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WO2023232100A1 - Combinaison pharmaceutique pour le traitement d'une tumeur utérine maligne - Google Patents

Combinaison pharmaceutique pour le traitement d'une tumeur utérine maligne Download PDF

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Publication number
WO2023232100A1
WO2023232100A1 PCT/CN2023/097702 CN2023097702W WO2023232100A1 WO 2023232100 A1 WO2023232100 A1 WO 2023232100A1 CN 2023097702 W CN2023097702 W CN 2023097702W WO 2023232100 A1 WO2023232100 A1 WO 2023232100A1
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Prior art keywords
treatment
antibody
antigen
binding fragment
pharmaceutically acceptable
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PCT/CN2023/097702
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English (en)
Chinese (zh)
Inventor
王训强
张喜全
于鼎
崔思思
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Priority to CN202380044160.3A priority Critical patent/CN119278053A/zh
Publication of WO2023232100A1 publication Critical patent/WO2023232100A1/fr
Anticipated expiration legal-status Critical
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    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present disclosure belongs to the field of biomedicine, and specifically relates to drug combinations for treating uterine malignant tumors.
  • Endometrial cancer is a group of epithelial malignant tumors that occur in the endometrium, also known as uterine body cancer. It is one of the three common malignant tumors of the female reproductive tract. It mostly occurs in perimenopausal and postmenopausal women. With the increase in the average life span of the population and changes in 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 the female reproductive system. In my country, it has become the second most common gynecological malignant tumor after cervical cancer, accounting for about 20%-30% of gynecological malignant tumors.
  • the incidence rate of endometrial cancer in some developed cities has reached the first place among gynecological malignancies.
  • the postoperative recurrence rate in patients with stage I and stage II disease is approximately 15%, of which 50%-70% relapse is symptomatic. Most relapses occur within 3 years of treatment. Recurrences limited 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 based on surgery, supplemented by comprehensive treatments such as radiotherapy, drug therapy, and hormones.
  • progestins are often used for conservative treatment to preserve fertility function; for late-stage patients, appropriate chemotherapy should be taken before surgery to reduce the tumor volume and reasonable selection of chemotherapy drugs. It can significantly increase the surgical resection rate; for metastatic endometrial cancer and postoperative recurrence of endometrial cancer, hormonal drugs such as progestins, gonadotropin-releasing hormone analogs, and aromatase inhibitors are currently commonly used.
  • chemotherapy drugs such as paclitaxel, carboplatin, and doxorubicin.
  • Uterine sarcoma refers to primary malignant tumors derived from uterine mesenchymal tissue. Its histopathological classification mainly includes uterine leiomyosarcoma, endometrial stromal sarcoma, undifferentiated uterine sarcoma, and other rare types. , such as uterine adenosarcoma, malignant perivascular epithelioid cell tumor and rhabdomyosarcoma, etc., the most common of which is uterine leiomyosarcoma. Uterine sarcomas spread through direct spread, lymphatic or hematogenous spread and metastasis. Currently, there is no consensus on the best treatment options for this disease.
  • Programmed death factor 1 and one of its ligands, programmed death ligand-1 (PD-L1), are a pair of immune costimulatory factors. Under normal circumstances, PD-1 plays an important immune regulatory role through its ligand PD-L1. Activation of the PD-1/PD-L1 signaling pathway can lead to the formation of an immunosuppressive tumor immune microenvironment, allowing tumor cells to escape immune surveillance and killing. Blocking the PD-1/PD-L1 signaling pathway can reverse immunosuppressive tumors. The immune microenvironment enhances endogenous anti-tumor immune effects.
  • the present disclosure provides a pharmaceutical combination for treating uterine malignant tumors, which includes: an anti-PD-L1 antibody or an antigen-binding fragment thereof and a chemotherapy drug.
  • the uterine malignant tumor is endometrial cancer and/or uterine sarcoma.
  • the uterine malignant tumor is endometrial cancer.
  • the uterine malignant tumor is uterine sarcoma.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof includes: a heavy chain CDR1 region having at least 80% homology with the amino acid sequence shown in SEQ ID NO:1 or SEQ ID NO:4, and a heavy chain CDR1 region with SEQ ID NO:1 or SEQ ID NO:4.
  • At least 80% of the amino acid sequence shown in NO:2 or SEQ ID NO:5 A heavy chain CDR2 region with homology, a heavy chain CDR3 region with at least 80% homology with the amino acid sequence shown in SEQ ID NO:3 or SEQ ID NO:6, and a heavy chain CDR3 region with SEQ ID NO:7 or SEQ ID NO: A light chain CDR1 region that has at least 80% homology to the amino acid sequence shown in 10, a light chain CDR2 region that has at least 80% homology to the amino acid sequence shown in SEQ ID NO: 8 or SEQ ID NO: 11, and A light chain CDR3 region having at least 80% homology with the amino acid sequence shown in SEQ ID NO:9 or SEQ ID NO:12.
  • the chemotherapeutic drugs include, but are not limited to, platinum anti-tumor drugs, taxane anti-tumor drugs, antimetabolite anti-tumor drugs, camptothecin anti-tumor drugs, nitrogen mustard anti-tumor drugs, One or more of anthracycline anti-tumor drugs, vinblastine anti-tumor drugs, podophyllin alkaloid anti-tumor drugs, and hormonal anti-tumor drugs.
  • the chemotherapy drug is selected from one or more of platinum anti-tumor drugs, taxane anti-tumor drugs, anthracycline anti-tumor drugs, and antimetabolite anti-tumor drugs.
  • the chemotherapeutic drug is a platinum-based anti-tumor drug and/or a taxane-based anti-tumor drug.
  • the platinum anti-tumor drug is selected from the group consisting of cisplatin, carboplatin, nedaplatin, bicycloplatin, picoplatin, oxaliplatin, imiplatin, loplatin, loplatin, triplatinum tetranitrate, phenanthroplatin or One or more of sataplatin; preferably the platinum anti-tumor drug is carboplatin and/or cisplatin; more preferably the platinum anti-tumor drug is carboplatin.
  • the taxane anti-tumor drug is selected from one or more of paclitaxel, paclitaxel liposome, albumin-bound paclitaxel, and docetaxel; preferably, the taxane anti-tumor drug It is paclitaxel and/or docetaxel and/or paclitaxel liposome; more preferably, the taxane anti-tumor drug is paclitaxel or docetaxel.
  • the anthracycline anti-tumor drug is selected from the group consisting of doxorubicin, doxorubicin liposome, epirubicin, pirarubicin, amrubicin, arubicin, and idarubicin , one or more of daunorubicin, mitoxantrone, idarubicin, valrubicin, zorubicin, pixantron, and liposomal doxorubicin; preferably the anthracene
  • the cyclic antineoplastic drug is doxorubicin.
  • the antimetabolite anti-tumor drug is selected from the group consisting of carmofur, 5-fluorouracil, tegafur, capecitabine, tegio, furfururacil, deoxyfluridine, trifluridine, and One or more of glycocytidine, gemcitabine, azacitidine, amcitabine, mercaptopurine, fludarabine, methotrexate, and pemetrexed; preferably the antimetabolite anti-tumor drug For gemcitabine.
  • the chemotherapeutic drugs are platinum antineoplastic drugs and paclitaxel. In some embodiments, the chemotherapeutic drugs are carboplatin and taxane antineoplastic drugs. In some embodiments, the chemotherapeutic drugs are carboplatin and paclitaxel.
  • the chemotherapeutic drug is an anthracycline anti-tumor drug. In other embodiments, the chemotherapeutic agent is doxorubicin.
  • the chemotherapeutic drugs are taxane anti-tumor drugs and antimetabolite anti-tumor drugs. In other embodiments, the chemotherapeutic drugs are docetaxel and gemcitabine.
  • the pharmaceutical combination further includes anlotinib or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a pharmaceutical combination for treating uterine malignancy, which includes a first pharmaceutical combination, and optionally, a second pharmaceutical combination.
  • the pharmaceutical combination includes a first pharmaceutical combination administered to a patient in need thereof during a first treatment phase, and optionally, a second pharmaceutical combination administered to a patient in need thereof during a second treatment phase.
  • the first treatment phase includes 1 to 14 treatment cycles, preferably 2 to 12 treatment cycles, further preferably 4 to 10 treatment cycles, for example: 4 to 10 treatment cycles, 5 to 10 Treatment cycles, 6 to 10 treatment cycles, 4 to 9 treatment cycles, 5 to 9 treatment cycles, 6 to 9 treatment cycles, 4 to 8 treatment cycles, 5 to 8 treatment cycles, or 6 to 8 Treatment cycles, most preferably 6 to 8 treatment cycles, for example: 6 treatment cycles, 7 treatment cycles, and/or 8 treatment cycles.
  • a treatment cycle is every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, treatment cycles are every 3 weeks.
  • the second treatment phase follows the first treatment phase. In some embodiments, the second treatment phase is continued from the end of the first treatment phase until clinical benefit is lost, toxicity is intolerable, efficacy is assessed as disease progression, and/or the investigator determines that continued treatment is not appropriate.
  • the present disclosure provides a pharmaceutical combination for treating uterine malignancy, comprising a first pharmaceutical combination, and optionally, a second pharmaceutical combination.
  • a drug combination wherein the first drug combination includes an anti-PD-L1 antibody or an antigen-binding fragment thereof and a chemotherapy drug.
  • the chemotherapeutic drugs in the first drug combination are platinum-based antitumor drugs and taxane-based antitumor drugs.
  • the chemotherapeutic drug in the first drug combination is a platinum anti-tumor drug and paclitaxel.
  • the chemotherapeutic drug in the first drug combination is carboplatin and a taxane anti-tumor drug.
  • the chemotherapeutic drugs in the first drug combination are carboplatin and paclitaxel.
  • the chemotherapeutic drug in the first drug combination is an anthracycline anti-tumor drug. In other embodiments, the chemotherapeutic drug in the first drug combination is doxorubicin. In other embodiments, the chemotherapeutic drugs in the first drug combination are taxane anti-tumor drugs and antimetabolite anti-tumor drugs. In other embodiments, the chemotherapeutic drugs in the first drug combination are docetaxel and gemcitabine.
