microsatellite，MS)是指细胞基因组中以少数几个核苷酸(多为1-6个)为单位串联重复的DNA序列，又称短串联重复(short tandem repeat,STR)。DNA错配修复(mismatch repair,MMR)功能出现异常时，微卫星出现的复制错误得不到纠正并不断积累，使得微卫星长度或碱基组成发生改变，称为微卫星不稳定性(microsatellite instability,MSI)，同时导致基因组呈现高突变表型。MSI根据程度可以被分成3类：微卫星高度不稳定(MSI-high,MSI-H)、微卫星低度不稳定性(MSI-low,MSI-L)、微卫星稳定(microsatellite stability,MSS)。
程序性死亡因子1及其配体(PD-1/PD-L1)是一对免疫共刺激因子。正常情况下，PD-1通过其配体PD-L1发挥免疫调控作用。PD-1/PD-L1信号通路的激活可导致免疫抑制性肿瘤微环境形成，使肿瘤细胞逃避机体免疫监视和杀伤，而阻断PD-1/PD-L1信号通路可逆转肿瘤免疫微环境，增强内源性抗肿瘤免疫效应。
发明内容
一方面，本申请提供了抗PD-L1抗体在制备用于治疗MSI-H子宫内膜癌和/或dMMR子宫内膜癌的药物中的用途。
另一方面，本申请提供了含抗PD-L1抗体的药物组合物在制备用于治疗MSI-H子宫内膜癌和/或dMMR子宫内膜癌的药物中的用途。
另一方面，本申请还提供了抗PD-L1抗体用于治疗MSI-H子宫内膜癌和/或dMMR子宫内膜癌的用途。
另一方面，本申请还提供了含抗PD-L1抗体的药物组合物用于治疗MSI-H子宫内膜癌和/或dMMR子宫内膜癌的用途。
在一些实施方案中，所述的药物组合物进一步包括药学上可接受的载体。
一方面，本申请提供一种用于治疗子宫内膜癌的药物组合，其包括：抗PD-L1抗体，和安罗替尼或其药学上可接受的盐。在一些实施方案中，提供一种用于治疗非MSI-H和/或非dMMR的子宫内膜癌的药物组合，其包括：抗PD-L1抗体，和安罗替尼或其药学上可接受的盐。
另一方面，本申请提供了抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合在制备用于治疗子宫内膜癌的药物的用途。在一些实施方案中，提供了含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合在制备用于治疗子宫内膜癌的药物的用途。在一些实施方案中，提供了抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合在制备用于治疗非MSI-H和/或非dMMR的子宫内膜癌的药物的用途。在一些实施方案中，提供了含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合在制备用于治疗非MSI-H和/或非dMMR的子宫内膜癌的药物的用途。
另一方面，本申请提供了抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合用于治疗子宫内膜癌的用途。在一些实施方案中，提供了含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合用于治疗子宫内膜癌的用途。在一些实施方案中，本申请提供了抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合用于治疗非MSI-H和/或非dMMR的子宫内膜癌的用途。在一些实施方案中，本申请提供了含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合用于治疗非MSI-H和/或非dMMR的子宫 内膜癌的用途。
在一些实施方案中，所述的药物组合进一步包括药学上可接受的载体。
一方面，本申请提供了抗PD-L1抗体在制备用于治疗MSI-H和/或dMMR肿瘤的药物中的用途。在一些实施方案中，提供了抗PD-L1抗体在制备用于治疗MSI-H和/或dMMR恶性肿瘤的药物中的用途。在一些实施方案中，提供了抗PD-L1抗体在制备用于治疗MSI-H和/或dMMR实体瘤的药物中的用途。在一些实施方案中，提供了抗PD-L1抗体在制备用于治疗MSI-H和/或dMMR恶性实体瘤的药物中的用途。
另一方面，本申请提供了含抗PD-L1抗体的药物组合物在制备用于治疗MSI-H和/或dMMR肿瘤的药物中的用途。在一些实施方案中，提供了含抗PD-L1抗体的药物组合物在制备用于治疗MSI-H和/或dMMR恶性肿瘤的药物中的用途。在一些实施方案中，提供了含抗PD-L1抗体的药物组合物在制备用于治疗MSI-H和/或dMMR实体瘤的药物中的用途。在一些实施方案中，提供了含抗PD-L1抗体的药物组合物在制备用于治疗MSI-H和/或dMMR恶性实体瘤的药物中的用途。
另一方面，本申请还提供了抗PD-L1抗体用于治疗MSI-H和/或dMMR肿瘤的用途。在一些实施方案中，提供了抗PD-L1抗体用于治疗MSI-H和/或dMMR恶性肿瘤的用途。在一些实施方案中，提供了抗PD-L1抗体用于治疗MSI-H和/或dMMR实体瘤的用途。在一些实施方案中，提供了抗PD-L1抗体用于治疗MSI-H和/或dMMR恶性实体瘤的用途。
另一方面，本申请还提供了含抗PD-L1抗体的药物组合物用于治疗MSI-H和/或dMMR肿瘤的用途。在一些实施方案中，提供了含抗PD-L1抗体的药物组合物用于治疗MSI-H和/或dMMR恶性肿瘤的用途。在一些实施方案中，提供了含抗PD-L1抗体的药物组合物用于治疗MSI-H和/或dMMR实体瘤的用途。在一些实施方案中，提供了含抗PD-L1抗体的药物组合物用于治疗MSI-H和/或dMMR恶性实体瘤的用途。
再一方面，本申请还提供了一种治疗MSI-H子宫内膜癌和/或dMMR子宫内膜癌的方法，其包括向有需要的患者给予治疗有效量的抗PD-L1抗体。
再一方面，本申请提供了一种治疗MSI-H子宫内膜癌和/或dMMR子宫内膜癌的方法，其包括向有需要的患者给予治疗有效量的含抗PD-L1抗体的药物组合物。
再一方面，本申请还提供了一种子宫内膜癌的治疗方法，其包括向有需要的患者给予治疗有效量的抗PD-L1抗体和安罗替尼或其药学上可接受的盐。在一些实施方案中，本申请还提供了一种非MSI-H和/或非dMMR的子宫内膜癌的治疗方法，其包括向有需要的患者给予治疗有效量的抗PD-L1抗体和安罗替尼或其药学上可接受的盐。在一些实施方案中，抗PD-L1抗体和安罗替尼或其药学上可接受的盐可同时、先后或者依次序给药。在一些实施方案中，申请还提供了一种子宫内膜癌的治疗方法，其包括向有需要的患者给予治疗有效量的含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合物。
在一些实施方案中，本申请还提供了一种非dMMR和/或非MSI-H的子宫内膜癌的治疗方法，其包括向有需要的患者给予治疗有效量的抗PD-L1抗体的药物组合物和安罗替尼或其药学上可接受的盐的药物组合物。在一些实施方案中，抗PD-L1抗体的药物组合物和安罗替尼或其药学上可接受的盐的药物组合物可同时、先后或者依次序给药。在一些实施方案中，本申请还提供了一种非dMMR和/或非MSI-H的子宫内膜癌的治疗方法，其包括向有需要的患者给予治疗有效量的含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合物。
再一方面，本申请还提供了一种治疗MSI-H和/或dMMR肿瘤的方法，其包括向有需要的患者给予治疗有效量的抗PD-L1抗体。在一些实施方案中，提供了治疗MSI-H和/或dMMR恶性肿瘤的方法，其包括向有需要的患者给予治疗有效量的抗PD-L1抗体。在一些实施方案中，提供了治疗MSI-H和/或dMMR恶性实体瘤的方法，其包括向有需要的患者给予治疗有效量的抗PD-L1抗体。
再一方面，本申请还提供了一种治疗MSI-H和/或dMMR肿瘤的方法，其包括向有需要的患者给予治疗有效量的含抗PD-L1抗体的药物组合物。在一些实施方案中，提供了治疗MSI-H和/或dMMR恶性肿瘤的方法，其包括向有需要的患者给予治疗有效量的含抗PD-L1抗体的药物组合物。在一些实施方案中，提供了治疗MSI-H和/或dMMR恶性实体瘤的方法，其包括向有需要的患者给予治疗有效量的含抗PD-L1抗体的药物组合物。
又一方面，本申请提供了用于治疗MSI-H子宫内膜癌和/或dMMR子宫内膜癌的试剂盒，其包括抗PD-L1抗体。在一些实施方案中，该试剂盒进一步包含治疗子宫内膜癌的说明。
再一方面，本申请提供了用于治疗MSI-H子宫内膜癌和/或dMMR子宫内膜癌的试剂盒，其包括含抗PD-L1抗体的药物组合物；在一些实施方案中，该试剂盒进一步包含治疗子宫内膜癌的说明。
又一方面，本申请提供了用于治疗子宫内膜癌的试剂盒，其包括：抗PD-L1抗体；和安罗替尼或其药学上可接受的盐；在一些实施方案中，抗PD-L1抗体包含在第一隔室中，以及安罗替尼或其药学上可接受的盐包含在第二隔室中，可同时、先后或者依次序给予有需要的患者。在一些实施方案中，该试剂盒进一步包含抗PD-L1抗体和安罗替尼或其药学上可接受的盐联合使用治疗子宫内膜癌的说明。在一些实施方案中，所述试剂盒包括：抗PD-L1抗体的药物组合物；和安罗替尼或其药学上可接受的盐的药物组合物。
在一些实施方案中，本申请提供了用于治疗非MSI-H子宫内膜癌和/或非dMMR子宫内膜癌的试剂盒，其包括：抗PD-L1抗体；和安罗替尼或其药学上可接受的盐，其中：抗PD-L1抗体包含在第一隔室中，以及安罗替尼或其药学上可接受的盐包含在第二隔室中，可同时、先后或者依次序给予有需要的患者。该试剂盒进一步包含抗PD-L1抗体和安罗替尼或其药学上可接受的盐联合使用治疗非MSI-H子宫内膜癌和/或非dMMR子宫内膜癌的说明。在一些实施方案中，所述试剂盒包括：抗PD-L1抗体的药物组合物；和安罗替尼或其药学上可接受的盐的药物组合物。
又一方面，本申请提供了用于治疗MSI-H和/或dMMR肿瘤的试剂盒，其包括抗PD-L1抗体；在一些实施方案中，该试剂盒进一步包含治疗MSI-H和/或dMMR肿瘤的说明。在一些实施方案中，本申请提供了用于治疗MSI-H和/或dMMR恶性肿瘤的试剂盒，其包括抗PD-L1抗体；在一些实施方案中，该试剂盒进一步包含治疗MSI-H和/或dMMR恶性肿瘤的说明。在一些实施方案中，本申请提供了用于治疗MSI-H和/或dMMR恶性实体瘤的试剂盒，其包括抗PD-L1抗体；在一些实施方案中，该试剂盒进一步包含治疗MSI-H和/或dMMR恶性实体瘤的说明。
再一方面，本申请提供了治疗MSI-H和/或dMMR肿瘤的试剂盒，其包括含抗PD-L1抗体的药物组合物；在一些实施方案中，该试剂盒进一步包含治疗MSI-H和/或dMMR肿瘤的说明。在一些实施方案中，本申请提供了用于治疗MSI-H和/或dMMR恶性肿瘤的试剂盒，其包括含抗PD-L1抗体的药物组合物。在一些实施方案中，该试剂盒进一步包含治疗MSI-H和/或dMMR恶性肿瘤的说明。在一些实施方案中，本申请提供了用于治疗MSI-H和/或dMMR恶性实体瘤的试剂盒，其包括含抗PD-L1抗体的药物组合物。在一些实施方案中，该试剂盒进一步包含治疗MSI-H和/或dMMR恶性实体瘤的说明。
给予抗PD-L1抗体的量、给药方案可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄和健康状态来确定。例如，在一些实施方案中，给予抗PD-L1抗体的日剂量可为600-2400mg，在一些实施方案中，给予抗PD-L1抗体的日剂量可为600、800、1000、1200、1400、1600、1800、2000、2200、2400mg。在一些实施方案中，抗PD-L1抗体以胃肠外给药的方式给药。在一些实施方案中，抗PD-L1抗体以静脉内给药的方式给药。在一些实施方案中，抗PD-L1抗体以10-60mg/mL的浓度给药。在一些实施方案中，抗PD-L1抗体以10、20、30、40、50或者60mg/mL的浓度给药。在一些实施方案中，对于抗PD-L1抗体，每1周、每2周、每3周、或者每4周为一个治疗周期。在一些实施方案中，抗PD-L1抗体每个治疗周期给药一次。在一些实施方案中，抗PD-L1抗体每周、每2周、每3周、或者每4周施用一次。在一些实施方案中，对于抗PD-L1抗体，每3周为一个治疗周期。在一些实施方案中，抗PD-L1抗体每3周、或者每4周施用一次。
在一些实施方案中，在每个治疗周期，给予600-2400mg的抗PD-L1抗体。在一些实施方案中，在每个治疗周期，抗PD-L1抗体的给药剂量为600、800、1000、1200、1400、1600、1800、2000、2200或2400mg。在一些具体实施方案中，每个治疗周期，抗PD-L1抗体的给药剂量为1200mg。在一些实施方案中，在每个治疗周期的第一天给予抗PD-L1抗体。在一些具体的实施方案中，每3周为一个治疗周期。在一些具体的实施方案中，抗PD-L1抗体每三周给药一次，每次给药剂量为600-2400mg。在一些实施方案中，3周(21天)为一个治疗周期，在每个治疗周期的第一天向有需要的患者给予抗PD-L1抗体。在一些具体的实施方案中，抗PD-L1抗体在每三周的第一天给药一次，每次给药剂量为600-2400mg。在一些具体的实施方案中，抗PD-L1抗体在每三周的第一天给药一次，每次给药剂量为1200mg。
在一些实施方案中，本申请所述的药物组合包括：抗PD-L1人源化单克隆抗体和安罗替尼或其药学上可接受的盐。
在一些实施方案中，本申请所述的含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合包括：抗PD-L1抗体的药物组合物，和安罗替尼或其药学上可接受的盐的药物组合物。在一些实施方案中，所述的药物组合物进一步含有药学上可接受的载体。
在一些实施方案中，本申请所述的含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合包括：含600-2400mg抗PD-L1抗体的药物组合物。在一些实施方案中，所述药物组合包括：含600-2400mg抗PD-L1抗体的药物组合物，其中抗PD-L1抗体的药物组合物为单位剂量或者多剂量。
在一些实施方案中，本申请所述的含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合包括：6mg-12mg安罗替尼或其药学上可接受的盐的药物组合物。在一些实施方案中，所述药物组合包括：单位剂量为6mg、8mg、10mg和/或12mg安罗替尼或其药学上可接受的盐的药物组合物。
在一些实施方案中，本申请所述的含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合包括：600-2400mg抗PD-L1抗体的药物组合物和单位剂量为6mg、8mg、10mg和/或12mg安罗替尼或其药学上可接受的盐的药物组合物，其中抗PD-L1抗体的药物组合物为单位剂量或者多剂量。在一些实施方案中，所述药物组合包括：600-2400mg抗PD-L1抗体以多剂量形式提供的药物组合物和单位剂量为6mg、8mg、10mg和/或12mg安罗替尼或其药学上可接受的盐的药物组合物。在一些实施方案中，所述药物组合为适用于在单个治疗周期(例如21天的一个治疗周期)内施用的制剂，包括600-2400mg抗PD-L1抗 体的药物组合物和84-168mg安罗替尼或其药学上可接受的盐的药物组合物。
在一些实施方案中，本申请所述的含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合包括：重量比为(0.35-29):1、(3.5-29):1、(3.5-14.5):1、或(7-14.5):1的抗PD-L1抗体和安罗替尼或其药学上可接受的盐。其中，抗PD-L1抗体和安罗替尼或其药学上可接受的盐可分开地包装或者包装在一起。其中，安罗替尼能够以多个等份(例如2等份、7等份、14等份、28等份或更多等份)进行包装；抗PD-L1抗体能够以单等份或多个等份(例如2等份、4等份或更多等份)进行包装。
在一些实施方案中，本申请所述的含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合中，所述抗PD-L1抗体和安罗替尼或其药学上可接受的盐各自呈药物组合物的形式，可同时、先后或依次给药。
在一些实施方案中，本申请所述的抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合包括抗PD-L1抗体的药物组合物和安罗替尼的药物组合物，其中抗PD-L1抗体被制备为适合第一次给药时向患者给予600-2400mg的抗PD-L1抗体的单位剂量或多剂量，所述安罗替尼或其药学上可接受的盐的药物组合物被制备为适合连续14天、每天向患者给予6mg、8mg、10mg和/或12mg安罗替尼或其药学上可接受的盐的单位剂量。
在一些实施方案中，本申请所述的抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合包括：抗PD-L1抗体浓度为10-60mg/mL的抗PD-L1抗体的药物组合物，和单位剂量为6mg、8mg、10mg和/或12mg安罗替尼或其药学上可接受的盐的药物组合物。
在一些实施方案中，本申请所述的抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合包括：1200mg的抗PD-L1抗体以多剂量形式提供的药物组合物，和单位剂量为8mg、10mg和/或12mg安罗替尼或其药学上可接受的盐的药物组合物。
在一些实施方案中，所述的试剂盒为适用于在单个治疗周期(例如21天的一个治疗周期)内施用的试剂盒，包括含600-2400mg的抗PD-L1抗体的药物组合物和含84-168mg的安罗替尼或其药学上可接受的盐的药物组合物。
在一些实施方案中，提供了一种治疗非MSI-H和/或非dMMR子宫内膜癌的方法，其包括：向有需要的患者给予治疗有效量的抗PD-L1抗体和安罗替尼或其药学上可接受的盐。在一些实施方案中，抗PD-L1抗体和安罗替尼或其药学上可接受的盐同时、先后、依次给药。在一些实施方案中，抗PD-L1抗体每1周、每2周、每3周、或者每4周给药一次。在一些实施方案中，抗PD-L1抗体每次以600-2400mg的剂量给药。在一些实施方案中，抗PD-L1抗体的单次给药剂量为600、800、1000、1200、1400、1600、1800、2000、2200或2400mg。在一些实施方案中，安罗替尼或其药学上可接受的盐以6mg-12mg的日剂量给药。在一些实施方案中，安罗替尼或其药学上可接受的盐以8mg-12mg的日剂量给药。在一些实施方案中，安罗替尼或其药学上可接受的盐以6mg、8mg、10mg或者12mg的日剂量给药。在一些实施方案中，安罗替尼或其药学上可接受的盐以每日一次6mg、8mg、10mg或者12mg的剂量给药。在一些实施方案中，安罗替尼或其药学上可接受的盐以连续用药2周、停1周的给药方案给药。在一些实施方案中，每3周为一个治疗周期。在一些实施方案中，21天为一个治疗周期，在每个治疗周期的第一天向患者给予抗PD-L1抗体。在一些实施方案中，每3周为一个治疗周期，抗PD-L1抗体在每个周期的第一天给药，安罗替尼或其药学上可接受的盐在每个周期的第1-14天给药。在一些实施方案中，抗PD-L1抗体以胃肠外给药的方式给药。在一些实施方案中，抗PD-L1抗体的药物组合物的浓度为10-60mg/mL；在一些实施方案中，抗PD-L1抗体的药物组合物的浓度为10、20、30、40、50或者60mg/mL。在一些实施方案中，安罗替尼或其药学上可接受的盐口服给药。
再一方面，本申请提供了一种治疗子宫内膜癌的方法，其包括：(1)获得或者已经获得患者的生物样本；(2)对生物样本进行检测或者已经对生物样本进行了检测，确定样本是否为MSI-H和/或dMMR；(3)如果检测结果为MSI-H和/或dMMR，则向患者给予治疗有效量的抗PD-L1抗体或者含抗PD-L1抗体的药物组合物；以及(4)如果检测结果为非MSI-H和/或非dMMR时，则向患者给予治疗有效量的抗PD-L1抗体和安罗替尼或其药学上可接受的盐。
又一方面，本申请提供了一种治疗MSI-H和/或dMMR肿瘤的方法，其包括：(1)获得或者已经获得患者的生物样本；(2)对生物样本进行检测或者已经对生物样本进行了检测，确定样本是否为MSI-H或者dMMR；以及(3)如果检测结果为MSI-H或dMMR，则向患者给予治疗有效量的抗PD-L1抗体或者含抗PD-L1抗体的药物组合物。
安罗替尼或其药学上可接受的盐
安罗替尼的化学名为1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺，其具有如下的结构式：
Figure PCTCN2021103687-appb-000001
所述安罗替尼的药学上可接受的盐包括但不限于安罗替尼与选自以下的酸所形成的盐：盐酸、氢溴酸、硫酸、硝酸、磷酸、乙酸、三氟乙酸、丙酸、己酸、庚酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、对氯苯磺酸、对甲苯磺酸、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、羟基萘甲酸、水杨酸、硬脂酸。在一些实施方案中，所述药学上可接受的盐为盐酸盐和马来酸盐。在一些实施方案中，所述药学上可接受的盐为二盐酸盐。
本申请中涉及的安罗替尼或其药学上可接受的盐的剂量，除非另有说明，均基于安罗替尼游离碱的分子量。
安罗替尼或其药学上可接受的盐可通过多种途径给药，该途径包括经胃肠道给药以及肠胃外给药途径，包括但不限于口服、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、吸入、阴道、眼内、皮下、脂肪内、关节内、腹膜内和鞘内。在一些特定的实施方案中，通过口服给药。给予安罗替尼或其药学上可接受的盐的量可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄和健康状态来确定。例如，给予安罗替尼或其药学上可接受的盐的日剂量可为2毫克至20毫克。在一些实施方案中，给予安罗替尼或其药学上可接受的盐的日剂量可为2、3、4、5、6、7、8、9、10、11、12、13、14、15和16毫克。安罗替尼或其药学上可接受的盐可以每日施用一次或多次。在一些实施方案中，安罗替尼或其药学上可接受的盐以口服固体制剂每天给药一次。
安罗替尼或其药学上可接受的盐的给药方案可根据药物的活性、毒性以及患者的耐受性等来综合确定。优选地，以间隔给药的方式给予安罗替尼或其药学上可接受的盐。所述的间隔给药包括给药期和停药期，在给药期内可以每天一次或多次给予安罗替尼或其药学上可接受的盐。例如给药期和停药期的以天数计的比值为2:(0.5-5)，2:(0.5-3)，2:(0.5-2)，或者2:(0.5-1)。在一些实施方案中，连续给药2周停药2周。在一些实施方案中，连续给药2周停药1周。在一些实施方案中，连续给药5天停药2天。例如安罗替尼或其药学上可接受的盐可以每日一次6mg、8mg、10mg或者12mg的剂量口服给药，连续用药2周，停1周的给药方式给药。
安罗替尼或其药学上可接受的盐的药物组合物
在本申请的一些实施方案中，所述安罗替尼或其药学上可接受的盐的药物组合物的单位剂量包括6mg、8mg、10mg、或12mg的安罗替尼。
在本申请的一些实施方案中，按照给药2周停1周的治疗周期，每个周期给予所述安罗替尼或其药学上可接受的盐的药物组合物的总剂量包括84-168mg。在部分方案中，所述安罗替尼或其药学上可接受的盐的药物组合物的总剂量包括选自84mg、112mg、140mg、168mg或上述任意值形成的范围。在部分方案中，所述安罗替尼或其药学上可接受的盐的药物组合物的总剂量包括112mg-168mg。
在一些实施方案中，所述药物组合物包括但不限于适合口服、肠道外给药的制剂。在一些实施方案中，所述药物组合物为适合口服的制剂。在一些实施方案中，所述药物组合物为适合口服的固体制剂。在一些实施方案中，所述药物组合物包括但不限于片剂、胶囊。
抗PD-L1抗体
在一些实施方案中，所述的抗PD-L1抗体为抗PD-L1人源化单克隆抗体。
在本申请的一些实施方案中，所述抗PD-L1抗体为WO2016022630或CN107001463A中的抗体。
在本申请的一些实施方案中，所述抗PD-L1抗体包含如下氨基酸序列：与SEQ ID NO:1或SEQ ID NO:4所示的氨基酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性的重链CDR1区；与SEQ ID NO:2或SEQ ID NO:5所示的氨基酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性的重链CDR2区；与SEQ ID NO:3或SEQ ID NO:6所示的氨基酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性的重链CDR3区；与SEQ ID NO:7或SEQ ID NO:10所示的氨基酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性 的轻链CDR1区；与SEQ ID NO:8或SEQ ID NO:11所示的氨基酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性的轻链CDR2区；与SEQ ID NO:9或SEQ ID NO:12所示的氨基酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性的轻链CDR3区。
在本申请的一些实施方案中，所述抗PD-L1抗体包含如下氨基酸序列：选自SEQ ID NO:1或SEQ ID NO:4的重链CDR1区；选自SEQ ID NO:2或SEQ ID NO:5的重链CDR2区；选自SEQ ID NO:3或SEQ ID NO:6的重链CDR3区；选自SEQ ID NO:7或SEQ ID NO:10的轻链CDR1区；选自SEQ ID NO:8或SEQ ID NO:11的轻链CDR2区；选自SEQ ID NO:9或SEQ ID NO:12的轻链CDR3区。
在本申请的一些实施方案中，本文所述的分离的抗PD-L1抗体包含：具有以SEQ ID NO:1示出的氨基酸序列的重链CDR1区，具有以SEQ ID NO:2示出的氨基酸序列的重链CDR2区，具有以SEQ ID NO:3示出的氨基酸序列的重链CDR3区；以及具有以SEQ ID NO:7示出的氨基酸序列的轻链CDR1区，具有以SEQ ID NO:8示出的氨基酸序列的轻链CDR2区，具有以SEQ ID NO:9示出的氨基酸序列的轻链CDR3区。
本文所述的各CDR区及其上述的各种变体能够特异性地识别并结合PD-L1，从而有效地阻断PD-L1和PD-1之间的信号传导。
在本申请的一些实施方案中，所述抗PD-L1抗体包含如下氨基酸序列：与SEQ ID NO:13或SEQ ID NO:14所示的氨基酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性的重链可变区；与SEQ ID NO:15或SEQ ID NO:16所示的氨基酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性的轻链可变区。
在本申请的一些实施方案中，所述抗PD-L1抗体包含如下氨基酸序列：如SEQ ID NO:13所示的重链可变区；如SEQ ID NO:15所示的轻链可变区。
在本申请的一些实施方案中，所述抗PD-L1抗体包含如下氨基酸序列：如SEQ ID NO:14所示的重链可变区；如SEQ ID NO:16所示的轻链可变区。
在本申请的一些实施方案中，所述抗PD-L1抗体包含如下氨基酸序列：如SEQ ID NO:17所示的重链氨基酸序列；如SEQ ID NO:18所示的轻链氨基酸序列。