  • the first pharmaceutical combination further includes anlotinib or a pharmaceutically acceptable salt thereof.
  • the first drug combination includes an anti-PD-L1 antibody or antigen-binding fragment thereof, a chemotherapeutic agent, and anlotinib or a pharmaceutically acceptable salt thereof.
  • the first pharmaceutical combination includes an anti-PD-L1 antibody or antigen-binding fragment thereof, paclitaxel, carboplatin, and anlotinib or a pharmaceutically acceptable salt thereof.
  • the first pharmaceutical combination includes an anti-PD-L1 antibody or antigen-binding fragment thereof, doxorubicin, and anlotinib or a pharmaceutically acceptable salt thereof.
  • the first pharmaceutical combination includes an anti-PD-L1 antibody or antigen-binding fragment thereof, docetaxel, gemcitabine, and anlotinib or a pharmaceutically acceptable salt thereof.
  • the second drug combination includes an anti-PD-L1 antibody or antigen-binding fragment thereof. In some embodiments, the second pharmaceutical combination includes an anti-PD-L1 antibody, or antigen-binding fragment thereof, and anlotinib, or a pharmaceutically acceptable salt thereof.
  • the drug combination includes a first drug combination administered to a patient in need thereof during a first treatment phase, and a second drug combination administered to a patient in need thereof during a second treatment phase, said
  • the first drug combination includes an anti-PD-L1 antibody or an antigen-binding fragment thereof, carboplatin, and paclitaxel
  • the second drug combination includes an anti-PD-L1 antibody or an antigen-binding fragment thereof.
  • the drug combination includes a first drug combination administered to a patient in need thereof during a first treatment phase, and a second drug combination administered to a patient in need thereof during a second treatment phase, so
  • the first drug combination includes an anti-PD-L1 antibody or an antigen-binding fragment thereof, anlotinib or a pharmaceutically acceptable salt thereof, carboplatin, and paclitaxel
  • the second drug combination includes an anti-PD-L1 antibody or an antigen thereof. Binding fragment and anlotinib or a pharmaceutically acceptable salt thereof.
  • the drug combination includes a first drug combination administered to a patient in need thereof during a first treatment phase, and a second drug combination administered to a patient in need thereof during a second treatment phase, so
  • the first drug combination includes an anti-PD-L1 antibody or an antigen-binding fragment thereof, anlotinib or a pharmaceutically acceptable salt thereof, and doxorubicin
  • the second drug combination includes an anti-PD-L1 antibody or an antigen thereof. Binding fragment and anlotinib or a pharmaceutically acceptable salt thereof.
  • the drug combination includes a first drug combination administered to a patient in need thereof during a first treatment phase, and a second drug combination administered to a patient in need thereof during a second treatment phase, so
  • the first drug combination includes an anti-PD-L1 antibody or an antigen-binding fragment thereof, anlotinib or a pharmaceutically acceptable salt thereof, docetaxel and gemcitabine
  • the second drug combination includes an anti-PD-L1 antibody or Its antigen-binding fragment and anlotinib or its pharmaceutically acceptable salt.
  • the first pharmaceutical combination or the second pharmaceutical combination includes 600-2400 mg, 1200-2400 mg, 1200-1800 mg, or 1800-2400 mg anti-PD-L1 antibody or antigen-binding fragment thereof; in some embodiments , the first pharmaceutical combination or the second pharmaceutical combination includes 600 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, 1600 mg, 1800 mg, 2000 mg, 2200 mg or 2400 mg anti-PD-L1 antibody or antigen-binding fragment thereof; in some embodiments, the The first drug combination or the second drug combination includes 1200 mg of anti-PD-L1 antibody or antigen-binding fragment thereof.
  • the first pharmaceutical combination or the second pharmaceutical combination includes 6-12 mg of anlotinib or a pharmaceutically acceptable salt thereof; in some embodiments, the first pharmaceutical combination or the second pharmaceutical combination includes 6-12 mg of anlotinib or a pharmaceutically acceptable salt thereof; The pharmaceutical combination includes 6 mg, 8 mg, 10 mg or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof; in some embodiments, the first pharmaceutical combination or the second pharmaceutical combination includes 8 mg or 10 mg of anlotinib. or a pharmaceutically acceptable salt thereof.
  • the first pharmaceutical combination or the second pharmaceutical combination includes 600-2400 mg, 1200-2400 mg, 1200-1800 mg, or 1800-2400 mg of an anti-PD-L1 antibody or antigen-binding fragment thereof, and 6-12 mg of Anlotinib or its pharmaceutically acceptable salt.
  • the first pharmaceutical combination or the second pharmaceutical combination includes 600 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, 1600 mg, 1800 mg, 2000 mg, 2200 mg, or 2400 mg of an anti-PD-L1 antibody or antigen-binding fragment thereof; and 6 mg , 8 mg, 10 mg or 12 mg of anlotinib or its pharmaceutically acceptable salt.
  • the first pharmaceutical combination or the second pharmaceutical combination includes 1200 mg of anti-PD-L1 antibody or antigen-binding fragment thereof; and 6 mg, 8 mg, 10 mg or 12 mg of anlotinib or a pharmaceutically acceptable thereof Salt. In some embodiments, the first pharmaceutical combination or the second pharmaceutical combination includes 1200 mg of anti-PD-L1 antibody or antigen-binding fragment thereof; and 8 mg or 10 mg of anlotinib or a pharmaceutically acceptable salt thereof.
  • the content of the anti-PD-L1 antibody or antigen-binding fragment thereof in the first pharmaceutical combination or the second pharmaceutical combination is a daily dose.
  • the pharmaceutical combination contains the anti-PD-L1 antibody or antigen-binding fragment thereof in a once-daily dose.
  • the content of the anti-PD-L1 antibody or antigen-binding fragment thereof in the first pharmaceutical combination or the second pharmaceutical combination is a unified dose.
  • the content of the anti-PD-L1 antibody or antigen-binding fragment thereof in the first pharmaceutical combination or the second pharmaceutical combination is a dose for one treatment cycle, and each treatment cycle is 3 weeks.
  • the content of anlotinib or a pharmaceutically acceptable salt thereof in the first pharmaceutical combination or the second pharmaceutical combination is a daily dose.
  • the pharmaceutical combination contains anlotinib or a pharmaceutically acceptable salt thereof in a once-daily dose.
  • the unit dose of the anti-PD-L1 antibody or antigen-binding fragment thereof is 10-1800 mg, 100-1500 mg, 100-1200 mg, 600-1200 mg, or 100-600 mg. In some embodiments, the unit dose of the anti-PD-L1 antibody or antigen-binding fragment thereof is about 10 mg, about 40 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220mg, about 240mg, about 260mg, about 280mg, about 300mg, about 320mg, about 340mg, about 360mg, about 380mg, about 400mg, about 420mg, about 440mg, about 460mg, about 480mg, about 500mg, about 520mg, about 540mg, About 560mg, about 580mg, about 600mg, about 620mg, about 640mg, about 660mg, about 680mg, about 700
  • the unit dose of anlotinib or a pharmaceutically acceptable salt thereof is 6 mg, 8 mg, 10 mg and/or 12 mg.
  • the pharmaceutical combination further includes pharmaceutically acceptable excipients.
  • Excipient is used herein to describe any ingredient other than the active ingredient. The choice of excipient will depend largely on factors such as the specific mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • pharmaceutically acceptable excipients include, but are not limited to, carriers, excipients, diluents, fillers, binders, disintegrants, solubilizers, stabilizers, colorants, flavoring agents, surface Active agents, emulsifiers, buffers or encapsulating materials. The amount of each excipient used may vary within the conventional range in the art.
  • the present disclosure includes a pharmaceutical combination comprising an anti-PD-L1 antibody or an antigen-binding fragment thereof and a chemotherapeutic drug, wherein the anti-PD-L1 antibody or an antigen-binding fragment thereof and a chemotherapeutic drug (such as paclitaxel and carbotaxel) Platinum, doxorubicin, or, alternatively, docetaxel and gemcitabine) are each in the form of pharmaceutical compositions that can be administered simultaneously, sequentially, or at intervals.
  • a chemotherapeutic drug such as paclitaxel and carbotaxel
  • Platinum, doxorubicin, or, alternatively, docetaxel and gemcitabine are each in the form of pharmaceutical compositions that can be administered simultaneously, sequentially, or at intervals.
  • the pharmaceutical combination includes a pharmaceutical composition containing an anti-PD-L1 antibody or antigen-binding fragment thereof and a chemotherapeutic agent (e.g., carboplatin and paclitaxel, doxorubicin, or, docetaxel and Gemcitabine) pharmaceutical composition.
  • a chemotherapeutic agent e.g., carboplatin and paclitaxel, doxorubicin, or, docetaxel and Gemcitabine
  • the pharmaceutical combination comprising an anti-PD-L1 antibody or an antigen-binding fragment thereof and a chemotherapeutic drug described in the present disclosure further includes anlotinib or a pharmaceutically acceptable salt thereof, wherein the anti-PD-L1 antibody or an antigen-binding fragment thereof and a chemotherapy drug.
  • the pharmaceutical combination includes a pharmaceutical composition containing an anti-PD-L1 antibody or antigen-binding fragment thereof, a chemotherapeutic agent (e.g., carboplatin and paclitaxel, doxorubicin, or, docetaxel and Gemcitabine) pharmaceutical compositions, and pharmaceutical compositions containing anlotinib or a pharmaceutically acceptable salt thereof.
  • a chemotherapeutic agent e.g., carboplatin and paclitaxel, doxorubicin, or, docetaxel and Gemcitabine
  • the pharmaceutical combination of the present disclosure is packaged in the same kit, which also includes instructions for treating uterine malignant tumors.
  • kits for treating uterine malignant tumors which includes: an anti-PD-L1 antibody or an antigen-binding fragment thereof and a chemotherapeutic drug (for example, carboplatin and paclitaxel, doxorubicin, or polypeptide). sitaxel and gemcitabine).
  • a chemotherapeutic drug for example, carboplatin and paclitaxel, doxorubicin, or polypeptide. sitaxel and gemcitabine.
  • an anti-PD-L1 antibody or antigen-binding fragment thereof is contained in the first compartment and a chemotherapeutic agent (e.g., carboplatin and paclitaxel, doxorubicin, or, docetaxel and gemcitabine) is contained in the first compartment.