在本申请的一些实施方案中，所述抗PD-L1抗体包含如下氨基酸序列：如SEQ ID NO:19所示的重链氨基酸序列；如SEQ ID NO:20所示的轻链氨基酸序列。
在本申请的一些实施方案中，所述抗PD-L1抗体包含如下氨基酸序列：如SEQ ID NO:21所示的重链氨基酸序列；如SEQ ID NO:18所示的轻链氨基酸序列。
在一个具体实施方案中，本申请提供的抗PD-L1人源化单抗包含选自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、SEQID 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、SEQ ID NO:21中的一个或多个的保守置换变体。包含所述保守置换变体的抗PD-L1人源化单抗保留了特异性地识别并结合PD-L1的能力。
在本申请的一些实施方案中，所述抗PD-L1抗体可为IgG1或IgG4抗体。
在本申请的一些实施方案中，所述抗PD-L1抗体为IgG1抗体。在部分实施方案中，所述抗PD-L1抗体为糖基化的IgG1抗体。
在本申请的一些实施方案中，所述抗PD-L1抗体包含选自13C5或5G11抗体的重链互补决定区(CDR)，和选自13C5或5G11抗体的轻链互补决定区。在一个实施方案中，本申请所述的抗PD-L1抗体包含选自ch5G11-hIgG1、ch5G11-hIgG4、ch13C5-hIgG1、ch13C5-hIgG4嵌合抗体的可变重链，和选自ch5G11-hIgG1、ch5G11-hIgG4、ch13C5-hIgG1、ch13C5-hIgG4嵌合抗体的可变轻链。在一个实施方案中，本申请所述的抗PD-L1抗体包含选自hu13C5-hIgG1、hu13C5-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4人源化抗体的可变重链，和选自hu13C5-hIgG1、hu13C5-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4人源化抗体的可变轻链。可以参考专利文献WO2016022630或CN107001463A的记载：13C5、ch13C5-hIgG1、ch13C5-hIgG4、hu13C5-hIgG1或hu13C5-hIgG4的HCDR1序列为SYGMS(SEQ ID NO:4)，HCDR2序列为SISSGGSTYYPDSVKG(SEQ ID NO:5)，HCDR3序列为GYDSGFAY(SEQ ID NO:6)，LCDR1序列为ASQSVSTSSSSFMH(SEQ ID NO:10)，LCDR2序列为YASNLES(SEQ ID NO:11)，LCDR3序列为QHSWEIPYT(SEQ ID NO:12)；5G11、ch5G11-hIgG1、ch5G11-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4的HCDR1序列为TYGVH(SEQ ID NO:1)，HCDR2序列为VIWRGVTTDYNAAFMS(SEQ ID NO:2)，HCDR3序列为LGFYAMDY(SEQ ID NO:3)，LCDR1序列为KASQSVSNDVA(SEQ ID NO:7)，LCDR2序列为YAANRYT(SEQ ID NO:8)，LCDR3序列为QQDYTSPYT(SEQ ID NO:9)。
在本申请的一些实施方案中，所述药物组合中的抗PD-L1抗体可以选自一种或多种。如本申请所用，术语“多种”可以是多于一种，例如，两种、三种、四种、五种或更多种。例如，在本申请的一些实施方案中，所述抗PD-L1抗体选自包含如SEQ ID NO:13所示的重链可变区和如SEQ ID NO:15所示的轻链可变区，或选自包含如SEQ ID NO:14所示的重链可变区和如SEQ ID NO:16所示的轻链可变区，或选自上述的组合。又例如，所述抗PD-L1抗体选自如SEQ ID NO:17所示的重链氨基酸序列和如SEQ ID NO:18所示的轻链氨基酸序列，或选自如SEQ ID NO:19所示的重链氨基酸序列和如SEQ ID NO:20所示的轻链氨基酸序列，或选自如SEQ ID NO:21所示的重链氨基酸序列和如SEQ ID NO:18所示的轻链氨基酸序列，或选自上述任选多种的组合。
在一些实施方案中，抗PD-L1抗体包含如下氨基酸序列：与SEQ ID NO:1或SEQ ID NO:4所示的氨基酸序列有至少80％同源性的重链CDR1区；与SEQ ID NO:2或SEQ ID NO:5所示的氨基酸序列有至少80％同源性的重链CDR2区；与SEQ ID NO:3或SEQ ID NO:6所示的氨基酸序列有至少80％同源性的重链CDR3区；与SEQ ID NO:7或SEQ ID NO:10所示的氨基酸序列有至少80％同源性的轻链CDR1区；与SEQ ID NO:8或SEQ ID NO:11所示的氨基酸序列有至少80％同源性的轻链CDR2区；与SEQ ID NO:9或SEQ ID NO:12所示的氨基酸序列有至少80％同源性的轻链CDR3区。
抗PD-L1抗体的药物组合物
在本申请的一些实施方案中，所述抗PD-L1抗体的药物组合物含有600-2400mg的抗PD-L1抗体。在部分方案中，所述抗PD-L1抗体的药物组合物含有选自600mg、900mg、1200mg、1500mg、1800mg、2100mg、2400mg、或上述任意值形成的范围的抗PD-L1抗体。在部分方案中，所述抗PD-L1抗体的药物组合物含有600-2100mg、或900mg-1500mg的抗PD-L1抗体；其中所述抗PD-L1抗体的药物组合物可以多剂量或者单位剂量形式存在。
在本申请的一些实施方案中，所述抗PD-L1抗体的药物组合物中含300mg、600mg或者1200mg的抗PD-L1抗体。在本申请的一些实施方案中，提供了一种配制成单位剂量的抗PD-L1抗体的药物组合物，其含有300mg、600mg或1200mg的抗PD-L1抗体。
在一些实施方案中，所述抗PD-L1抗体的药物组合物为注射用溶液剂。在一些实施方案中，所述抗PD-L1抗体的药物组合物为注射用水溶液。在本申请的一些实施方案中，所述抗PD-L1抗体的药物组合物包含缓冲液、等渗调节剂、稳定剂和/或表面活性剂中的一种或多种。特别地，所述抗PD-L1抗体的药物组合物包含1-150mg/mL抗PD-L1抗体(例如单抗)、3-50mM缓冲液、2-150mg/mL等渗调节剂/稳定剂和0.01-0.8mg/mL表面活性剂，且pH为4.5-6.8。
在本申请的一些实施方案中，所述抗PD-L1抗体的药物组合物以w/v计算，抗PD-L1单抗浓度为5-150mg/mL；在一些实施方案中为10-60mg/mL；在一些实施方案中为10-30mg/mL。在一些具体方案中，抗PD-L1单抗质量体积浓度为10mg/mL、20mg/mL、30mg/mL、40mg/mL、50mg/mL、60mg/mL、70mg/mL、80mg/mL、90mg/mL、100mg/mL、110mg/mL或120mg/mL；在一些实施方案中，为10mg/mL、20mg/mL、30mg/mL、40mg/mL、50mg/mL或60mg/mL；在一些实施方案中，为10mg/mL、20mg/mL或30mg/mL。在一些实施方案中，抗PD-L1单抗质量体积浓度为10mg/mL。在另一些实施方案中，抗PD-L1单抗质量体积浓度为30mg/mL。在另一些实施方案中，抗PD-L1单抗质量体积浓度为60mg/mL。
在本申请的一些实施方案中，所述缓冲液为组氨酸盐缓冲液。所述组氨酸盐缓冲液浓度为5-30mM；在一些实施方案中，为10-25mM；在一些实施方案中，为10-20mM；在一些实施方案中，为10-15mM。在一些具体方案中，所述组氨酸盐缓冲液浓度为5mM、10mM、15mM、20mM、25mM或30mM。在一些实施方案中，所述组氨酸盐缓冲液浓度为10mM。在另一些实施方案中，所述组氨酸盐缓冲液浓度为15mM。在另一些实施方案中，所述组氨酸盐缓冲液浓度为20mM。其中，所述组氨酸盐缓冲液包含组氨酸和盐酸。
在本申请的一些实施方案中，以w/v计算，所述等渗调节剂/稳定剂为20-150mg/mL的蔗糖；在一些实施方案中，为40-100mg/mL的蔗糖；在一些实施方案中，为60-80mg/mL的蔗糖。在一些具体方案中，所述蔗糖的浓度为40mg/mL、50mg/mL、60mg/mL、70mg/mL、80mg/mL、90mg/mL或100mg/mL。在一些具体实施方案中，所述蔗糖的浓度为60mg/mL。在一些具体实施方案中，所述蔗糖的浓度为70mg/mL。在一些具体实施方案中，所述蔗糖的浓度为80mg/mL。在一些具体实施方案中，所述蔗糖的浓度为90mg/mL。
在本申请的一些实施方案中，所述表面活性剂选自聚山梨酯80、聚山梨酯20、泊洛沙姆188；在一些实施方案中，选自聚山梨酯80或聚山梨酯20；在一些实施方案中，选自聚山梨酯80。在一些方案中，以w/v计算，所述表面活性剂的浓度为0.05-0.6mg/mL；在一些实施方案中，为0.1-0.4mg/mL；在一些实施方案中，为0.2-0.3mg/mL。
在本申请的一些实施方案中，以w/v计算，所述表面活性剂为0.01-0.8mg/mL的聚山梨酯80或聚山梨酯20。在一些具体方案中，所述表面活性剂为0.05-0.6mg/mL的聚山梨酯80；在一些实施方案中，为 0.1-0.4mg/mL的聚山梨酯80；在一些实施方案中，为0.2-0.3mg/mL的聚山梨酯80；在一些实施方案中，为0.2mg/mL的聚山梨酯80。在一些实施方案中，所述药物组合物中聚山梨酯80含量为0.1mg/mL、0.2mg/mL、0.3mg/mL、0.4mg/mL、0.5mg/mL或0.6mg/mL。在一些实施方案中，所述药物组合物中聚山梨酯80含量为0.2mg/mL、0.3mg/mL、0.4mg/mL或0.5mg/mL。在一些实施方案中，所述药物组合物中聚山梨酯80含量为0.2mg/mL、0.3mg/mL或0.4mg/mL。在一些实施方案中，所述药物组合物中聚山梨酯80含量为0.2mg/mL。在一些实施方案中，所述药物组合物中聚山梨酯80含量为0.1mg/mL。在另一些实施方案中，所述药物组合物中聚山梨酯80含量为0.2mg/mL。在一些实施方案中，所述药物组合物中聚山梨酯80含量为0.3mg/mL。在另一些实施方案中，所述药物组合物中聚山梨酯80含量为0.4mg/mL。在一些实施方案中，所述药物组合物中聚山梨酯80含量为0.5mg/mL。
在本申请的一些实施方案中，所述药物组合物的水溶液pH值选自4.0-6.8；在一些实施方案中，为4.5-6.5；在一些实施方案中，为5.5-6.0；在一些实施方案中，为5.5。在一些实施方案中，药物组合物水溶液的pH值为4.5、4.8、5.0、5.2、5.4、5.5、5.6、5.8或6.0；在一些实施方案中，为5.0、5.2、5.4、5.5或5.6；在一些实施方案中，为5.5。在一些实施方案中，药物组合物水溶液的pH值为5.0。在一些实施方案中，药物组合物水溶液的pH值为5.2。在一些实施方案中，药物组合物水溶液的pH值为5.4。在一些实施方案中，药物组合物水溶液的pH值为5.5。在一些实施方案中，药物组合物水溶液的pH值为5.6。在一些实施方案中，药物组合物水溶液的pH值为5.8。在一些实施方案中，药物组合物水溶液的pH值为6.0。
在本申请的一些具体实施方案中，所述药物组合物包含：(a)质量体积浓度为20mg/mL的抗PD-L1抗体，(b)质量体积浓度为70mg/mL的蔗糖，(c)质量体积浓度为0.1mg/mL的聚山梨酯80，(d)摩尔浓度为20mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为5.0。本申请的一个具体实施方案中，所述药物组合物包含：(a)质量体积浓度为20mg/mL的抗PD-L1单抗，(b)质量体积浓度为70mg/mL的蔗糖，(c)质量体积浓度为0.1mg/mL的聚山梨酯80，(d)摩尔浓度为20mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为5.0。
在本申请的另一个具体实施方案中，所述药物组合物包含：(a)质量体积浓度为10mg/mL的抗PD-L1抗体，(b)质量体积浓度为80mg/mL的蔗糖，(c)质量体积浓度为0.2mg/mL的聚山梨酯80，(d)摩尔浓度为10mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为5.5。
在本申请的另一个具体实施方案中，所述药物组合物包含：(a)质量体积浓度为50mg/mL的抗PD-L1抗体，(b)质量体积浓度为80mg/mL的蔗糖，(c)质量体积浓度为0.3mg/ml的聚山梨酯80，(d)摩尔浓度为10mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为5.5。
在本申请的另一个具体实施方案中，所述药物组合物包含：(a)质量体积浓度为100mg/mL的抗PD-L1抗体，(b)质量体积浓度为80mg/mL的蔗糖，(c)质量体积浓度为0.5mg/mL的聚山梨酯80，(d)摩尔浓度为10mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为5.5。
在本申请的另一个具体实施方案中，所述药物组合物包含：(a)质量体积浓度为30mg/mL的抗PD-L1抗体，(b)质量体积浓度为80mg/mL的蔗糖，(c)质量体积浓度为0.2mg/mL的聚山梨酯80，(d)摩尔浓度为10mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为5.5。
在本申请的另一个具体实施方案中，所述药物组合物包含：(a)质量体积浓度为60mg/mL的抗PD-L1抗体，(b)质量体积浓度为80mg/mL的蔗糖，(c)质量体积浓度为0.2mg/mL的聚山梨酯80，(d)摩尔浓度为10mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为5.5。
在本申请的另一个具体实施方案中，所述药物组合物包含：(a)质量体积浓度为10mg/mL的抗PD-L1抗体，(b)质量体积浓度为70mg/mL的蔗糖，(c)质量体积浓度为0.4mg/mL的聚山梨酯80，(d)摩尔浓度为20mM的组氨酸，(e)任选醋酸适量，调节组合物的pH值为6.5。
在本申请的另一个具体实施方案中，所述药物组合物包含：(a)质量体积浓度为10mg/mL的抗PD-L1单抗，(b)质量体积浓度为80mg/mL的蔗糖，(c)质量体积浓度为0.2mg/mL的聚山梨酯80，(d)摩尔浓度为20mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为5.5。
在本申请的另一个具体实施方案中，药物组合物为水溶性注射液。在一些实施方案中，所述水溶性注射液包括但不限于未经冻干的水溶性制剂或冻干粉重构的水溶性制剂。在另一些方案中，药物组合物为冻干制剂。所述冻干制剂是指水溶液经历冻干过程制备的制剂，在该过程中物质首先被冷冻，然后先通过升华降低溶剂数量(初级干燥过程)，然后通过脱附作用降低溶剂数量(二级干燥过程)，直到溶剂数量为不再支持生物学活性或化学反应的值。本申请的冻干制剂还可以通过本领域已知的其它方法干燥，如喷雾干燥和鼓泡干燥(bubble drying)。
子宫内膜癌
本申请中，所述的子宫内膜癌包括但不限于Ⅰ型(雌激素依赖型)子宫内膜癌或Ⅱ型(非雌激素依赖型)子宫内膜癌。
在本申请的一些实施方案中，所述的子宫内膜癌为晚期子宫内膜癌。在本申请的一些实施方案中，所述的子宫内膜癌为难治性子宫内膜癌。
在本申请的一些实施方案中，所述的子宫内膜癌为复发性和/或转移性的子宫内膜癌。
在本申请的一些实施方案中，所述的子宫内膜癌为复发性和/或转移性的晚期子宫内膜癌。
在本申请的一些实施方案中，所述非微卫星不稳定高突变型(非MSI-H)子宫内膜癌包括微卫星低度不稳定型(MSI-L)子宫内膜癌和微卫星稳定型(MSS)子宫内膜癌。
在本申请的一些实施方案中，所述非错配修复缺陷(非dMMR)子宫内膜癌包括错配修复功能完整(pMMR)的子宫内膜癌。
在本申请的一些实施方案中，所述子宫内膜癌的患者已接受过一种或两种以上药物治疗。在本申请的一些实施方案中，所述子宫内膜癌为至少一种药物治疗失败的子宫内膜癌。在一些实施方案中，所述的治疗失败包括在治疗期间疾病进展，以及治疗结束后疾病进展和/或复发。
在本申请的一些实施方案中，所述子宫内膜癌的患者已接受过一种或两种以上化疗。在本申请的一些实施方案中，所述子宫内膜癌为至少一种化疗治疗失败的子宫内膜癌。在一些实施方案中，所述的治疗失败包括在治疗期间疾病进展或者无客观缓解，以及治疗结束后疾病进展和/或复发。在本申请的一些实施方案中，所述子宫内膜癌的患者既往接受过1-2线全身标准化疗方案，治疗失败或不能耐受。
本申请中，所述药物治疗包括但不限于化疗、靶向药物的治疗和激素治疗。
本申请的一些实施方案中，所述的化疗包括但不限于紫杉烷类、长春碱类抗肿瘤药、铂配合物、氟尿嘧啶及其衍生物、喜树碱及其衍生物、蒽环类化合物、鬼臼类化合物中的一种或多种。其中所述紫杉烷类包括但不限于为紫杉醇、白蛋白结合的紫杉醇以及多烯紫杉醇(多西他赛)中的一种或多种；所述的长春碱类抗肿瘤药包括但不限于选自长春碱、长春新碱、长春地辛、长春瑞滨、长春富宁(vinflunine)、去甲长春花碱中的一种或多种；所述铂配合物包括但不限于选自米铂、顺铂、卡铂、双环铂、奈达铂、奥沙利铂、乐铂(Lobaplatin)、四硝酸三铂、菲铂、吡铂、沙铂中的一种或多种；所述氟尿嘧啶及其衍生物包括但不限于选自阿糖胞苷、阿扎胞苷、安西他滨、卡培他滨、吉西他滨、氟尿嘧啶、双呋氟尿嘧啶、去氧氟尿苷、三氟尿苷、替加氟、卡莫氟、优福定中的一种或多种；所述喜树碱及其衍生物包括但不限于为喜树碱、羟基喜树碱、伊立替康、拓扑替康中的一种或多种；所述蒽环类化合物包括但不限于为表柔比星(表阿霉素)、阿霉素、柔红霉素、吡柔比星、氨柔比星、伊达柔比星、米托蒽醌、阿柔比星、戊柔比星、佐柔比星、匹杉琼、吡喃阿霉素、脂质体阿霉素中的一种或多种；所述鬼臼类化合物包括但不限于为依托泊苷(足叶乙苷)、替尼铂苷、表鬼臼毒吡喃葡萄糖甙中的一种或多种。
在本申请的一些实施方案中，所述靶向药物包括但不限于EGFR拮抗剂、VEGF抑制剂、HER2抑制剂、PARP抑制剂、PI3K/Akt/mTOR通路抑制剂、PD-1/PD-L1抑制剂、或FGFR抑制剂中的一种或多种。
在本申请的一些实施方案中，所述EGFR拮抗剂包括但不限于曲妥珠单抗(trastuzumab)、西妥昔单抗(cetuximab)、埃克替尼(icotinib)、吉非替尼(gefitinib)、厄洛替尼(erlotinib)、拉帕替尼(lapatinib)中的一种或多种。在本申请的一些实施方案中，所述VEGF抑制剂包括但不限于贝伐珠单抗(bevacizumab)、雷珠单抗(ranibizumab)、阿昔替尼(axitinib)、莫替沙尼(motesanib)、阿柏西普(aflibercept)、西地尼布(cediranib)、尼达尼布(nintedanib)、索拉非尼(sorafenib)、或舒尼替尼(sunitinib)。在本申请的一些实施方案中，所述PARP抑制剂包括但不限于奥拉帕利(olaparib)、尼拉帕利(niraparib)、或芦卡帕利(rucaparib)中的一种或多种。在本申请的一些实施方案中，所述PI3K/Akt/mTOR通路抑制剂包括但不限于NVP-BKM120、XL147、哌立福新(perifosine)、雷帕霉素(rapamycin)、坦罗莫司(temsirolimus)、依维莫司(everolimus)、西罗莫司(sirolimus)、或地磷莫司(ridaforolimus)中的一种或多种。在本申请的一些实施方案中，所述PD-1/PD-L1抑制剂包括但不限于阿特珠单抗(atezolizumab)、纳武利尤单抗(nivolumab)、或帕博利珠单抗(pembrolizumab)中的一种或多种。在本申请的一些实施方案中，所述FGFR抑制剂包括但不限于度维替尼(dovitinib)、或NVP-BGJ398。
在本申请的一些实施方案中，所述激素治疗药物包括但不限于孕激素类、抗雌激素类、芳香化酶抑制剂中的一种或多种。在本申请的一些实施方案中，所述孕激素类药物包括但不限于黄体酮、醋酸甲地孕酮、氯地孕酮、醋酸甲羟孕酮、醋酸羟孕酮、己酸羟孕酮、醋酸环丙孕酮、地屈孕酮、地美孕酮、普美孕酮、利奈孕酮、炔诺酮、左炔孕酮、去氧孕烯、地诺孕素、或屈螺酮中的一种或多种。在本申请的一些实施方案中，所述抗雌激素类药物包括但不限于氯米芬、他莫昔芬、托瑞米芬、雷洛昔芬、曲普瑞林、亮丙瑞林、或戈舍瑞林中的一种或多种。在本申请的一些实施方案中，所述芳香化酶抑制剂包括但不限于氨鲁米特、福美司坦(Formestane)、依西美坦、来曲唑、阿那曲唑、罗谷亚氨(Rogletimide)、或法倔唑(Fadrozole)中的一种或多种。
MSI-H和/或dMMR肿瘤
在一些实施方案中，所述的肿瘤为实体瘤；在一些实施方案中，所述的肿瘤为恶性肿瘤；在一些实施方案中，所述的肿瘤为恶性实体瘤。
本申请所述的MSI-H和/或dMMR肿瘤，是基于生物标志物的检测结果，例如显示为MSI-H和/或dMMR，而不限制肿瘤的类型。
本申请中，所述的实体瘤不包括血液系统(Hematologic/Blood)肿瘤。
在一些实施方案中，所述的肿瘤包括但不限于乳腺癌(例如激素受体阳性的乳腺癌、三阴性乳腺癌、HER2/neu阳性或者阴性的乳腺癌)、消化系统/胃肠道肿瘤(例如肛门癌、阑尾癌、胆管癌、胃肠道基质瘤、胃肠道类癌、结直肠癌、胃癌、食道癌、胆囊癌、胆管癌、肝癌、胰腺癌、胰岛细胞瘤、胰腺神经内分泌肿瘤)、内分泌系统肿瘤和神经内分泌癌(例如肾上腺皮质癌、甲状腺癌、皮肤神经内分泌肿瘤、甲状旁腺癌)、眼癌、泌尿生殖系统癌(例如膀胱癌、肾癌、前列腺癌、睾丸癌、尿道癌、尿路上皮癌)、妇科癌症(例如子宫内膜癌、卵巢癌、宫颈癌、输卵管癌、原发性腹膜癌、阴道癌、外阴癌)、头颈癌(例如下咽癌、喉癌、唇和口腔癌、口腔癌、鼻咽癌、口咽癌、鼻旁窦和鼻腔癌、咽癌、唾液腺癌、咽喉癌)、呼吸系统癌(例如肺癌(包括但不限于非小细胞肺癌、小细胞肺癌)、恶性间皮瘤、胸腺癌)、皮肤癌(例如默克尔细胞癌、皮肤鳞状细胞癌、黑色素瘤)、神经系统肿瘤(例如脑癌、胶质细胞瘤、神经母细胞瘤、垂体瘤、原发性中枢神经系统淋巴瘤)、骨癌、软组织肉瘤、血液系统(Hematologic/Blood)肿瘤(例如白血病Leukemia、淋巴瘤Lymphoma)中的一种或者多种。
在一些实施方案中，所述的恶性肿瘤包括但不限于乳腺癌(例如激素受体阳性的乳腺癌、三阴性乳腺癌、HER2/neu阳性或者HER2/neu阴性的乳腺癌)、消化系统癌/胃肠道癌(例如肛门癌、阑尾癌、胆管癌、胃肠道基质瘤、胃肠道类癌、结直肠癌、胃癌、食道癌、胆囊癌、胆管癌、肝癌、胰腺癌)、内分泌系统癌和神经内分泌癌(例如肾上腺皮质癌、甲状腺癌、皮肤神经内分泌肿瘤、甲状旁腺癌)、眼癌、泌尿生殖系统癌(例如膀胱癌、肾癌、前列腺癌、睾丸癌、尿道癌、尿路上皮癌)、妇科癌症(例如子宫内膜癌、卵巢癌、宫颈癌、输卵管癌、原发性腹膜癌、阴道癌、外阴癌)、头颈癌(例如下咽癌、喉癌、唇和口腔癌、口腔癌、鼻咽癌、口咽癌、鼻旁窦癌和鼻腔癌、咽癌、唾液腺癌、咽喉癌)、呼吸系统癌(例如肺癌(包括但不限于非小细胞肺癌、小细胞肺癌)、恶性间皮瘤、胸腺癌)、皮肤癌(例如默克尔细胞癌、皮肤鳞状细胞癌、黑色素瘤)、神经系统恶性肿瘤(例如脑癌、胶质细胞瘤、神经母细胞瘤、原发性中枢神经系统淋巴瘤)、骨癌、软组织肉瘤、血液系统恶性肿瘤(Hematologic/Blood cancer)(例如白血病Leukemia、淋巴瘤Lymphoma)中的一种或者多种。
在本申请一些实施例中，所述MSI-H和/或dMMR肿瘤为宫颈癌(包括但不限于宫颈鳞癌、宫颈腺癌)。在本申请一些实施例中，所述MSI-H和/或dMMR肿瘤为肝胆道系统癌(包括但不限于肝癌、胆囊癌、胆管癌)。在本申请一些实施例中，所述MSI-H和/或dMMR肿瘤为肝癌(包括但不限于肝细胞癌、肝内胆管细胞癌、肝外胆管细胞癌)。在本申请一些实施例中，所述MSI-H和/或dMMR肿瘤为尿路上皮癌(包括但不限于膀胱癌、尿道癌)。在本申请一些实施例中，所述MSI-H和/或dMMR肿瘤为肺癌(例如小细胞肺癌、非小细胞肺癌(包括但不限于肺鳞状细胞癌、肺腺癌))。在本申请一些实施例中，所述MSI-H和/或dMMR肿瘤为白血病(包括但不限于急性髓系白血病、慢性髓细胞白血病、慢性淋巴细胞性白血病)。在本申请一些实施例中，所述MSI-H和/或dMMR肿瘤为淋巴瘤(包括但不限于霍奇金淋巴瘤、原发性纵隔大B细胞淋巴瘤)。在本申请一些实施例中，所述MSI-H和/或dMMR肿瘤为结直肠癌。
在本申请的一些实施方案中，所述的肿瘤为晚期和/或转移性的肿瘤。在本申请的一些实施方案中，所述的肿瘤为难治性的和/或复发性的肿瘤。
在本申请的一些实施方案中，所述的MSI-H和/或dMMR恶性肿瘤为晚期的MSI-H和/或dMMR恶性肿瘤。在本申请的一些实施方案中，所述的MSI-H和/或dMMR恶性肿瘤为难治性的MSI-H和/或dMMR恶性肿瘤。
在本申请的一些实施方案中，所述的MSI-H和/或dMMR恶性肿瘤为复发性和/或转移性的MSI-H和/或dMMR恶性肿瘤。
在本申请的一些实施方案中，所述的MSI-H和/或dMMR恶性肿瘤为复发性和/或转移性的晚期的MSI-H和/或dMMR恶性肿瘤。
在本申请的一些实施方案中，所述的MSI-H和/或dMMR的实体瘤包括但不限于乳腺癌(例如激素受体阳性的乳腺癌、三阴性乳腺癌、HER2/neu阳性或者阴性的乳腺癌)、消化系统/胃肠道肿瘤(例如肛门癌、阑尾癌、胆管癌、胃肠道基质瘤、胃肠道类癌、结直肠癌、胃癌、食道癌、胆囊癌、胆管癌、肝癌、胰腺癌、胰岛细胞瘤、胰腺神经内分泌肿瘤)、内分泌系统肿瘤和神经内分泌癌(例如肾上腺皮质癌、甲状腺癌、皮肤神经内分泌肿瘤、甲状旁腺癌)、眼癌、泌尿生殖系统癌(例如膀胱癌、肾癌、前列腺癌、睾丸癌、尿道癌、尿路上皮癌)、妇科癌症(例如子宫内膜癌、卵巢癌、宫颈癌、输卵管癌、原发性腹膜癌、阴道癌、外阴癌)、头颈癌(例如下咽癌、喉癌、唇和口腔癌、口腔癌、鼻咽癌、口咽癌、鼻旁窦和鼻腔癌、咽癌、唾液腺癌、咽喉癌)、呼吸系统癌(例如肺癌(包括但不限于非小细胞肺癌、小细胞肺癌)、恶性间皮瘤、胸腺癌)、皮肤癌(例如默克尔细胞癌、皮肤鳞状细胞癌、黑色素瘤)、神经系统肿瘤(例如脑癌、胶质细胞瘤、神经母细胞瘤、垂体瘤、原发性中枢神经系统淋巴瘤)、骨癌、软组织肉瘤中的一种或 者多种。
在本申请的一些实施方案中，所述的MSI-H和/或dMMR实体瘤为恶性实体瘤。
在本申请的一些实施方案中，所述的MSI-H和/或dMMR恶性实体瘤为晚期的恶性实体瘤。在本申请的一些实施方案中，所述的MSI-H和/或dMMR恶性实体瘤为难治性的恶性实体瘤。
在本申请的一些实施方案中，所述的MSI-H和/或dMMR恶性实体瘤为复发性和/或转移性的恶性实体瘤。
在本申请的一些实施方案中，所述的MSI-H和/或dMMR恶性实体瘤为复发性和/或转移性的晚期的恶性实体瘤。
在本申请的一些实施方案中，所述MSI-H和/或dMMR肿瘤的患者已接受过一种或以上的在先治疗。在本申请的一些实施方案中，所述MSI-H和/或dMMR肿瘤为接受在先治疗后疾病进展和/或没有令人满意的替代治疗的MSI-H和/或dMMR肿瘤。
在本申请的一些实施方案中，所述MSI-H和/或dMMR肿瘤的患者已接受过一种或两种以上药物治疗。在本申请的一些实施方案中，所述MSI-H和/或dMMR肿瘤为至少一种药物治疗失败的MSI-H和/或dMMR肿瘤。在一些实施方案中，所述的治疗失败包括在治疗期间疾病进展，以及治疗结束后疾病进展和/或复发。