  • a chemotherapeutic agent e.g., carboplatin and paclitaxel, doxorubicin, or, docetaxel and gemcitabine
  • the number of compartments in the kit can optionally be increased according to the type of chemotherapeutic drugs, in which the anti-PD-L1 antibody or its antigen-binding fragment and the chemotherapeutic drugs can be administered simultaneously, sequentially or at intervals when needed. patient.
  • the kit for treating uterine malignant tumors described in the present disclosure further includes anlotinib or a pharmaceutically acceptable salt thereof.
  • an anti-PD-L1 antibody or antigen-binding fragment thereof is contained in the first compartment
  • anlotinib or a pharmaceutically acceptable salt thereof is contained in the second compartment
  • a chemotherapeutic agent e.g., Platinum and paclitaxel, doxorubicin, or, docetaxel and gemcitabine
  • the kit further includes instructions for treating uterine malignancy.
  • the kit includes: a pharmaceutical composition containing an anti-PD-L1 antibody or antigen-binding fragment thereof and a chemotherapeutic agent (e.g., carboplatin and paclitaxel, doxorubicin, or docetaxel and gemcitabine) pharmaceutical compositions.
  • a chemotherapeutic agent e.g., carboplatin and paclitaxel, doxorubicin, or docetaxel and gemcitabine
  • the kit includes: a pharmaceutical composition containing an anti-PD-L1 antibody or antigen-binding fragment thereof, and a chemotherapeutic agent (e.g., carboplatin and paclitaxel, doxorubicin, or docetaxel). and gemcitabine), and pharmaceutical compositions containing anlotinib or a pharmaceutically acceptable salt thereof.
  • each component of a pharmaceutical combination of the present disclosure e.g., an anti-PD-L1 antibody or antigen-binding fragment thereof and a chemotherapeutic agent (e.g., carboplatin and paclitaxel, doxorubicin, or doxorubicin) taxel and gemcitabine); or anti-PD-L1 antibodies or antigen-binding fragments thereof, chemotherapy drugs (e.g., carboplatin and paclitaxel, doxorubicin, or docetaxel and gemcitabine) and anlotinib or its pharmaceutical above acceptable salts) are packaged separately in respective kits, which kits also include instructions for treating uterine malignant tumors with the pharmaceutical combination of the present disclosure.
  • kits also include instructions for treating uterine malignant tumors with the pharmaceutical combination of the present disclosure.
  • Each chemotherapeutic drug can be formulated independently, or part or all of it can be formulated together with pharmaceutically acceptable excipients to form a suitable pharmaceutical composition.
  • each chemotherapeutic drug can be formulated independently with pharmaceutically acceptable excipients.
  • Formulated together to form a suitable pharmaceutical composition for example, carboplatin, paclitaxel, doxorubicin, gemcitabine, and docetaxel are each independently formulated together with pharmaceutically acceptable excipients to form a pharmaceutical composition suitable for injection (such as injection solution or powder for injection).
  • the kit of the present disclosure is a kit suitable for administration within a single treatment cycle (for example, 3 weeks is a treatment cycle), which includes a pharmaceutical combination containing 600-2400 mg of anti-PD-L1 antibodies or antigen-binding fragments thereof. things.
  • the kit is a kit suitable for administration within a single treatment cycle (eg, 3 weeks is a treatment cycle), which includes 600-2400 mg of an anti-PD-L1 antibody or antigen-binding fragment thereof.
  • a treatment cycle is every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In a preferred embodiment, treatment cycles are every 3 weeks.
  • the dose of anti-PD-L1 antibody or antigen-binding fragment thereof administered can be determined based on the severity of the disease, response to the disease, any treatment-related toxicities, and the patient's age and health status.
  • the daily dose administered to the anti-PD-L1 antibody or antigen-binding fragment thereof may be 600-2400 mg, 1200-2400 mg, 1200-1800 mg, or 1800-2400 mg; in some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is administered
  • the daily dose of the binding fragment may be 600, 800, 1000, 1200, 1400, 1600, 1800, 2000, 2200 or 2400 mg; in a preferred embodiment, the daily dose of the anti-PD-L1 antibody or antigen-binding fragment thereof may be 1200mg.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof is administered parenterally; in some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is administered intravenously. Medication.
  • the dosage regimen of anti-PD-L1 antibodies or antigen-binding fragments thereof can be comprehensively determined based on the activity, toxicity, and patient tolerance of the drug.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof is a treatment cycle every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks; in some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof The antigen-binding fragment is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of 600-2400 mg per treatment cycle; In some specific embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of 1200 mg per treatment cycle. In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is administered every 3 weeks at a dose of 600-2400 mg. In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of 1200 mg once every 3 weeks.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof is administered once on Day 1 of each treatment cycle (eg, a 3-week treatment cycle) at a dose of 1200 mg each time. In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is administered intravenously once at a dose of 1200 mg on Day 1 of each treatment cycle (e.g., a 3-week treatment cycle). medicine.
  • Carboplatin is administered according to known dosage regimens (including dosage, route and regimen). In some embodiments, carboplatin is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks for a treatment cycle; in some embodiments, carboplatin is administered every 1 week, every 2 weeks, every 3 weeks, or Apply every 4 weeks. In some embodiments, carboplatin is administered at an AUC of 5 mg/mL/min, 3.75 mg/mL/min, or 2.5 mg/mL/min during each treatment cycle. In some embodiments, carboplatin is administered at an AUC of 5 mg/mL/min during each treatment cycle.
  • carboplatin is administered every 3 weeks at an AUC of 5 mg/mL/min, 3.75 mg/mL/min, or 2.5 mg/mL/min. In some embodiments, carboplatin is administered every 3 weeks at an AUC of 5 mg/mL/min. In some embodiments, carboplatin is administered parenterally; in some embodiments, carboplatin is administered intravenously. In some embodiments, carboplatin is administered once on Day 1 of each treatment cycle (eg, a 3-week treatment cycle) at an AUC of 5 mg/mL/min. In some embodiments, carboplatin is administered intravenously once on Day 1 of each treatment cycle (eg, a 3-week treatment cycle) at an AUC of 5 mg/mL/min.
  • Paclitaxel is administered according to known dosage regimens (including dosage, route, and regimen). In some embodiments, paclitaxel is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks for a treatment cycle; in some embodiments, paclitaxel is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. Apply once a week. In some embodiments, paclitaxel is administered at a dose of 175 mg/m2, 131.25 mg/m2, or 87.5 mg/m2 in each treatment cycle. In some embodiments, paclitaxel is administered at a dose of 175 mg/m2 per treatment cycle.
  • paclitaxel is administered every 3 weeks at a dose of 175 mg/m2, 131.25 mg/m2, or 87.5 mg/m2. In some embodiments, paclitaxel is administered every 3 weeks at a dose of 175 mg/m2. In some embodiments, paclitaxel is administered parenterally; in some embodiments, paclitaxel is administered intravenously. In some embodiments, paclitaxel is administered once on Day 1 of each treatment cycle (eg, a 3-week treatment cycle) at a dose of 175 mg/m2. In some embodiments, paclitaxel is administered intravenously once on Day 1 of each treatment cycle (eg, a 3-week treatment cycle) at a dose of 175 mg/m2.
  • Doxorubicin is administered according to known dosage regimens (including dosage, route and regimen). In some embodiments, doxorubicin is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks for a treatment cycle; in some embodiments, doxorubicin is administered every 1 week, every 2 weeks, every 4 weeks. Apply every 3 weeks or every 4 weeks. In some embodiments, doxorubicin is administered at a dose of 60 mg/m2, 45 mg/m2, or 30 mg/m2 per treatment cycle. In some embodiments, the dose of doxorubicin administered per treatment cycle is 60 mg/m2. In some embodiments, doxorubicin is administered every 3 weeks at a dose of 60 mg/m2, 45 mg/m2, or 30 mg/m2.
  • doxorubicin is administered at a dose of 60 mg/m2 every 3 weeks. In some embodiments, doxorubicin is administered parenterally; in some embodiments, doxorubicin is administered intravenously. In some embodiments, doxorubicin is administered once on Day 1 of each treatment cycle (eg, a 3-week treatment cycle) at a dose of 60 mg/m2. In some embodiments, doxorubicin is administered intravenously once on Day 1 of each treatment cycle (eg, a 3-week treatment cycle) at a dose of 60 mg/m2.
  • Gemcitabine is administered according to known dosing regimens (including dosage, route and schedule). In some embodiments, gemcitabine is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks for a treatment cycle; in some embodiments, gemcitabine is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. Apply twice a week. In some embodiments, gemcitabine is administered at a dose of 1800 mg/m2, 1350 mg/m2, or 900 mg/m2 per treatment cycle. In some embodiments, gemcitabine is administered at a dose of 1800 mg/m2 per treatment cycle. In some embodiments, gemcitabine is administered twice every 3 weeks at a dose of 900 mg/m2, 67.5 mg/m2, or 450 mg/m2 Amount applied.
  • gemcitabine is administered at a dose of 900 mg/m2 twice every 3 weeks. In some embodiments, gemcitabine is administered parenterally; in some embodiments, gemcitabine is administered intravenously. In some embodiments, gemcitabine is administered once on days 1 and 8 of each treatment cycle (eg, a 3-week treatment cycle) at a dose of 900 mg/m2. In some embodiments, gemcitabine is administered intravenously at a dose of 900 mg/m2 once each on days 1 and 8 of each treatment cycle (eg, a 3-week treatment cycle).
  • Docetaxel is administered according to known dosage regimens (including dosage, route and schedule). In some embodiments, docetaxel is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks as a treatment cycle; in some embodiments, docetaxel is administered every 1 week, every 2 weeks, every 4 weeks. Apply every 3 weeks or every 4 weeks. In some embodiments, docetaxel is administered at a dose of 75 mg/m2, 56.25 mg/m2, or 37.5 mg/m2 in each treatment cycle. In some embodiments, docetaxel is administered at a dose of 75 mg/m per treatment cycle. In some embodiments, docetaxel is administered every 3 weeks at a dose of 75 mg/m2, 56.25 mg/m2, or 37.5 mg/m2.