在本申请的一些实施方案中，所述MSI-H和/或dMMR肿瘤的患者已接受过一种或两种以上化疗。在本申请的一些实施方案中，所述MSI-H和/或dMMR肿瘤为至少一种化疗治疗失败的MSI-H和/或dMMR肿瘤。在一些实施方案中，所述的治疗失败包括在治疗期间疾病进展，以及治疗结束后疾病进展和/或复发。在本申请的一些实施方案中，所述MSI-H和/或dMMR肿瘤的患者既往接受过1-2线全身标准化疗方案，治疗失败或不能耐受。
抗PD-L1抗体或其药物组合物的给药方案
在本申请的一些实施方案中，所述用途或治疗方法中，所述抗PD-L1抗体可以每周(q1w)、每2周(q2w)、每3周(q3w)、或者每4周(q4w)施用一次。在一个具体的实施方案中，每3周给予抗PD-L1抗体一次。在一些实施方案中，所述抗PD-L1抗体每次以600-2400mg的剂量施用。
在本申请的一些实施方案中，所述用途或者治疗方法中，21天为一个治疗周期，在每个周期的第一天给予PD-L1抗体。
在本申请的一些实施方案中，所述用途或者治疗方法中，所述抗PD-L1抗体可以包括选自0.01至40mg/kg、0.1至30mg/kg、0.1至20mg/kg、0.1至15mg/kg、0.1至10mg/kg、1至15mg/kg、1至20mg/kg、1至3mg/kg、3至10mg/kg、3至15mg/kg、3至20mg/kg、3至30mg/kg、10至20mg/kg、或15至20mg/kg的剂量给予受试者；或者以60mg至2400mg、90mg至约1800mg、120mg至1500mg、300mg至900mg、600mg至900mg、300mg至1200mg、600mg至1200mg、或900mg至1200mg的剂量施用于受试者。
在所述用途或者治疗方法的一些实施方案中，21天为一个治疗周期，在每个周期的第一天给予1200mg的PD-L1抗体。
抗PD-L1抗体或其药物组合物的施用方式
下述内容并非限制本申请抗体或其药物组合物的施用方式。
本申请的抗PD-L1抗体及其药物组合物中可以适合的途径施用，包括但不限于，口服或肠胃外(例如通过静脉内、肌内、局部或皮下途径)。在一些实施方案中，可注射施用，例如静脉注射或腹腔注射。
本申请的药物组合物，包括但不限于，片剂、含片、丸剂、胶囊剂(例如硬胶囊、软胶囊、肠溶胶囊、微囊剂)、酏剂、颗粒剂、糖浆剂、注射剂(肌肉内、静脉内、腹腔内)、颗粒剂、乳剂、悬浮液、溶液、分散剂和用于口服或非口服给药的缓释制剂的剂型。
本申请的药物组合物可进一步含有药学上可接受的载体和/或赋形剂。
药物组合的给药方案
在本申请的一些实施方案中，上述用途或者治疗方法中，所述抗PD-L1抗体和安罗替尼或其药学上可接受的盐各自呈药物组合物的形式，可同时、先后或依次给药。
在本申请的一些实施方案中，上述用途或者治疗方法中，所述抗PD-L1抗体和安罗替尼各自以间隔给药的方式给药。在一些实施方案中，所述抗体和安罗替尼分别以相同或者不同的给药方案进行给药。在一些实施方案中，分别以不同的给药方案进行给药。
在本申请的一些实施方案中，所述用途或治疗方法中，所述抗PD-L1抗体可以每1周(q1w)、每2周(q2w)、每3周(q3w)、或者每4周(q4w)施用一次。在一个具体的实施方案中，每3周给予抗PD-L1抗体一次。在一些实施方案中，所述抗PD-L1抗体每次以600-2400mg的剂量施用。
所述安罗替尼或其药学上可接受的盐可以每日一次6mg、8mg、10mg或者12mg的剂量，连续用药2周，停1周的给药方案给药。
在一些实施方案中，抗PD-L1抗体和安罗替尼或其药学上可接受的盐分别具有相同或者不同的治疗周期。在一些具体的实施方案中，抗PD-L1抗体和安罗替尼具有相同的治疗周期，例如每1周、每2周、每 3周或者每4周为一个治疗周期。
在本申请的一些实施方案中，所述用途或者治疗方法中，21天为一个治疗周期，在每个周期的第一天给予PD-L1抗体，在每个周期的第1-14天每天给予安罗替尼或其药学上可接受的盐。在一个具体的实施方案中，在每个周期的第一天给予PD-L1抗体一次，在每个周期的第1-14天每天一次给予安罗替尼或其药学上可接受的盐。
在本申请的一些实施方案中，所述用途或者治疗方法中，其中所述抗PD-L1抗体可以包括选自0.01至40mg/kg、0.1至30mg/kg、0.1至20mg/kg、0.1至15mg/kg、0.1至10mg/kg、1至15mg/kg、1至20mg/kg、1至3mg/kg、3至10mg/kg、3至15mg/kg、3至20mg/kg、3至30mg/kg、10至20mg/kg、或15至20mg/kg的剂量给予受试者；或者以60mg至2400mg、90mg至1800mg、120mg至1500mg、300mg至900mg、600mg至900mg、300mg至1200mg、600mg至1200mg、或900mg至1200mg的剂量施用于受试者。
在所述用途或者治疗方法的一些实施方案中，21天为一个治疗周期，在每个周期的第一天给予1200mg的PD-L1抗体，在每个周期的第1-14天每天给予6mg、8mg、10mg和/或12mg的安罗替尼或其药学上可接受的盐。
在本申请的一些实施方案中，每三周为一个治疗周期，以(0.35-29):1、(3.5-29):1、(3.5-14.5):1、或者(7-14.5):1的重量比向受试者给予抗PD-L1抗体和安罗替尼或其药学上可接受的盐，其中，将所述抗PD-L1抗体和安罗替尼或其药学上可接受的盐分别以单位剂量和多剂量进行给予。
药物组合的施用方式
下述内容并非限制本申请药物组合的施用方式。
本申请的药物组合中的组分可以各自独立地、或者其中的部分或全部共同以适合的各种途径施用，包括但不限于，口服或肠胃外(通过静脉内、肌内、局部或皮下途径)。在一些实施方案中，本申请的药物组合的组分可以各自独立地、或者其中的部分或全部共同口服施用或注射施用，例如静脉注射或腹腔注射。
本申请的药物组合中的组分可以各自独立地、或者其中的部分或全部共同是适合的剂型，包括但不限于，片剂、含片、丸剂、胶囊剂(例如硬胶囊、软胶囊、肠溶胶囊、微囊剂)、酏剂、颗粒剂、糖浆剂、注射剂(肌肉内、静脉内、腹腔内)、颗粒剂、乳剂、悬浮液、溶液、分散剂和用于口服或非口服给药的缓释制剂的剂型。
本申请的药物组合中的组分可以各自独立地、或者其中的部分或全部共同含有药学上可接受的载体和/或赋形剂。
本申请的抗PD-L1抗体可以安全、有效地治疗子宫内膜癌。
在一些实施方案中，本申请的抗PD-L1抗体显示出对MSI-H或dMMR子宫内膜癌较高的敏感性，MSI-H或dMMR子宫内膜癌患者在接受抗PD-L1抗体治疗后，患者的客观缓解率(ORR)远超15％；在具体的实施方案中，ORR达到或者超过30％。在一些实施方案中，接受抗PD-L1抗体治疗后，患者的疾病控制率(DCR)达到或超过50％。在具体的实施方案中，DCR达到或超过80％。
在一个具体的实施方案中，本申请提供的抗PD-L1抗体治疗MSI-H或dMMR子宫内膜癌，可显著降低不良反应(TRAE)发生率和严重程度，不良反应发生率低于80％，3级以上不良反应发生率低于20％。在一些实施方案中，本申请提供的抗PD-L1抗体治疗MSI-H或dMMR子宫内膜癌，不良反应发生率低于70％，3级以上不良反应发生率不超过16％。
本申请的抗PD-L1抗体显示出对MSI-H和/或dMMR肿瘤较高的敏感性，例如MSI-H和/或dMMR恶性肿瘤，可以安全、有效地治疗MSI-H和/或dMMR肿瘤，患者的客观缓解率(ORR)远超15％。在一些具体的实施方案中，对于MSI-H和/或dMMR肿瘤，例如MSI-H或dMMR子宫内膜癌，接受抗PD-L1抗体治疗后，患者的客观缓解率(ORR)远超15％。在一些具体的实施方案中，ORR达到或者超过30％。在一些实施方案中，抗PD-L1抗体治疗后，患者的疾病控制率(DCR)达到或超过50％。在一些具体的实施方案中，DCR达到或超过80％。
在一些实施方案中，本申请提供的抗PD-L1抗体治疗MSI-H或dMMR肿瘤，可显著降低不良反应(TRAE)的发生率和严重程度，不良反应发生率低于80％，3级以上不良反应发生率低于20％。在一些实施方案中，本申请提供的抗PD-L1抗体治疗MSI-H或dMMR恶性肿瘤，不良反应发生率低于70％，3级以上不良反应发生率不超过16％。
在一些实施方案中，本申请的含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合可安全、有效地治疗子宫内膜癌。
在一些实施方案中，本申请的含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合可安全、有效地治疗非MSI-H和/或非dMMR子宫内膜癌。在一些实施方案中，本申请的含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合在非MSI-H和/或非dMMR子宫内膜癌患者中，ORR(客观缓解率)超过15％。在具体的实施方案中，ORR达到或超过25％。在具体的实施方案中，ORR达到或超过30％。 疾病控制率(DCR)达到或超过80％。在一些具体的实施方案中，DCR达到或超过90％。
在一些实施方案中，本申请中的抗PD-L1抗体和安罗替尼或其药学上可接受的盐治疗子宫内膜癌具有协同作用。在一些具体实施方案中，本申请中的抗PD-L1抗体和安罗替尼或其药学上可接受的盐治疗非MSI-H和/或非dMMR子宫内膜癌具有显著的协同作用。
在一些实施方案中，本申请提供的抗PD-L1抗体和安罗替尼或其药学上可接受的盐治疗子宫内膜癌，尤其是非MSI-H和/或非dMMR子宫内膜癌，可显著降低不良反应(TRAE)的发生率和严重程度，不良反应发生率低于80％，3级以上不良反应发生率低于10％。在一些实施方案中，本申请提供的抗PD-L1抗体和安罗替尼或其药学上可接受的盐治疗非MSI-H和/或非dMMR子宫内膜癌，不良反应发生率不超过75％，3级以上不良反应发生率不超过7％。
在一些实施方案中，根据计算IRC评估的客观缓解例数(PR+CR)占总病例数的比率及95％CI，来计算ORR。
在本申请的一些实施方案中，对患者的免疫原性进行研究；所述的免疫原性研究包括抗药抗体ADA和中和抗体Nab的研究，若检测出患者的抗药抗体(ADA)呈阳性时，则加测中和抗体(Nab)。在一些实施方案中，免疫原性监测的时间点以抗体注射液给药时间为准；抗体延迟给药时，免疫原性采血相应延迟。
本申请中，所述的MSI(微卫星不稳定，microsatellite instability)是由DNA错配修复(mismatch repair，MMR)蛋白功能缺失导致。本申请中，MSI的状态可按照本领域公知的方法进行检测，检测MSI状态的方法包括但不限于免疫组织化学检测MMR蛋白、多重荧光聚合酶链反应PCR检测微卫星位点、基于二代测序(NGS)平台的MSI的检测。在一个具体的实施方案中，使用多重荧光聚合酶链反应PCR检测MSI。例如使用可商业购买获得的试剂盒检测MSI的状态。在一些实施方案中，按照多重荧光聚合酶链反应PCR检测微卫星位点，判读标准随试剂盒位点数目变化而发生改变，根据可商业购买获得的合格的试剂盒的判定标准，判断MSI的状态，如MSI-H(微卫星高度不稳定)、MSI-L(微卫星低度不稳定)以及MSS(微卫星稳定)。
本申请中，MMR的状态(例如dMMR)可按照本领域公知的方法进行检测，例如可使用免疫组织化学(IHC)检测MMR蛋白，例如可主要检测患者的肿瘤样本中的四个MMR蛋白(MLH1、MSH2、MSH6和PMS2)，其中任一MMR蛋白缺失即为dMMR，无MMR蛋白缺失即为非dMMR；判读方法可采用美国病理学家协会(the college of American Pathologists，CAP)标准判断MMR蛋白表达是否缺失；例如也可使用PCR方法检测微卫星位点。
在一些实施方案中，采用PCR(聚合酶链式反应)和/或ICH(免疫组织化学)检测来确定是否为MSI-H或者dMMR子宫内膜癌，或者确定否为非MSI-H或者非dMMR子宫内膜癌。
定义和说明
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本申请中出现商品名时，意在指代其对应的商品或其活性成分。
本文中，除非另有说明，其中涉及安罗替尼或其药学上可接受的盐的量，均是指其中活性成分安罗替尼游离碱的量。
除非另有说明，术语“剂量”是指不考虑患者的重量或体表面积(BSA)施用给患者的剂量。例如，60kg人和100kg人将接受相同剂量的抗体(例如，240mg抗PD-1抗体)。
术语“MSI”是指微卫星不稳定(microsatellite instability)。
术语“MSI-H”是指微卫星高度不稳定或微卫星不稳定高突变型(MSI-high)。
术语“MSI-L”是指微卫星低度不稳定(MSI-low)。
术语“MSS”是指微卫星稳定(microsatellite stability)。
术语“MMR”是指错配修复(mismatch repair)。
术语“dMMR”是指错配修复功能缺陷(deficient mismatch repair)。
术语“pMMR”是指错配修复功能完整(proficient mismatch repair)。
如文本所用，术语“药物组合”是指同时或先后施用的两种或以上的活性成分(以各自的活性成分本身的形式施用，或者以其各自的药学上可接受的盐或酯等衍生物、前药或组合物的形式施用)的组合。所述活性物质可以各自作为单一制剂同时地、或各自作为单一制剂以任何顺序依次地施用于受试者。
如本文所用，术语“抗体”是指具有至少一个抗原结合结构域的结合蛋白。本申请的抗体和其片段可以是整个抗体或其任何片段。因此，本申请的抗体和片段包括单克隆抗体或其片段和抗体变体或其片段，以及免疫缀合物。抗体片段的实例包括Fab片段、Fab'片段、F(ab')2片段、Fv片段、分离的CDR区、单链Fv分子(scFv)、Fd片段和本领域已知的其它抗体片段。抗体和其片段还可以包括重组多肽、融合蛋白和双特异性抗体。本文所述的抗PD-L1抗体和其片段可以是IgG1、IgG2、IgG3或IgG4同种型。术语“同 种型”是指由重链恒定区基因编码的抗体种类。在一个实施方案中，本文所述的抗PD-L1抗体和其片段是IgG1或IgG4同种型。本申请的PD-L1抗体和其片段可以衍生自任何物种，其包括但不限于小鼠、大鼠、兔、灵长类动物、美洲驼和人。PD-L1抗体和其片段可以是嵌合抗体、人源化抗体或完整的人抗体。在一个实施方案中，抗PD-L1抗体是由源自小鼠的杂交瘤细胞系产生的抗体。因此，在一个实施方案中，抗PD-L1抗体是鼠类抗体。在另一个实施方案中，抗PD-L1抗体是嵌合抗体。在另一个实施方案中，嵌合抗体是小鼠-人嵌合抗体。在另一个实施方案中，抗体是人源化抗体。在另一个实施方案中，抗体衍生自鼠类抗体并且是人源化的。