  • docetaxel is administered at a dose of 75 mg/m2 every 3 weeks. In some embodiments, docetaxel is administered parenterally; in some embodiments, docetaxel is administered intravenously. In some embodiments, docetaxel is administered once on day 8 of each treatment cycle (eg, a 3-week treatment cycle) at a dose of 75 mg/m2. In some embodiments, docetaxel is administered intravenously at a dose of 75 mg/m2 once on day 8 of each treatment cycle (eg, a 3-week treatment cycle).
  • anlotinib or a pharmaceutically acceptable salt thereof is a treatment cycle every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, anlotinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 6 mg, 8 mg, 10 mg, or 12 mg for 2 weeks on and off for 1 week. In some embodiments, anlotinib or a pharmaceutically acceptable salt thereof is administered once daily on days 8 to 21 of each treatment cycle (e.g., 3 weeks is a treatment cycle), at 6 mg, 8 mg, Administer in doses of 10mg or 12mg.
  • anlotinib or a pharmaceutically acceptable salt thereof is administered once daily on days 8 to 21 of each treatment cycle (e.g., 3 weeks is a treatment cycle), at 6 mg, 8 mg, Doses of 10 mg or 12 mg are administered orally. In some embodiments, anlotinib or a pharmaceutically acceptable salt thereof is administered once daily at 8 mg or 10 mg on days 8 to 21 of each treatment cycle (e.g., a 3-week treatment cycle). Dosage is administered orally.
  • an anti-PD-L1 antibody or antigen-binding fragment thereof, a chemotherapeutic drug such as paclitaxel and carboplatin, doxorubicin, or, docetaxel and gemcitabine
  • anlotinib or a pharmaceutically acceptable drug thereof Dosage regimens of salts received may be adjusted based on disease severity, disease response, any treatment-related toxicities, and the patient's age and health status.
  • every 9 weeks can be adjusted as a treatment cycle; for example, a treatment cycle of anti-PD-L1 antibody or its antigen-binding fragment can be adjusted as 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, or 15 weeks; for example, a treatment cycle of anlotinib or its pharmaceutically acceptable salt can be adjusted to 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or 9 weeks.
  • the pharmaceutical composition comprising an anti-PD-L1 antibody or an antigen-binding fragment thereof and a chemotherapeutic drug described in the present disclosure includes a pharmaceutical composition containing an anti-PD-L1 antibody or an antigen-binding fragment thereof and a chemotherapeutic drug.
  • a pharmaceutical composition containing an anti-PD-L1 antibody or an antigen-binding fragment thereof and a chemotherapeutic drug for example, carboplatin and paclitaxel, doxorubicin, or docetaxel and gemcitabine
  • the pharmaceutical composition containing an anti-PD-L1 antibody or an antigen-binding fragment thereof is prepared to be suitable for each administration Patients were administered 600-2400 mg, 1200-2400 mg, 1200-1800 mg, or 1800-2400 mg of anti-PD-L1 antibody or antigen-binding fragment thereof in a single or multiple dose form.
  • a pharmaceutical composition containing an anti-PD-L1 antibody or antigen-binding fragment thereof is formulated to be administered to a patient at a first administration of 600-2400 mg, 1200-2400 mg, 1200-1800 mg, or 1800-2400 mg. Single-dose or multiple-dose forms of anti-PD-L1 antibodies or antigen-binding fragments thereof.
  • a pharmaceutical composition containing an anti-PD-L1 antibody or antigen-binding fragment thereof is formulated to be suitable for administration to a patient at 600 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, 1600 mg, 1800 mg, 2000 mg, 2200 mg per administration or 2400 mg of an anti-PD-L1 antibody or antigen-binding fragment thereof in a multiple-dose form.
  • a pharmaceutical composition containing an anti-PD-L1 antibody or an antigen-binding fragment thereof is formulated to be suitable for administration to a patient at the first administration of 600 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, 1600 mg, 1800 mg, 2000 mg, Multiple dose form of 2200 mg or 2400 mg anti-PD-L1 antibody or antigen-binding fragment thereof.
  • pharmaceutical compositions containing anti-PD-L1 antibodies or antigen-binding fragments thereof are formulated Prepare a multi-dose form suitable for administering to the patient 1200 mg of the anti-PD-L1 antibody or antigen-binding fragment thereof at each dose.
  • a pharmaceutical composition containing an anti-PD-L1 antibody or antigen-binding fragment thereof is formulated in a multi-dose form suitable for administering to a patient 1200 mg of an anti-PD-L1 antibody or antigen-binding fragment thereof at the first administration.
  • the present disclosure includes a pharmaceutical combination comprising an anti-PD-L1 antibody or an antigen-binding fragment thereof and a chemotherapeutic drug, which further includes a pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof, wherein, the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof is prepared to be suitable for administering 6 mg, 8 mg, 10 mg and/or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof to the patient every day. single dose form. In some embodiments, the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof is formulated to be suitable for daily administration to a patient of 8 mg and/or 10 mg of anlotinib or a pharmaceutically acceptable salt thereof. single dose form.
  • the pharmaceutical combination comprising an anti-PD-L1 antibody or antigen-binding fragment thereof and a chemotherapeutic drug described in the present disclosure includes: 600-2400 mg, 1200-2400 mg, 1200-1800 mg provided in multiple dosage forms , or a pharmaceutical composition of 1800-2400 mg anti-PD-L1 antibody or antigen-binding fragment thereof.
  • the pharmaceutical combination comprising an anti-PD-L1 antibody or an antigen-binding fragment thereof and a chemotherapeutic drug described in the present disclosure includes: 600 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, 1600 mg provided in multiple dosage forms , a pharmaceutical composition of 1800 mg, 2000 mg, 2200 mg or 2400 mg anti-PD-L1 antibody or antigen-binding fragment thereof.
  • the pharmaceutical combination comprising an anti-PD-L1 antibody or an antigen-binding fragment thereof and a chemotherapeutic drug described in the present disclosure includes: 1200 mg of an anti-PD-L1 antibody or an antigen-binding fragment thereof provided in a multi-dose form pharmaceutical compositions.
  • the pharmaceutical combination comprising an anti-PD-L1 antibody or an antigen-binding fragment thereof and a chemotherapeutic drug described in the present disclosure includes: an anti-PD-L1 antibody or an antigen-binding fragment thereof with a unit dose of 100 mg or 600 mg. Fragmented pharmaceutical compositions. In some embodiments, the pharmaceutical combination comprising an anti-PD-L1 antibody or an antigen-binding fragment thereof and a chemotherapeutic drug described in the present disclosure further includes: anlotinib with a unit dose of 8 mg, 10 mg and/or 12 mg. or a pharmaceutical composition of a pharmaceutically acceptable salt thereof.
  • the drug combination described in the present disclosure including an anti-PD-L1 antibody or an antigen-binding fragment thereof and a chemotherapeutic drug is a drug combination suitable for administration within a single treatment cycle (for example, a treatment cycle of 3 weeks), including a drug combination containing A pharmaceutical composition of 600-2400 mg, 1200-2400 mg, 1200-1800 mg, or 1800-2400 mg anti-PD-L1 antibody or antigen-binding fragment thereof.
  • the pharmaceutical combination comprising an anti-PD-L1 antibody or antigen-binding fragment thereof and a chemotherapeutic agent described in the present disclosure is a pharmaceutical combination suitable for administration within a single treatment cycle (eg, a 3-week treatment cycle) , including pharmaceutical compositions containing 600 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, 1600 mg, 1800 mg, 2000 mg, 2200 mg or 2400 mg of anti-PD-L1 antibodies or antigen-binding fragments thereof.
  • the pharmaceutical combination comprising an anti-PD-L1 antibody or antigen-binding fragment thereof and a chemotherapeutic agent described in the present disclosure is a pharmaceutical combination suitable for administration within a single treatment cycle (eg, a 3-week treatment cycle) , including a pharmaceutical composition containing 1200 mg of anti-PD-L1 antibody or antigen-binding fragment thereof.
  • the pharmaceutical combination comprising an anti-PD-L1 antibody or an antigen-binding fragment thereof and a chemotherapy drug described in the present disclosure further includes 84-168 mg or 112-140 mg anlotinib or a pharmaceutically acceptable drug combination thereof.
  • the pharmaceutical combination comprising an anti-PD-L1 antibody or antigen-binding fragment thereof and a chemotherapy drug described in the present disclosure further includes a drug containing 112 mg or 140 mg anlotinib or a pharmaceutically acceptable salt thereof combination.
  • a treatment cycle is every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In a preferred embodiment, a treatment cycle is every 3 weeks.
  • the pharmaceutical combination comprising an anti-PD-L1 antibody or an antigen-binding fragment thereof and a chemotherapeutic drug described in the present disclosure further includes anlotinib or a pharmaceutically acceptable salt thereof, wherein the anti-PD-L1 antibody or The weight ratio of the antigen-binding fragment and anlotinib or its pharmaceutically acceptable salt is (0.35-29):1, preferably (3.5-29):1, more preferably (3.5-14.5):1, most preferably (7-14.5):1 or (8-11.5):1.
  • the anti-PD-L1 antibody or its antigen-binding fragment and anlotinib or its pharmaceutically acceptable salt can be packaged separately or packaged together.
  • anlotinib or a pharmaceutically acceptable salt thereof can be packaged in multiple equal parts (such as 2 equal parts, 7 equal parts, 14 equal parts, 28 equal parts or more equal parts); anti-PD- L1 antibodies or antigen-binding fragments thereof can be packaged in single aliquots or multiple aliquots (eg, 1 aliquot, 2 aliquots, 4 aliquots, or more).
  • the present disclosure also provides the use of the pharmaceutical combination of the present disclosure or the kit of the present disclosure in the preparation of medicaments for treating uterine malignant tumors.
  • the present disclosure also provides a method for treating uterine malignant tumors, comprising administering an effective amount of a drug of the present disclosure to a patient in need. composition, or kit of the present disclosure.
  • the present disclosure also provides the use of the pharmaceutical combination of the present disclosure or the kit of the present disclosure for treating uterine malignant tumors.
  • the treatment is first-line treatment for uterine malignancy.