“人源化抗体”是下述抗体：所述抗体含有衍生自非人抗体的互补决定区(CDR)；和衍生自人抗体的框架区以及恒定区。例如，本文所述的抗PD-L1抗体可以包含衍生自一种或多种鼠类抗体的CDR以及人框架区和恒定区。因此，在一个实施方案中，本文所述的人源化抗体与所述抗体的CDR所衍生自的鼠类抗体结合PD-L1上的相同表位。在一些实施方案中，所述的抗PD-L1抗体为人源化抗体。包含本文提供的重链CDR和轻链CDR的另外的抗PD-L1抗体或其变体可以使用任何人框架序列产生，并且也包括在本申请中。在一个实施方案中，适用于在本申请中使用的框架序列包括在结构上与本文提供的框架序列类似的那些框架序列。可以在框架区中进行另外修饰以改进本文提供的抗体的特性。此类另外的框架修饰可以包括化学修饰；点突变以降低免疫原性或去除T细胞表位；或使突变回复为原始种系序列中的残基。在一些实施方案中，此类修饰包括对应于本文示例的突变的那些修饰，包括对种系序列的回复突变。例如，在一个实施方案中，本文所述的人源化抗体的VH和/或VL的人框架区中的一个或多个氨基酸被回复突变为亲本鼠类抗体中对应的氨基酸。例如，对于人源化5G11和人源化13C5的VH和VL，上述模板人抗体的框架氨基酸的几个位点被回复突变为小鼠5G11和13C5抗体中对应的氨基酸序列。在一个实施方案中，轻链可变区的位置53和/或60和/或67处的氨基酸被回复突变为在小鼠5G11或13C5轻链可变区中的所述位置处发现的对应的氨基酸。在另一个实施方案中，重链可变区的位置24和/或28和/或30和/或49和/或73和/或83和/或94处的氨基酸被回复突变为在小鼠5G11或13C5重链可变区中的所述位置处发现的对应的氨基酸。在一个实施方案中，人源化5G11抗体包含轻链可变区，其中在位置60处的氨基酸从Ser(S)突变为Asp(D)，并且在位置67处的氨基酸从Ser(S)突变为Tyr(Y)；以及重链可变区，其中在位置24处的氨基酸从Phe(F)突变为Val(V)，在位置49处的氨基酸从Ala(A)突变为Gly(G)，在位置73处的氨基酸从Thr(T)突变为Asn(N)，并且在位置83处的氨基酸从Thr(T)突变为Asn(N)。在一个实施方案中，人源化13C5抗体包含轻链可变区，其中在位置53处的氨基酸从Tyr(Y)突变为Lys(K)；以及重链可变区，其中在位置28处的氨基酸从Thr(T)突变为Ile(I)，在位置30处的氨基酸从Ser(S)突变为Arg(R)，在位置49处的氨基酸从Ser(S)突变为Ala(A)，并且在位置94处的氨基酸从Tyr(Y)突变为Asp(D)。另外的或另选的回复突变可以在本文提供的人源化抗体的框架区中进行以改进抗体的特性。本申请还包括下述人源化抗体，所述人源化抗体结合PD-L1并且包含对应于本文所述的相对于任何合适的框架序列的示例性修饰的框架修饰，以及以其它方式改进抗体特性的其它框架修饰。
本申请描述了结合PD-L1的分离的抗体或其片段，其中所述抗体可以由杂交瘤产生，所述杂交瘤选自本文称为13C5、5G11的杂交瘤。本申请还提供了编码本文提供的抗体和其片段的分离的多核苷酸。本申请还包括包含分离的多核苷酸的表达载体，和包含所述表达载体的宿主细胞。
“分离的抗体”表示这样的抗体：其基本上不含有具有不同抗原特异性的其它抗体(例如，分离的特异性地结合PD-1的抗体基本上不含有特异性地结合除PD-1以外的抗原的抗体)。但是，分离的特异性地结合PD-1的抗体可以具有与其它抗原(诸如来自不同物种的PD-1分子)的交叉反应性。此外，分离的抗体可以基本上不含有其它细胞材料和/或化学物质。
术语“单克隆抗体”(“mAb”)表示单一分子组成的抗体分子(即，这样的抗体分子：其基本序列是基本上相同的，并且其表现出对特定表位的单一结合特异性和亲和力)的非天然存在的制备物。mAb是分离的抗体的一个例子。通过本领域技术人员已知的杂交瘤技术、重组技术、转基因技术或其它技术，可以生产mAb。
本文所述的抗体和其抗原结合片段对PD-L1是特异性的。在一个实施方案中，抗体或/和其片段对PD-L1是特异性的。在一个实施方案中，本文所述的抗体和片段结合人或灵长类动物PD-L1，但不结合来自任何其它哺乳动物的PD-L1。在另一个实施方案中，抗体或/和其片段不结合小鼠PD-L1。术语“人PD-L1”、“hPD-L1”和“huPD-L1”等在本文中可互换使用，并且是指人PD-L1和人PD-L1的变体或同种型。“特异性”意指抗体和其片段以比任何其他靶标更大的亲和力结合PD-L1。
术语“治疗”一般是指获得需要的药理和/或生理效应。该效应根据部分或完全稳定或治愈疾病和/或由于疾病产生的副作用，可以是治疗性的。本文使用的“治疗”涵盖了对患者疾病的任何治疗，包括：(a)抑制疾病的症状，即阻止其发展；或(b)缓解疾病的症状，即，导致疾病或症状退化。
术语“有效量”意指(i)治疗特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本 申请化合物的用量。构成“治疗有效量”的活性物质(例如本申请的抗体或化合物)的量可根据一些因素而变化，诸如个体的疾病状态、年龄、性别和重量，以及治疗剂或治疗剂组合在个体中引发所需应答的能力。有效量也可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“施用”表示，使用本领域技术人员已知的多种方法和递送系统中的任一种，向主体物理引入包含治疗剂的组合物。免疫检查点抑制剂(例如，抗PD-1抗体或抗PD-L1抗体)的施用途径包括胃肠外施用途径(包括但不限于静脉内、肌肉内、皮下、腹膜内、脊柱或其它胃肠外施用途径)，例如通过注射或输注。在一些实施方案中，本文中使用的短语“胃肠外施用”或“胃肠外给药”可互换使用，通常是指通过注射进行的除了肠内和局部施用以外的施用模式，且包括但不限于，静脉内、肌肉内、动脉内、鞘内、淋巴管内、病灶内、囊内、眶内、心内、真皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内、硬膜外和胸骨内注射和输注、以及体内电穿孔。在某些实施方案中，所述免疫检查点抑制剂(例如，抗PD-1抗体或抗PD-L1抗体)通过非胃肠外途径施用；在某些实施方案中，口服施用。其它非胃肠外途径包括局部、表皮或粘膜施用，例如，鼻内、阴道内、直肠内、舌下或局部施用。还可以执行施用，例如，一次、多次，和/或在一个或多个延长的时间段中。
术语“药学上可接受的”是针对那些化合物、材料、组合物和/或剂型而言，它们适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症。
术语“药学上可接受的盐”包括游离碱与酸形成的盐或酸与游离碱形成的盐，例如包括盐酸盐、氢溴酸盐、硝酸盐、硫酸盐、磷酸盐、甲酸盐、乙酸盐、三氟乙酸盐、富马酸盐、草酸盐、马来酸盐、柠檬酸盐、琥珀酸盐、甲磺酸盐、苯磺酸盐或对甲基苯磺酸盐；在一些实施方案中，为盐酸盐、氢溴酸盐、硫酸盐、甲酸盐、乙酸盐、三氟乙酸盐、富马酸盐、马来酸盐、甲磺酸盐、对甲基苯磺酸盐、钠盐、钾盐、铵盐、氨基酸盐等。本申请中，当形成药学上可接受的盐时，所述酸与游离碱的摩尔量之比为1:0.2-1:5；在一些实施方案中，为1:0.5、1:1、1:2、1:3、1:4、1:5、1:6、1:7或1:8。
在本文中，术语“受试者”或“患者”可互换使用。在一些实施方案中，术语“受试者”或“患者”是哺乳动物。在部分实施方案中，所述受试者或患者是小鼠。在部分实施方案中，所述受试者或患者是人。
术语“单位剂量”是指含有一定量药品的最小包装单元，例如一盒药有七粒胶囊，则每个胶囊为单位剂量；或者每瓶注射液为单位剂量。
术语“多剂量”由多个单位剂量组成。
术语“药物组合物”是指一种或多种本申请的活性成分或其药物组合与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对受试者给予本申请的化合物或其药物组合。
在本文中，除非另有说明，否则单数术语涵盖复数的指代物，反之亦然。
在本文中，除非另有说明，否则术语“包含、包括和含有(comprise、comprises和comprising)”或等同物为开放式表述，意味着除所列出的要素、组分和步骤外，还可涵盖其它未指明的要素、组分和步骤。
为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它出版物在此明确地并入本文。这些出版物仅因为它们的公开早于本申请的申请日而提供。所有关于这些文件的日期的声明或这些文件的内容的表述是基于申请者可得的信息，并且不构成任何关于这些文件的日期或这些文件的内容的正确性的承认。而且，在任何国家，在本中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。
具体实施方式
为清楚起见，进一步用实施例来阐述本申请，但是实施例并非限制本申请的范围。本申请所使用的所有试剂是市售的，无需进一步纯化即可使用。实施例中抗PD-L1抗体按WO2016022630中所述方法制得，经亲和层析后，按常规的抗体纯化方法得到含有该抗体的洗脱液。
实施例1子宫内膜癌的II期临床试验
符合入选标准的子宫内膜癌受试者，首先通过免疫组化或PCR的方法检测MMR/MSI状态，根据MSI-H/dMMR检测结果入组，对于非MSI-H/非dMMR的受试者，给予抗PD-L1抗体和盐酸安罗替尼(队列一)，对于MSI-H或dMMR的受试者，给予抗PD-L1抗体(队列二)，疾病控制(CR+PR+SD)且不良反应可以耐受的受试者，可持续用药，至失去临床获益、毒性不可耐受、疗效评价为PD/iCPD、研究者认为不适合继续用药时研究结束。从第1治疗周期第1天开始，每6周(42天)±3天进行一次疗效评估，54周后每12周(84天)±3天进行一次疗效评估，直至受试者发生肿瘤影像学证实的疾病进展。
1.1主要入选标准：
1)经组织学或细胞学确诊，不可切除的复发性或转移性晚期子宫内膜癌(既往接受1-2线全身标准化疗方案治疗失败或不能耐受。允许前期进行新辅助或辅助化疗)。
2)按照实体瘤疗效评估标准(RECIST 1.1)，证实具有至少一个可测量病灶。
3)年龄：≥18周岁；ECOG PS评分：0-1分；预计生存期超过3个月。
1.2试验药
抗PD-L1抗体注射剂hu5G11-hIgG1：1200mg抗PD-L1抗体注射液(规格：600mg/20mL)用生理盐水稀释至250mL，输注时间60±10min(输注时间以开始输注抗PD-L1抗体注射剂为起点，抗PD-L1抗体注射剂输注结束且生理盐水(建议用20mL)冲管结束为终点)。抗PD-L1抗体注射剂在第一天给药，每21天给药一次，即21天为一个治疗周期(d1/q3w)。
盐酸安罗替尼胶囊(活性成分为安罗替尼二盐酸盐)：每日1次(早餐前空腹口服)，每次1粒(12mg)。连续口服2周停1周，即21天为一治疗周期，在每个周期的第1-14天给药。无特殊情况，建议每天固定时间服用。(即，盐酸安罗替尼胶囊：12mg/qd，d1-14/q3w)
研究者可根据疾病的状况以及安全性等方面，调整盐酸安罗替尼胶囊的剂量，例如：12mg、10mg、8mg。
1.3评价标准
安全性评价标准：采用NCI-CTC AE 5.0标准判断不良事件严重程度。
有效性评价标准：采用RECIST 1.1、iRECIST标准判定疾病状态。以RECIST 1.1标准评价为主，同时使用iRECIST标准对疗效进行确认。即按RECIST 1.1标准判定为疾病进展(PD)的受试者，按iRECIST标准进一步确认，从而决定是否进一步用药观察。
1.4终点指标
主要终点：IRC评估的客观缓解率(ORR)
次要终点：(1)研究者评估的客观缓解率(ORR)、疾病控制率(DCR)、缓解持续时间(DOR)、无进展生存期(PFS)、总生存期(OS)、DOR率(≥6个月)等；(2)不良事件(AE)和严重不良事件(SAE)的发生率和严重程度，以及异常实验室检查指标。
1.5结果
初步研究显示，盐酸安罗替尼和抗PD-L1抗体联用可以安全、有效地治疗非MSI-H和/或非dMMR子宫内膜癌，受试者有临床获益。截止数据统计日，本项研究中，队列一(盐酸安罗替尼联合抗PD-L1抗体组)中有22名受试者完成了至少2周期的治疗，其中14名受试者(14/22)的最佳疗效为SD(疾病稳定)，5名受试者(5/22)的最佳疗效为PR(部分缓解)，1名受试者(1/22)的最佳疗效为CR，客观缓解率(ORR)达到27.27％，疾病控制率(DCR)达到90.91％，不良反应发生率为75％，3级以上不良反应发生率为7％。具体情况见表1。
初步研究显示，抗PD-L1抗体可以安全、有效地治疗MSI-H和/或dMMR的肿瘤，尤其是MSI-H和/或dMMR子宫内膜癌，受试者有临床获益。截止数据统计日，本项研究中，队列二(抗PD-L1抗体组)中有6名受试者完成了至少2周期的治疗，其中2名受试者(2/6)的最佳疗效为SD(疾病稳定)，1名受试者(1/6)的最佳疗效为PR(部分缓解)，客观缓解率达到16.67％，疾病控制率达到50.00％，不良反应发生率为67％，3级以上不良反应发生率为16％，具体情况见表1。
表1至少完成2周期的治疗后最佳疗效汇总
Figure PCTCN2021103687-appb-000002
*表示：其中1例受试者目前最佳疗效为iUPD(iRECIST标准)，需进一步评估疗效；
**表示：其中3例受试者目前最佳疗效为iUPD(iRECIST标准)，需进一步评估疗效。

Claims (25)

  1. 抗PD-L1抗体或其药物组合物在制备用于治疗MSI-H和/或dMMR肿瘤的药物中的用途，其中，所述抗PD-L1抗体包含如下氨基酸序列：与SEQ ID NO:1或SEQ ID NO:4所示的氨基酸序列有至少80％同源性的重链CDR1区；与SEQ ID NO:2或SEQ ID NO:5所示的氨基酸序列有至少80％同源性的重链CDR2区；与SEQ ID NO:3或SEQ ID NO:6所示的氨基酸序列有至少80％同源性的重链CDR3区；与SEQ ID NO:7或SEQ ID NO:10所示的氨基酸序列有至少80％同源性的轻链CDR1区；与SEQ ID NO:8或SEQ ID NO:11所示的氨基酸序列有至少80％同源性的轻链CDR2区；与SEQ ID NO:9或SEQ ID NO:12所示的氨基酸序列有至少80％同源性的轻链CDR3区。
  2. 根据权利要求1所述的用途，其中，所述MSI-H和/或dMMR肿瘤选自乳腺癌、头颈癌、皮肤癌、软组织肉瘤、呼吸系统癌、神经系统恶性肿瘤、消化系统肿瘤、内分泌系统肿瘤、泌尿生殖系统癌、妇科癌症、血液系统恶性肿瘤。
  3. 根据权利要求1或2所述的用途，其中，所述MSI-H和/或dMMR肿瘤为MSI-H和/或dMMR恶性实体瘤。
  4. 根据权利要求1-3任一所述的用途，其中，所述MSI-H和/或dMMR肿瘤为MSI-H和/或dMMR子宫内膜癌。
  5. 含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合在制备用于治疗子宫内膜癌的药物的用途，其中，所述抗PD-L1抗体包含如下氨基酸序列：与SEQ ID NO:1或SEQ ID NO:4所示的氨基酸序列有至少80％同源性的重链CDR1区；与SEQ ID NO:2或SEQ ID NO:5所示的氨基酸序列有至少80％同源性的重链CDR2区；与SEQ ID NO:3或SEQ ID NO:6所示的氨基酸序列有至少80％同源性的重链CDR3区；与SEQ ID NO:7或SEQ ID NO:10所示的氨基酸序列有至少80％同源性的轻链CDR1区；与SEQ ID NO:8或SEQ ID NO:11所示的氨基酸序列有至少80％同源性的轻链CDR2区；与SEQ ID NO:9或SEQ ID NO:12所示的氨基酸序列有至少80％同源性的轻链CDR3区。
  6. 根据权利要求5所述的用途，其中子宫内膜癌为非MSI-H和/或非dMMR的子宫内膜癌。
  7. 根据权利要求4-6任一所述的用途，其中所述子宫内膜癌为晚期子宫内膜癌和/或难治性和/或复发性和/或转移性的子宫内膜癌。
  8. 根据权利要求1-7任一所述的用途，其中所述抗PD-L1抗体或其药物组合物处于胃肠外给药的形式或者处于静脉内给药的形式。
  9. 根据权利要求1-8任一所述的用途，其中抗PD-L1抗体处于药物组合物的形式，所述药物组合物中抗PD-L1抗体的浓度为10-60mg/mL。
  10. 根据权利要求1-9任一所述的用途，其中抗PD-L1抗体或其药物组合物的单次给药剂量为600-2400mg或者600、800、1000、1200、1400、1600、1800、2000、2200或2400mg。
  11. 根据权利要求1-10任一所述的用途，其中抗PD-L1抗体或其药物组合物每周、每2周、每3周、或者每4周施用一次。
  12. 根据权利要求5-6任一所述的用途，其中抗PD-L1抗体和安罗替尼或其药学上可接受的盐可同时、先后或者依次序给药。
  13. 根据权利要求5-6和12任一所述的用途，其中每3周为一个治疗周期，抗PD-L1抗体在每个周期的第1天给药，安罗替尼或其药学上可接受的盐在每个周期的第1-14天给药。
  14. 根据权利要求5-6和12-13任一所述的用途，其中，所述药物组合为适用于在单个治疗周期(例如21天的一个治疗周期)内施用的制剂，包括600-2400mg抗PD-L1抗体的药物组合物和84-168mg安罗替尼或其药学上可接受的盐的药物组合物。
  15. 根据权利要求13或14所述的用途，其中每个治疗周期的第一天给予1200mg的PD-L1抗体，在每个周期的第1-14天每天给予6mg、8mg、10mg和/或12mg的安罗替尼或其药学上可接受的盐。
  16. 治疗子MSI-H和/或dMMR肿瘤的方法，包括：向有需要的患者给予治疗有效量的抗PD-L1抗体或其药物组合物，其中，所述抗PD-L1抗体包含如下氨基酸序列：与SEQ ID NO:1或SEQ ID NO:4所示的氨基酸序列有至少80％同源性的重链CDR1区；与SEQ ID NO:2或SEQ ID NO:5所示的氨基酸序列有至少80％同源性的重链CDR2区；与SEQ ID NO:3或SEQ ID NO:6所示的氨基酸序列有至少80％同源性的重链CDR3区；与SEQ ID NO:7或SEQ ID NO:10所示的氨基酸序列有至少80％同源性的轻链CDR1区；与SEQ ID NO:8或SEQ ID NO:11所示的氨基酸序列有至少80％同源性的轻链CDR2区；与SEQ ID NO:9或SEQ ID NO:12所示的氨基酸序列有至少80％同源性的轻链CDR3区。
  17. 根据权利要求16所述的方法，其中，所述MSI-H和/或dMMR肿瘤为MSI-H和/或dMMR子宫内膜癌。
  18. 治疗子宫内膜癌的方法，其包括向有需要的患者给予治疗有效量的抗PD-L1抗体和安罗替尼或其药学上可接受的盐，其中，所述抗PD-L1抗体包含如下氨基酸序列：与SEQ ID NO:1或SEQ ID NO:4所示的氨基酸序列有至少80％同源性的重链CDR1区；与SEQ ID NO:2或SEQ ID NO:5所示的氨基酸序列有至 少80％同源性的重链CDR2区；与SEQ ID NO:3或SEQ ID NO:6所示的氨基酸序列有至少80％同源性的重链CDR3区；与SEQ ID NO:7或SEQ ID NO:10所示的氨基酸序列有至少80％同源性的轻链CDR1区；与SEQ ID NO:8或SEQ ID NO:11所示的氨基酸序列有至少80％同源性的轻链CDR2区；与SEQ ID NO:9或SEQ ID NO:12所示的氨基酸序列有至少80％同源性的轻链CDR3区。
  19. 根据权利要求18所述的方法，其中子宫内膜癌为非MSI-H和/或非dMMR子宫内膜癌。
  20. 治疗子宫内膜癌的药物组合，其包括：抗PD-L1抗体，和安罗替尼或其药学上可接受的盐，其中，所述抗PD-L1抗体包含如下氨基酸序列：与SEQ ID NO:1或SEQ ID NO:4所示的氨基酸序列有至少80％同源性的重链CDR1区；与SEQ ID NO:2或SEQ ID NO:5所示的氨基酸序列有至少80％同源性的重链CDR2区；与SEQ ID NO:3或SEQ ID NO:6所示的氨基酸序列有至少80％同源性的重链CDR3区；与SEQ ID NO:7或SEQ ID NO:10所示的氨基酸序列有至少80％同源性的轻链CDR1区；与SEQ ID NO:8或SEQ ID NO:11所示的氨基酸序列有至少80％同源性的轻链CDR2区；与SEQ ID NO:9或SEQ ID NO:12所示的氨基酸序列有至少80％同源性的轻链CDR3区。
  21. 根据权利要求20所述的药物组合，其包括：含600-2400mg的抗PD-L1抗体以多剂量形式提供的药物组合物和单位剂量为6mg、8mg、10mg和/或12mg的安罗替尼或其药学上可接受的盐的药物组合物。
  22. 根据权利要求1-15任一所述的用途、或权利要求16-19任一所述的方法、或权利要求20-21任一所述的药物组合，其中，所述抗PD-L1抗体包含如下氨基酸序列：选自SEQ ID NO:1或SEQ ID NO:4的重链CDR1区；选自SEQ ID NO:2或SEQ ID NO:5的重链CDR2区；选自SEQ ID NO:3或SEQ ID NO:6的重链CDR3区；选自SEQ ID NO:7或SEQ ID NO:10的轻链CDR1区；选自SEQ ID NO:8或SEQ ID NO:11的轻链CDR2区；选自SEQ ID NO:9或SEQ ID NO:12的轻链CDR3区。
  23. 根据权利要求1-15任一所述的用途、或权利要求16-19任一所述的方法、或权利要求20-21任一所述的药物组合，其中，所述抗PD-L1抗体包含：具有以SEQ ID NO:1示出的氨基酸序列的重链CDR1区，具有以SEQ ID NO:2示出的氨基酸序列的重链CDR2区，具有以SEQ ID NO:3示出的氨基酸序列的重链CDR3区；以及具有以SEQ ID NO:7示出的氨基酸序列的轻链CDR1区，具有以SEQ ID NO:8示出的氨基酸序列的轻链CDR2区，具有以SEQ ID NO:9示出的氨基酸序列的轻链CDR3区。
  24. 根据权利要求1-15任一所述的用途、或权利要求16-19任一所述的方法、或权利要求20-21任一所述的药物组合，其中，所述抗PD-L1抗体包含如下氨基酸序列：与SEQ ID NO:13或SEQ ID NO:14所示的氨基酸序列有至少80％同源性的重链可变区；与SEQ ID NO:15或SEQ ID NO:16所示的氨基酸序列有至少80％同源性的轻链可变区。
  25. 根据权利要求1-15任一所述的用途、或权利要求16-19任一所述的方法、或权利要求20-21任一所述的药物组合，其中，所述抗PD-L1抗体包含：选自hu13C5-hIgG1、hu13C5-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4人源化抗体的可变重链，和选自hu13C5-hIgG1、hu13C5-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4人源化抗体的可变轻链。
PCT/CN2021/103687 2020-06-30 2021-06-30 用于治疗肿瘤的药物 WO2022002153A1 (zh)