  • a line of therapy refers to a position in the sequence in which a patient receives different drugs or other treatments, in which first-line therapy is the first or standard choice.
  • the present disclosure also provides the use of the pharmaceutical combination of the present disclosure or the kit of the present disclosure in the preparation of drugs for first-line treatment of uterine malignant tumors.
  • the present disclosure also provides a method for first-line treatment of uterine malignant tumors, including administering an effective amount of the pharmaceutical combination of the present disclosure or the kit of the present disclosure to a patient in need.
  • the present disclosure also provides the use of the pharmaceutical combination of the present disclosure or the kit of the present disclosure for first-line treatment of uterine malignant tumors.
  • the uses or methods of the present disclosure include administering to a patient in need thereof a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof and a chemotherapeutic agent.
  • a first drug combination is administered to a patient in need thereof during a first treatment phase; and optionally, a second drug combination is administered to a patient in need thereof during a second treatment phase combination.
  • the first drug combination includes an anti-PD-L1 antibody or antigen-binding fragment thereof and a chemotherapeutic agent.
  • the first drug combination includes an anti-PD-L1 antibody or antigen-binding fragment thereof, a chemotherapeutic agent, and anlotinib or a pharmaceutically acceptable salt thereof.
  • the second drug combination includes an anti-PD-L1 antibody or antigen-binding fragment thereof.
  • the second pharmaceutical combination includes an anti-PD-L1 antibody, or antigen-binding fragment thereof, and anlotinib, or a pharmaceutically acceptable salt thereof.
  • the use or method of the present disclosure which includes administering a first pharmaceutical combination to a patient in need thereof during a first treatment phase, and administering a second pharmaceutical combination to a patient in need thereof during a second treatment phase
  • the first drug combination includes anti-PD-L1 antibodies or antigen-binding fragments thereof, platinum anti-tumor drugs and taxane anti-tumor drugs
  • the second drug combination includes anti-PD-L1 antibodies or antigen-binding fragments thereof fragment.
  • the uses or methods of the present disclosure include administering a first drug combination to a patient in need thereof during a first treatment phase, and administering a second drug combination to a patient in need thereof during a second treatment phase.
  • the combination, wherein the first drug combination includes an anti-PD-L1 antibody or an antigen-binding fragment thereof, carboplatin and paclitaxel
  • the second drug combination includes an anti-PD-L1 antibody or an antigen-binding fragment thereof.
  • the uses or methods of the present disclosure include administering a first pharmaceutical combination to a patient in need thereof during a first treatment phase, and administering a second pharmaceutical combination to a patient in need thereof during a second treatment phase.
  • the first drug combination includes an anti-PD-L1 antibody or an antigen-binding fragment thereof, anlotinib or a pharmaceutically acceptable salt thereof, a platinum-based anti-tumor drug and a taxane-based anti-tumor drug
  • the second drug combination includes an anti-PD-L1 antibody or an antigen-binding fragment thereof and anlotinib or a pharmaceutically acceptable salt thereof.
  • the uses or methods of the present disclosure include administering a first pharmaceutical combination to a patient in need thereof during a first treatment phase, and administering a second pharmaceutical combination to a patient in need thereof during a second treatment phase.
  • Pharmaceutical combination wherein the first pharmaceutical combination includes anti-PD-L1 antibody or antigen-binding fragment thereof, anlotinib or a pharmaceutically acceptable salt thereof, carboplatin and paclitaxel
  • the second pharmaceutical combination includes anti-PD-L1 antibody or antigen-binding fragment thereof, anlotinib or a pharmaceutically acceptable salt thereof, carboplatin and paclitaxel -L1 antibody or antigen-binding fragment thereof and anlotinib or a pharmaceutically acceptable salt thereof.
  • the uses or methods of the present disclosure include administering a first pharmaceutical combination to a patient in need thereof during a first treatment phase, and administering a second pharmaceutical combination to a patient in need thereof during a second treatment phase.
  • the first drug combination includes an anti-PD-L1 antibody or an antigen-binding fragment thereof, anlotinib or a pharmaceutically acceptable salt thereof and an anthracycline anti-tumor drug
  • the second drug combination includes an anti-PD-L1 antibody or an antigen-binding fragment thereof -L1 antibody or antigen-binding fragment thereof and anlotinib or a pharmaceutically acceptable salt thereof.
  • the uses or methods of the present disclosure include administering a first pharmaceutical combination to a patient in need thereof during a first treatment phase, and administering a second pharmaceutical combination to a patient in need thereof during a second treatment phase.
  • Pharmaceutical combination wherein the first pharmaceutical combination includes an anti-PD-L1 antibody or an antigen-binding fragment thereof, anlotinib or a pharmaceutically acceptable salt thereof, and doxorubicin
  • the second pharmaceutical combination includes an anti-PD-L1 antibody or an antigen-binding fragment thereof, anlotinib or a pharmaceutically acceptable salt thereof, and doxorubicin.
  • -L1 antibody or antigen-binding fragment thereof and anlotinib or a pharmaceutically acceptable salt thereof thereof.
  • the uses or methods of the present disclosure include administering a first pharmaceutical combination to a patient in need thereof during a first treatment phase, and administering a second pharmaceutical combination to a patient in need thereof during a second treatment phase.
  • the first drug combination includes an anti-PD-L1 antibody or an antigen-binding fragment thereof, anlotinib or a pharmaceutically acceptable salt thereof, a taxane anti-tumor drug and an antimetabolite anti-tumor drug
  • the second drug combination includes an anti-PD-L1 antibody or an antigen-binding fragment thereof and anlotinib or a pharmaceutically acceptable salt thereof.
  • the use or method includes administering a first pharmaceutical combination to a patient in need thereof during a first treatment phase, and administering a second pharmaceutical combination to a patient in need thereof during a second treatment phase, wherein , the first drug combination includes anti-PD-L1 antibody or antigen-binding fragment thereof, anlotinib or a pharmaceutically acceptable salt thereof, docetaxel and gemcitabine, and the second drug combination includes anti-PD-L1 Antibodies or antigen-binding fragments thereof and anlotinib or pharmaceutically acceptable salts thereof.
  • the first treatment phase includes 1 to 14 treatment cycles, preferably 2 to 12 treatment cycles, further preferably 4 to 10 treatment cycles, for example: 4 to 10 treatment cycles, 5 to 10 Treatment cycles, 6 to 10 treatment cycles, 4 to 9 treatment cycles, 5 to 9 treatment cycles, 6 to 9 treatment cycles, 4 to 8 treatment cycles, 5 to 8 treatment cycles, or 6 to 8 Treatment cycles, most preferably 6 to 8 treatment cycles, for example: 6 treatment cycles, 7 treatment cycles, and/or 8 treatment cycles.
  • a treatment cycle is every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, treatment cycles are every 3 weeks.
  • the second treatment phase follows the first treatment phase. In some embodiments, the second treatment phase is continued from the end of the first treatment phase until clinical benefit is lost, toxicity is intolerable, efficacy is assessed as disease progression, and/or the investigator determines that continued treatment is not appropriate.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof, carboplatin, and paclitaxel are each in the form of a pharmaceutical composition, which can be administered simultaneously, sequentially, or at intervals.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof, carboplatin, paclitaxel and anlotinib or a pharmaceutically acceptable salt thereof are each in the form of a pharmaceutical composition, which can be administered simultaneously, sequentially or at intervals.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof, doxorubicin and anlotinib or a pharmaceutically acceptable salt thereof are each in the form of a pharmaceutical composition, which can be administered simultaneously, sequentially or at intervals.
  • anti-PD-L1 antibody or antigen-binding fragment thereof, docetaxel, gemcitabine and anlotinib or a pharmaceutically acceptable salt thereof are each in the form of a pharmaceutical composition, which can be administered simultaneously, sequentially or at intervals.
  • the uterine malignant tumors described in this disclosure are endometrial cancer and/or uterine sarcoma.
  • the uterine malignant tumor is endometrial cancer.
  • the uterine malignant tumor is uterine sarcoma.
  • anlotinib 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy [Basic]methyl]cyclopropylamine, which has the structural formula of formula (I):
  • anlotinib can be administered in its free base form or in the form of its pharmaceutically acceptable salt.
  • Pharmaceutically acceptable salts of anlotinib include, but are not limited to, salts formed by anlotinib and an acid selected from the following: 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, cinnamic acid, Mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chloro
  • anlotinib or a pharmaceutically acceptable salt thereof in this disclosure are based on the molecular weight of the anlotinib free base.
  • Anlotinib or a pharmaceutically acceptable salt thereof can be administered through a variety of routes, including gastrointestinal and parenteral routes, including but not limited to oral, intraperitoneal, and intravenous , intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, Vaginal, intraocular, topical, subcutaneous, intrafatty, intraarticular, intraperitoneal and intrathecal administration. In some specific embodiments, administration is via oral administration.
  • the dosage of anlotinib or its pharmaceutically acceptable salt to be administered can be determined based on the severity of the disease, response to the disease, any treatment-related toxicities, and the age and health status of the patient.
  • the daily dose of anlotinib or a pharmaceutically acceptable salt thereof may be 2 mg to 20 mg.
  • the daily dose of anlotinib or a pharmaceutically acceptable salt thereof 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 once or multiple times daily.
  • anlotinib, or a pharmaceutically acceptable salt thereof is administered once daily in the form of an oral solid dosage form.
  • the dosage regimen of anlotinib or its pharmaceutically acceptable salt can be comprehensively determined based on the activity, toxicity and patient tolerance of the drug.
  • anlotinib or a pharmaceutically acceptable salt thereof is administered at intervals.
  • the interval administration includes a administration period and a drug withdrawal period.
  • anlotinib or its pharmaceutically acceptable salt can be administered once or multiple times a day.
  • the ratio in days between the dosing period and the drug-free period is 2: (0.5-5), 2: (0.5-3), 2: (0.5-2), or 2: (0.5-1).
  • the dosing is for 2 weeks on and off for 2 weeks. In some embodiments, dosing lasts for 2 weeks and then stops for 1 week.
  • dosing is continued for 5 days and 2 days off.
  • anlotinib or its pharmaceutically acceptable salt can be administered orally at a dose of 6 mg, 8 mg, 10 mg or 12 mg once daily for 2 weeks and 1 week off.