Priority Applications (6)

Application Number Priority Date Filing Date Title
JP2022580273A JP2023531090A (ja) 2020-06-30 2021-06-30 腫瘍を治療するための薬物
AU2021301947A AU2021301947A1 (en) 2020-06-30 2021-06-30 Drug for treating tumor
EP21833511.5A EP4174087A1 (en) 2020-06-30 2021-06-30 Drug for treating tumor
CA3188017A CA3188017A1 (en) 2020-06-30 2021-06-30 Drug for treating tumor
US18/003,718 US20230310596A1 (en) 2020-06-30 2021-06-30 Drug for treating tumor
CN202180041400.5A CN115698076A (zh) 2020-06-30 2021-06-30 用于治疗肿瘤的药物

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN202010619111 2020-06-30
CN202010620778 2020-06-30
CN202010619083 2020-06-30
CN202010619083.8 2020-06-30
CN202010620778.8 2020-06-30
CN202010619111.6 2020-06-30

Publications (1)

Publication Number Publication Date
WO2022002153A1 true WO2022002153A1 (zh) 2022-01-06

Family

ID=79317451

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/103687 WO2022002153A1 (zh) 2020-06-30 2021-06-30 用于治疗肿瘤的药物

Country Status (7)

Country Link
US (1) US20230310596A1 (zh)
EP (1) EP4174087A1 (zh)
JP (1) JP2023531090A (zh)
CN (1) CN115698076A (zh)
AU (1) AU2021301947A1 (zh)
CA (1) CA3188017A1 (zh)
WO (1) WO2022002153A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023232100A1 (zh) * 2022-06-02 2023-12-07 正大天晴药业集团股份有限公司 用于治疗子宫恶性肿瘤的药物组合

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016022630A1 (en) 2014-08-05 2016-02-11 Jiping Zha Anti-pd-l1 antibodies
CN107460221A (zh) * 2016-06-02 2017-12-12 正大天晴药业集团股份有限公司 一种降低抗pd‑l1抗体中蛋白聚合物的细胞培养方法
CN109071627A (zh) * 2016-02-05 2018-12-21 奥里尼斯生物科学公司 Cd8结合剂
CN110546160A (zh) * 2017-02-06 2019-12-06 奥里尼斯生物科学公司 靶向嵌合蛋白及其用途
CN110573172A (zh) * 2017-02-06 2019-12-13 奥里尼斯生物科学有限公司 靶向的工程化干扰素及其用途
CN110734493A (zh) * 2018-07-20 2020-01-31 厦门大学 抗pd-1抗体及其用途
CN112168961A (zh) * 2019-07-03 2021-01-05 正大天晴药业集团南京顺欣制药有限公司 治疗结直肠癌的联用药物组合物

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016022630A1 (en) 2014-08-05 2016-02-11 Jiping Zha Anti-pd-l1 antibodies
CN107001463A (zh) 2014-08-05 2017-08-01 中美冠科生物技术（太仓）有限公司 抗pd‑l1抗体
CN110964109A (zh) * 2014-08-05 2020-04-07 中美冠科生物技术（太仓）有限公司 抗pd-l1抗体
CN109071627A (zh) * 2016-02-05 2018-12-21 奥里尼斯生物科学公司 Cd8结合剂
CN107460221A (zh) * 2016-06-02 2017-12-12 正大天晴药业集团股份有限公司 一种降低抗pd‑l1抗体中蛋白聚合物的细胞培养方法
CN110546160A (zh) * 2017-02-06 2019-12-06 奥里尼斯生物科学公司 靶向嵌合蛋白及其用途
CN110573172A (zh) * 2017-02-06 2019-12-13 奥里尼斯生物科学有限公司 靶向的工程化干扰素及其用途
CN110734493A (zh) * 2018-07-20 2020-01-31 厦门大学 抗pd-1抗体及其用途
CN112168961A (zh) * 2019-07-03 2021-01-05 正大天晴药业集团南京顺欣制药有限公司 治疗结直肠癌的联用药物组合物

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
AMERICAN SOCIETY OF CLINICAL ONCOLOGY EDUCATIONAL BOOK: "A Review of Immune Checkpoint Blockade Therapy in Endometrial Cancer.", AM SOC CLIN ONCOL EDUC BOOK, vol. 40, 31 March 2020 (2020-03-31), pages 238 - 244, XP055883894, DOI: 10.1200/edbk_280503 *
RUBINSTEIN MARIA M., MAKKER VICKY: "Optimizing immunotherapy for gynecologic cancers", CURRENT OPINION IN OBSTETRICS & GYNECOLOGY, vol. 32, no. 1, 1 February 2020 (2020-02-01), pages 1 - 8, XP055883904, ISSN: 1040-872X, DOI: 10.1097/GCO.0000000000000603 *
SEBASTIEN TAURIN; CHIEH-HSIANG YANG; MARIA REYES; SUNGPIL CHO; DEMETRIUS M COOMBS; ELKE A JARBOE; THERESA L WERNER; MATTHEW PETERS: "Endometrial Cancers Harboring Mutated Fibroblast Growth Factor Receptor 2 Protein Are Successfully Treated With a New Small Tyrosine Kinase Inhibitor in an Orthotopic Mouse Model.", INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER, vol. 28, no. 1, 1 January 2018 (2018-01-01), pages 152 - 160, XP055735219, ISSN: 1048-891X, DOI: 10.1097/IGC.0000000000001129 *
THERESA LOUISE WERNER, ESTHER KANNAPEL, JUDY CHEN, MELISSA CHEN, ADAM LOUIS COHEN: "Safety and PK results from a phase IB study of AL3818 (anlotinib) hydrochloride in subjects with ovarian， cervical， and endometrial cancers.", JOURNAL OF CLINICAL ONCOLOGY, vol. 35, no. 15, 31 December 2017 (2017-12-31), pages e17071 - e17071, XP009532990, ISSN: 0732-183X, DOI: 10.1200/JCO.2017.35.15_suppl.e17071 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023232100A1 (zh) * 2022-06-02 2023-12-07 正大天晴药业集团股份有限公司 用于治疗子宫恶性肿瘤的药物组合

Also Published As

Publication number Publication date
CA3188017A1 (en) 2022-01-06
US20230310596A1 (en) 2023-10-05
EP4174087A1 (en) 2023-05-03
AU2021301947A1 (en) 2023-02-16
JP2023531090A (ja) 2023-07-20
CN115698076A (zh) 2023-02-03

Similar Documents

Publication Publication Date Title
EP3915583A1 (en) Combined pharmaceutical composition for treating tumor
WO2020187152A1 (zh) 治疗小细胞肺癌的联用药物组合物
WO2020249018A1 (zh) 治疗驱动基因阳性肺癌的联用药物组合物
CN113018429A (zh) 治疗卵巢癌的药物组合
WO2022002153A1 (zh) 用于治疗肿瘤的药物
WO2021219138A1 (zh) 用于治疗肾癌的联用药物
CN117642181A (zh) 用于治疗食管癌的药物组合
WO2023001283A1 (zh) 用于治疗胃癌和/或食管胃结合部癌的联用药物
WO2022033585A1 (zh) 用于治疗软组织肉瘤的联用药物
CN116370641A (zh) 用于治疗消化系统恶性肿瘤的联用药物
CN116036265A (zh) 用于癌症的联用药物
WO2022042626A1 (zh) 抗pd-1抗体在治疗鼻咽癌中的用途
WO2023232100A1 (zh) 用于治疗子宫恶性肿瘤的药物组合
WO2023098798A1 (zh) 用于治疗非小细胞肺癌的药物组合
CN116173198A (zh) 用于肝癌术后辅助治疗的联用药物
CN116209443A (zh) 治疗小细胞肺癌的药物组合
CN117085124A (zh) 一种包含抗PD-L1抗体和c-Met激酶抑制剂的药物组合
EP4382123A1 (en) Pharmaceutical composition for treating small cell lung cancer

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21833511

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3188017

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2022580273

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2021833511

Country of ref document: EP

Effective date: 20230130

ENP Entry into the national phase

Ref document number: 2021301947

Country of ref document: AU

Date of ref document: 20210630

Kind code of ref document: A