  • anlotinib or its pharmaceutically acceptable salt can be administered orally at a dose of 8 mg or 10 mg once daily for 2 weeks on and off for 1 week.
  • compositions containing anlotinib or its pharmaceutically acceptable salts are provided.
  • the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof is provided in a single dose.
  • the single dose of the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof includes 6 mg, 8 mg, 10 mg, or 12 mg of anlotinib.
  • the drug is administered according to a regimen of 2 weeks on and 1 week off, and every 3 weeks is a treatment cycle, and the anlotinib or a pharmaceutically acceptable salt thereof is administered in each treatment cycle.
  • Total dose is 84-168mg.
  • the drug is administered according to a regimen of 2 weeks on and 1 week off, and every 3 weeks is a treatment cycle.
  • the total dose of anlotinib or a pharmaceutically acceptable salt thereof administered in each treatment cycle includes Selected from the range of 84mg, 112mg, 140mg, 168mg or any of the above values.
  • the drug is administered according to a regimen of 2 weeks on and 1 week off, and every 3 weeks is a treatment cycle.
  • the total dose of anlotinib or a pharmaceutically acceptable salt thereof administered in each treatment cycle includes 112mg-140mg.
  • the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof includes, but is not limited to, formulations suitable for oral, parenteral, and topical administration; in some embodiments, the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof includes, but is not limited to, formulations suitable for oral, parenteral, and topical administration;
  • the pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof is a preparation suitable for oral administration, and the oral preparation can be prepared by conventional methods using pharmaceutically acceptable excipients well known in the art; in some embodiments , the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof is a solid preparation suitable for oral administration; in some embodiments, the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof Compositions include, but are not limited to, tablets and capsules.
  • the pharmaceutically acceptable excipients of the solid preparation suitable for oral administration include mannitol, microcrystalline cellulose, hydroxypropyl
  • the chemotherapeutic drugs include, but are not limited to, platinum anti-tumor drugs (including, but not limited to, oxaliplatin, cisplatin, carboplatin, nedaplatin, bicycloplatin, imiplatin, loplatin, Picoplatin, Lobaplatin, triplatin tetranitrate, phenanthroplatin, satraplatin), camptothecin anti-tumor drugs (including but not limited to camptothecin, hydroxycamptothecin, aminocamptothecin, Irinotecan, topotecan, irinotecan, rubitecan, lurotecan (lurtotecan), gemotecan, karenitecin, 7-ethylcamptothecin), taxane antineoplastic drugs (including but not limited to paclitaxel, paclitaxel liposomes, albumin-bound paclitaxel and docetaxel), nitrogen mustard anti-tumor drugs (including but
  • the chemotherapy drug is selected from one or more of platinum anti-tumor drugs, taxane anti-tumor drugs, anthracycline anti-tumor drugs, and antimetabolite anti-tumor drugs.
  • the chemotherapeutic drug is a platinum-based anti-tumor drug and/or a taxane-based anti-tumor drug.
  • the chemotherapeutic drug is an anthracycline anti-tumor drug.
  • the chemotherapeutic drug is a taxane anti-tumor drug and/or an antimetabolite anti-tumor drug.
  • the platinum anti-tumor drug is selected from the group consisting of cisplatin, carboplatin, nedaplatin, bicycloplatin, picoplatin, oxaliplatin, imiplatin, loplatin, loplatin, triplatinum tetranitrate, phenanthroplatin or One or more of sataplatin; preferably the platinum anti-tumor drug is carboplatin and/or cisplatin; more preferably the platinum anti-tumor drug is carboplatin.
  • the taxane anti-tumor drug is selected from one or more of paclitaxel, paclitaxel liposome, albumin-bound paclitaxel, and docetaxel; preferably, the taxane anti-tumor drug It is paclitaxel and/or docetaxel and/or paclitaxel liposome; more preferably, the taxane anti-tumor drug is paclitaxel.
  • the chemotherapeutic drugs are platinum antineoplastic drugs and paclitaxel. In some embodiments, the chemotherapeutic drugs are carboplatin and taxane antineoplastic drugs. In some embodiments, the chemotherapeutic drugs are carboplatin and paclitaxel.
  • the anthracycline anti-tumor drug is selected from the group consisting of doxorubicin, epirubicin, pirarubicin, amrubicin, arubicin, idarubicin, daunorubicin, and methotrexate.
  • doxorubicin epirubicin
  • pirarubicin amrubicin
  • arubicin idarubicin
  • daunorubicin daunorubicin
  • methotrexate methotrexate.
  • anthraquinone, idarubicin, valrubicin, zorubicin, pixantron, and liposomal doxorubicin preferably, the anthracycline anti-tumor drug is doxorubicin Than the stars.
  • the antimetabolite anti-tumor drug is selected from the group consisting of carmofur, 5-fluorouracil, tegafur, capecitabine, tegio, furfururacil, deoxyfluridine, trifluridine, and One or more of glycocytidine, gemcitabine, azacitidine, amcitabine, mercaptopurine, fludarabine, methotrexate, and pemetrexed; preferably the antimetabolite anti-tumor drug For gemcitabine.
  • the chemotherapeutic drug is an anthracycline anti-tumor drug. In other embodiments, the chemotherapeutic agent is doxorubicin.
  • the chemotherapeutic drugs are taxane anti-tumor drugs and antimetabolite anti-tumor drugs. In other embodiments, the chemotherapeutic drugs are docetaxel and gemcitabine.
  • doxorubicin includes its non-salt form (eg, free base) and its pharmaceutically acceptable salts, and the non-salt forms or salts are included in the protection scope of the present disclosure.
  • the pharmaceutically acceptable salt of anlotinib may be the hydrochloride salt.
  • gemcitabine includes its non-salt form (eg, free base) and its pharmaceutically acceptable salts, and the non-salt form or salts are included in the protection scope of the present disclosure.
  • the pharmaceutically acceptable salt of gemcitabine may be the hydrochloride salt.
  • the chemotherapeutic agent is administered according to known modes of administration, including dosage, route, and regimen.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof is the anti-PD-L1 antibody or antigen-binding fragment thereof in WO2016022630 or CN107001463A.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof is an isolated anti-PD-L1 antibody or antigen-binding fragment thereof; in some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof The antigen-binding fragment is an anti-PD-L1 humanized monoclonal antibody; in some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is an isolated anti-PD-L1 humanized monoclonal antibody; in some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is an isolated anti-PD-L1 humanized monoclonal antibody. In embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof can be an IgG1 or IgG4 antibody; in some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is an IgG1 antibody.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof comprises: at least 80% (e.g., 81%, 82%, 83%) of the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 4 %,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, with at least 80% (such as 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology Chain CDR2 region, with at least 80% (such as 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%) of the amino acid sequence shown in SEQ ID NO:3 or SEQ ID NO:6 , 89%,
  • amino acid sequence shown in SEQ ID NO:10 (such as 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the light chain CDR1 region of SEQ ID NO:8 or SEQ ID NO:11
  • the amino acid sequence shown has at least 80% (for example, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, A light chain CDR2 region that is 94%, 95%, 96%, 97%, 98%, 99% or 100%) homologous, and has at least one amino acid sequence with the amino acid sequence shown in SEQ ID NO:9 or SEQ ID NO:12 80% (such as 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%,
  • the anti-PD-L1 antibody or antigen-binding fragment thereof comprises: 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 NO :
  • the heavy chain CDR2 region of SEQ ID NO:3 or SEQ ID NO:6 is selected from the heavy chain CDR3 region of SEQ ID NO:7 or SEQ ID NO:10, which is selected from SEQ ID The light chain CDR2 region of NO:8 or SEQ ID NO:11, and the light chain CDR3 region selected from SEQ ID NO:9 or SEQ ID NO:12.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof comprises: a heavy chain CDR1 region as set forth in SEQ ID NO: 1, a heavy chain CDR2 region as set forth in SEQ ID NO: 2, as SEQ ID NO: 1
  • the heavy chain CDR3 region shown in ID NO:3 the light chain CDR1 region shown in SEQ ID NO:7, the light chain CDR2 region shown in SEQ ID NO:8, and the light chain CDR2 region shown in SEQ ID NO:9 Light chain CDR3 region.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof comprises: at least 80% (e.g., 81%, 82%, 83%) of the amino acid sequence shown in SEQ ID NO: 13 or SEQ ID NO: 14 %,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, and at least 80% (such as 81%, 82%, 83%, 84%, 85%) with the amino acid sequence shown in SEQ ID NO: 15 or SEQ ID NO: 16 %, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology The light chain variable region.
  • 80% e.g., 81%, 82%, 83%) of the amino acid sequence shown in SEQ ID NO: 13 or SEQ ID NO: 14
  • the anti-PD-L1 antibody or antigen-binding fragment thereof comprises: 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 . In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region as set forth in SEQ ID NO: 14, and a light chain variable region as set forth in SEQ ID NO: 16 .
  • the anti-PD-L1 antibody or antigen-binding fragment thereof comprises: at least 80% (e.g., 81%) of the amino acid sequence set forth in SEQ ID NO: 17, SEQ ID NO: 19, or SEQ ID NO: 21 , 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, and has at least 80% (e.g., 81%) of the amino acid sequence set forth in SEQ ID NO: 17, SEQ ID NO: 19, or SEQ ID NO: 21 , 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, and has at least 80% (e.g.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof comprises: a heavy chain as set forth in SEQ ID NO: 17, and a light chain as set forth in SEQ ID NO: 18. In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises: a heavy chain as set forth in SEQ ID NO: 19, and a light chain as set forth in SEQ ID NO: 20. In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises: a heavy chain as set forth in SEQ ID NO:21, and a light chain as set forth in SEQ ID NO:18.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof provided by the present disclosure may comprise SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10.
  • Anti-PD-L1 antibodies or antigen-binding fragments thereof comprising the conservative substitution variants retain the ability to specifically recognize and bind to PD-L1.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (CDR) selected from a 13C5 or 5G11 antibody, and a light chain complementarity determining region (CDR) selected from a 13C5 or 5G11 antibody. district.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof of the present disclosure comprises a heavy chain variable region selected from the group consisting of ch5G11-hlgG1, ch5G11-hlgG4, ch13C5-hlgG1, and ch13C5-hlgG4 chimeric antibodies.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof of the present disclosure comprises a heavy chain variable selected from hu13C5-hlgG1, hu13C5-hlgG4, hu5G11-hlgG1 or hu5G11-hlgG4 humanized antibody.
  • a light chain variable region selected from the group consisting of hu13C5-hlgG1, hu13C5-hlgG4, hu5G11-hlgG1, or hu5G11-hlgG4 humanized antibodies.
  • 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 ASQSVSTSSSFMH (SEQ ID NO:10), the LCDR2 sequence is YASNLES (SEQ ID NO:11), the LCDR3 sequence is QHSWEIPYT (SEQ ID NO:12); The HCDR1 sequence of 5G11, ch5G11-hIgG1, ch5G11-hIgG4, hu5G11-hIgG1 or hu5G11-hIg
  • the LCDR1 sequence is KASQSVSNDVA (SEQ ID NO:7)
  • the LCDR2 sequence is YAANRYT (SEQ ID NO:8)
  • the LCDR3 sequence is QQDYTSPYT (SEQ ID NO:9).
  • the anti-PD-L1 antibody or antigen-binding fragment thereof is Atezolizumab, Durvalumab, Avelumab, Envo Socazolimab (KN035), sugelimab (CS1001), SHR-1316, Socazolimab (ZKAB001), HS636, LP002, JS003, MSB2311, KL-A167 or STI-A1014.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof is hu5G11-hlgG1, which includes the heavy chain variable region amino acid sequence shown in SEQ ID NO: 13, and the amino acid sequence shown in SEQ ID NO: 13 : The amino acid sequence of the light chain variable region shown in 15.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof is hu5G11-hlgG1, which includes the heavy chain amino acid sequence shown in SEQ ID NO:17, and the heavy chain amino acid sequence shown in SEQ ID NO:18 The light chain amino acid sequence is shown.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof is hu5G11-hlgG1, the amino acid sequence of its heavy chain is shown in SEQ ID NO: 17, and the amino acid sequence of its light chain is shown in SEQ Shown as ID NO:18.
  • the anti-PD-L1 antibody is benmelstobart.
  • compositions containing anti-PD-L1 antibodies or antigen-binding fragments thereof are provided.
  • the pharmaceutical composition containing an anti-PD-L1 antibody or antigen-binding fragment thereof may be present in multiple doses or in a single dose.
  • the pharmaceutical composition contains 100 mg, 300 mg, 600 mg or 1200 mg of an anti-PD-L1 antibody or antigen-binding fragment thereof; in some embodiments, a pharmaceutical composition formulated as a single dose is provided , which contains 100 mg, 300 mg, 600 mg or 1200 mg of anti-PD-L1 antibody or antigen-binding fragment thereof. In some embodiments, a single dose of the pharmaceutical composition containing an anti-PD-L1 antibody or antigen-binding fragment thereof includes 100 mg, 300 mg, 600 mg, or 1200 mg of an anti-PD-L1 antibody or antigen-binding fragment thereof.
  • the pharmaceutical composition containing an anti-PD-L1 antibody or antigen-binding fragment thereof is an injectable solution.
  • the pharmaceutical composition containing an anti-PD-L1 antibody or antigen-binding fragment thereof is an aqueous solution for injection.
  • the aqueous solution for injection includes, but is not limited to, a water-soluble formulation that has not been lyophilized or a water-soluble formulation reconstituted with lyophilized powder.
  • the pharmaceutical composition containing an anti-PD-L1 antibody or antigen-binding fragment thereof is a lyophilized preparation.
  • the freeze-dried preparation refers to an aqueous solution prepared through a freeze-drying process.
  • Lyophilized formulations of the present disclosure may also be dried by other methods known in the art, such as spray drying and bubble drying.
  • the concentration of anti-PD-L1 antibody or antigen-binding fragment thereof in the pharmaceutical composition containing anti-PD-L1 antibody or antigen-binding fragment thereof is 1-200 mg/mL, 2-150 mg/mL, 4.5 -100mg/mL, 5-80mg/mL, 10-60mg/mL, 10-50mg/mL, or 10-30mg/mL. In some specific embodiments, the concentration of the anti-PD-L1 antibody or antigen-binding fragment thereof is about 4.8 mg/mL, about 5 mg/mL, about 10 mg/mL, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL.
  • the concentration of anti-PD-L1 antibody or antigen-binding fragment thereof is about 4.8 mg/mL. In some embodiments, the concentration of anti-PD-L1 antibody or antigen-binding fragment thereof is about 10 mg/mL. In some embodiments, the concentration of anti-PD-L1 antibody or antigen-binding fragment thereof is about 30 mg/mL. In some embodiments, the concentration of anti-PD-L1 antibody or antigen-binding fragment thereof is about 60 mg/mL.
  • the pharmaceutical composition containing an anti-PD-L1 antibody or an antigen-binding fragment thereof further includes one or more of a buffer, an isotonic regulator, a stabilizer and/or a surfactant.
  • the pharmaceutical composition containing an anti-PD-L1 antibody or an antigen-binding fragment thereof includes: a mass volume concentration of about 1-150 mg/mL anti-PD-L1 antibody or an antigen-binding fragment thereof, and a buffer of 3-50 mM solution, 2-150mg/mL isotonicity regulator/stabilizer and 0.01-0.8mg/mL surfactant, and the pH is about 4.5-6.8.
  • the pharmaceutical composition containing an anti-PD-L1 antibody or an antigen-binding fragment thereof includes: (a) an anti-PD-L1 antibody with a mass volume concentration of about 10 mg/mL or about 30 mg/mL, (b) sucrose with a mass volume concentration of approximately 80 mg/mL, (c) polysorbate 80 with a mass volume concentration of approximately 0.2 mg/mL, (d) histidine with a molar concentration of approximately 10 mM, (e) optional An appropriate amount of hydrochloric acid is used to adjust the pH value of the composition to about 5.5.
  • the pharmaceutical composition containing anti-PD-L1 antibody or antigen-binding fragment thereof is hu5G11-hlgG1 injection, with a specification of 100 mg/10 mL or 600 mg/20 mL.
  • the endometrial cancer includes endometrioid cancer, non-endometrioid cancer, and carcinosarcoma. In some embodiments, the endometrial cancer includes endometrioid carcinoma, serous carcinoma, clear cell carcinoma, endometrial undifferentiated carcinoma and dedifferentiated carcinoma, endometrial mixed adenocarcinoma, and uterine carcinosarcoma .
  • the endometrial cancer is late-stage, and/or recurrent, and/or metastatic endometrial cancer; in some embodiments, the endometrial cancer is Advanced endometrial cancer; in some embodiments, the endometrial cancer is recurrent endometrial cancer; in some embodiments, the endometrial cancer is advanced and/or recurrent uterine cancer Endometrial cancer; in some embodiments, the endometrial cancer is recurrent and/or metastatic endometrial cancer. In some embodiments, the endometrial cancer is recurrent and/or metastatic advanced endometrial cancer. In some embodiments, the endometrial cancer is stage III endometrial cancer.
  • the endometrial cancer is stage IV endometrial cancer. In some embodiments, the endometrial cancer is stage III or IV endometrial cancer. In some embodiments, the endometrial cancer is stage III or stage IV or recurrent endometrial cancer.
  • the patient with endometrial cancer has not received any anti-tumor treatment in the past; in some embodiments, the patient with endometrial cancer has not received systemic anti-tumor treatment in the past. Treatment; In some embodiments, the patient with endometrial cancer has not previously received first-line systemic anti-tumor therapy.
  • the patient with endometrial cancer is ineligible for treatment other than systemic therapy.
  • the patient with endometrial cancer is not a candidate for surgical treatment and/or radical radiotherapy.
  • the patient with endometrial cancer has previously received at least one treatment; in some embodiments, the patient with endometrial cancer has previously received surgical treatment; in some embodiments, The patient with endometrial cancer has received non-radical surgical treatment in the past; in some embodiments, the patient with endometrial cancer has received adjuvant treatment in the past; in some embodiments, the patient The patient with endometrial cancer has previously received neoadjuvant therapy; in some embodiments, the patient with endometrial cancer has previously received adjuvant and/or neoadjuvant therapy; in some embodiments, the patient The patient with endometrial cancer has previously received surgical treatment and adjuvant treatment; in some embodiments, the patient with endometrial cancer has previously received surgical treatment and neoadjuvant treatment; in some embodiments, the uterine The patient with endometrial cancer has previously received surgical treatment and adjuvant and/or neoadjuvant treatment; in some embodiments, the patient with endometrial cancer
  • the adjuvant or neoadjuvant treatment includes external beam radiotherapy (EBRT), vaginal post-loading radiotherapy, concurrent chemoradiotherapy, chemotherapy and sequential chemoradiotherapy.
  • the adjuvant therapy or neoadjuvant therapy includes platinum-containing chemotherapy, platinum-containing chemotherapy concurrent with radiotherapy, and platinum-containing chemotherapy followed by radiotherapy.
  • the platinum agent includes, but is not limited to, cisplatin, carboplatin, nedaplatin, bicycloplatin, picoplatin, oxaliplatin, imiplatin, loplatin, lobaplatin, triplatinum tetranitrate, phenanthrene platinum or sataplatin.
  • the endometrial cancer is advanced and/or recurrent endometrial cancer that has not received systemic anti-tumor treatment in the past; in some embodiments, the endometrial cancer is Advanced and/or recurrent endometrial cancer that has not received first-line systemic anti-tumor treatment in the past; in some embodiments, the endometrial cancer has not received first-line systemic anti-tumor treatment in the past and is not Endometrial cancer suitable for treatment other than systemic treatment; in some embodiments, the endometrial cancer is advanced and/or recurrent endometrium that is not suitable for surgical treatment and/or radical radiotherapy Cancer; in some embodiments, the endometrial cancer is an advanced and/or recurrent endometrial cancer that has not received first-line systemic anti-tumor treatment in the past and is not suitable for surgical treatment and/or radical radiotherapy.
  • the endometrial cancer is stage III or IV or recurrent endometrium that has not received first-line systemic anti-tumor treatment in the past and is not suitable for other treatments other than systemic treatment.
  • Cancer in some embodiments, the endometrial cancer is stage III or IV or recurrent intrauterine cancer that has not received first-line systemic anti-tumor treatment in the past and is not suitable for surgical treatment and/or radical radiotherapy.
  • Membranous cancer in some embodiments, the endometrial cancer is stage III or IV that has not received first-line systemic anti-tumor treatment in the past but has received surgical treatment, and is not suitable for other treatments other than systemic treatment.
  • Endometrial cancer in some embodiments, the endometrial cancer has not received first-line systemic anti-tumor treatment in the past but has received non-radical surgical treatment (for example, residual lesions remain after non-radical surgical treatment), Stage III or IV endometrial cancer that is not suitable for treatment other than systemic treatment; in some embodiments, the endometrial cancer has not received first-line systemic anti-tumor treatment but has undergone surgery.
  • the endometrial cancer has not been treated in the past Recurrent stage III or IV endometrial cancer that has received first-line systemic anti-tumor therapy but has received surgery, or surgery combined with adjuvant therapy and/or neoadjuvant therapy, and is not suitable for other treatments other than systemic therapy.
  • the time to recurrence in the patient with recurrent endometrial cancer is greater than 12 months after completion of initial treatment (eg, surgery, or surgery combined with adjuvant treatment). In some embodiments, the time to recurrence in the patient with recurrent endometrial cancer is greater than 6 months after completion of adjuvant and/or neoadjuvant therapy.
  • the adjuvant or neoadjuvant treatment includes external beam radiotherapy (EBRT), vaginal post-loading radiotherapy, concurrent chemoradiotherapy, chemotherapy and sequential chemoradiotherapy.
  • the endometrial cancer is microsatellite unstable endometrial cancer. In some embodiments, the endometrial cancer is microsatellite instability-high (MSI-H) endometrial cancer. In some embodiments, the endometrial cancer is low-grade microsatellite instability (MSI-L) endometrial cancer. In some embodiments, the endometrial cancer is microsatellite stable (MSS) endometrial cancer. In some embodiments, the endometrial cancer is MSS/MSI-L endometrial cancer.
  • the endometrial cancer is mismatch repair deficient (dMMR) endometrial cancer.
  • the endometrial cancer is a non-mismatch repair deficient (non-dMMR) endometrial cancer, including mismatch repair-complete (pMMR) endometrial cancer.
  • the endometrial cancer includes but is not limited to type I (estrogen-dependent) endometrial cancer or type II (non-estrogen-dependent) endometrial cancer. Endometrial cancer.
  • the uterine sarcoma includes uterine leiomyosarcoma, endometrial stromal sarcoma, undifferentiated uterine sarcoma, uterine adenosarcoma, malignant perivascular epithelioid cell tumor, and rhabdomyosarcoma.
  • the endometrial stromal sarcoma is high-grade endometrial stromal sarcoma or low-grade endometrial stromal sarcoma.
  • the uterine adenosarcoma is uterine adenosarcoma with sarcomatous overgrowth or uterine adenosarcoma without sarcomatous overgrowth.
  • the sarcomatous overgrowth is defined as pathology report demonstrating high-grade sarcomatoid component accounting for more than 25% of the total tumor volume.
  • the uterine sarcoma is an estrogen receptor positive and progesterone receptor positive (ER + /PR + ) uterine sarcoma.
  • the uterine sarcoma is an advanced, and/or recurrent, and/or metastatic uterine sarcoma; in some embodiments, the uterine sarcoma is an advanced uterine sarcoma; in some In embodiments, the uterine sarcoma is a recurrent uterine sarcoma; in some embodiments, the uterine sarcoma is an advanced and/or recurrent uterine sarcoma; in some embodiments, the uterine sarcoma is Recurrent and/or metastatic uterine sarcoma. In some embodiments, the uterine sarcoma is a stage I, stage II, stage III or stage IV uterine sarcoma.
  • the patient with uterine sarcoma has not received any anti-tumor treatment in the past; in some embodiments, the patient with uterine sarcoma has not received systemic anti-tumor treatment in the past; in some In embodiments, the patient with uterine sarcoma has not received first-line systemic anti-tumor treatment in the past.
  • the patient with uterine sarcoma is not suitable for treatment other than systemic therapy.
  • the patient with uterine sarcoma is not a candidate for surgical treatment and/or radical radiotherapy.
  • the patient with uterine sarcoma has received at least one treatment in the past; in some embodiments, the patient with uterine sarcoma has received surgical treatment in the past; in some embodiments, the patient with uterine sarcoma has received at least one treatment in the past; The patient with uterine sarcoma has previously received non-radical surgical treatment; in some embodiments, the patient with uterine sarcoma has previously received adjuvant therapy; in some embodiments, the patient with uterine sarcoma has previously received neoadjuvant therapy ; In some embodiments, the patient with uterine sarcoma has previously received adjuvant and/or neoadjuvant therapy; in some embodiments, the patient with uterine sarcoma has previously received surgical treatment and adjuvant therapy; in some embodiments In the program, the patient with uterine sarcoma has previously received surgical treatment and neoadjuvant treatment; in some embodiments, the patient with uterine
  • the adjuvant or neoadjuvant treatment includes external beam radiotherapy (EBRT), vaginal post-loading radiotherapy, concurrent chemoradiotherapy, chemotherapy and sequential chemoradiotherapy.
  • the adjuvant therapy or neoadjuvant therapy includes platinum-containing chemotherapy, platinum-containing chemotherapy concurrent with radiotherapy, and platinum-containing chemotherapy followed by radiotherapy.
  • the platinum agent includes, but is not limited to, cisplatin, carboplatin, nedaplatin, bicycloplatin, picoplatin, oxaliplatin, imiplatin, loplatin, lobaplatin, triplatinum tetranitrate, phenanthrene platinum or sataplatin.
  • the uterine sarcoma is a uterine sarcoma that has not received first-line systemic anti-tumor treatment in the past; in some embodiments, the uterine sarcoma is a uterine sarcoma that has not received first-line systemic anti-tumor treatment in the past, and Uterine sarcomas that are not suitable for treatment other than systemic treatment; in some embodiments, the uterine sarcomas are uterine sarcomas that are not suitable for surgical treatment and/or radical radiotherapy; in some embodiments, the uterine sarcomas are The sarcoma is a uterine sarcoma that has not received first-line systemic anti-tumor treatment in the past and is not suitable for surgical treatment and/or radical radiotherapy; in some embodiments, the uterine sarcoma has not received first-line systemic anti-tumor treatment in the past.
  • uterine leiomyosarcoma high-grade endometrial stromal sarcoma, undifferentiated uterine sarcoma, uterine adenosarcoma with sarcomatous overgrowth, malignant perivascular epithelioid cell tumor, and rhabdomyosarcoma that are not suitable for treatment other than systemic therapy.
  • the uterine sarcoma is a prior Uterine leiomyosarcoma, high-grade endometrial stromal sarcoma, undifferentiated uterine sarcoma, uterine adenosarcoma with sarcoma overgrowth, and malignancy that have not received first-line systemic anti-tumor therapy and are not suitable for surgical treatment and/or radical radiotherapy Perivascular epithelioid cell tumors and rhabdomyosarcoma; in some embodiments, the uterine sarcoma has not previously received first-line systemic anti-tumor therapy but has received surgical treatment and is not suitable for other treatments other than systemic therapy.
  • Uterine sarcoma in some embodiments, the uterine sarcoma has not received first-line systemic anti-tumor treatment in the past but has received non-radical surgical treatment (for example, residual disease remains after non-radical surgical treatment), and is not suitable for systemic treatment.
  • Uterine sarcoma treated other than systemic treatment in some embodiments, the uterine sarcoma has not received first-line systemic anti-tumor treatment in the past but has received non-radical surgical treatment (for example, the patient still has symptoms after non-radical surgical treatment).
  • the uterine sarcoma has not received first-line systemic anti-tumor treatment in the past but has received surgery, or surgery combined with adjuvant therapy and/or neoadjuvant therapy, and is not suitable for systemic treatment Uterine sarcoma treated other than other treatments; in some embodiments, the uterine sarcoma has not received first-line systemic anti-tumor treatment in the past but has received surgery, or surgery combined with adjuvant therapy and/or neoadjuvant therapy, and is not suitable for Uterine sarcoma treated other than other treatments; in some embodiments, the uterine sarcoma has not received first-line systemic anti-tumor treatment in the past but has received surgery, or surgery combined with adjuvant therapy and/or neoadjuvant therapy, and is not suitable for Uterine leiomyosarcoma, high-grade endometrial stromal sarcoma
  • the uterine sarcoma is recurrent uterine leiomyosarcoma, high-grade endometrial stromal sarcoma, undifferentiated uterine sarcoma, uterine adenosarcoma with sarcomatous overgrowth, malignant perivascular epithelioid cell tumor, and Rhabdomyosarcoma.
  • the time to relapse in the patient with recurrent uterine sarcoma is greater than 12 months after completion of initial treatment (eg, surgery, or surgery combined with adjuvant treatment).
  • the patient with recurrent uterine sarcoma has a time to relapse greater than 6 months after completion of adjuvant and/or neoadjuvant therapy.
  • the adjuvant or neoadjuvant treatment includes external beam radiotherapy (EBRT), vaginal post-loading radiotherapy, concurrent chemoradiotherapy, chemotherapy and sequential chemoradiotherapy.
  • EBRT external beam radiotherapy
  • vaginal post-loading radiotherapy concurrent chemoradiotherapy
  • chemotherapy sequential chemoradiotherapy
  • the patient with uterine sarcoma has previously received anti-estrogen therapy (eg, failed therapy).
  • the uterine sarcoma is a uterine sarcoma that has failed anti-estrogen therapy.
  • the uterine sarcoma is a low-grade endometrial stromal sarcoma that has failed anti-estrogen therapy, an adenosarcoma without sarcomatous overgrowth, or an ER + /PR + uterine sarcoma.
  • the anti-estrogen therapy is a treatment method that inhibits the proliferation of cancer cells caused by estrogen by blocking the binding of estrogen receptors to estrogen, thereby inhibiting the development and metastasis of cancer lesions.
  • the components of the pharmaceutical combinations of the present disclosure may be administered individually, or part or all thereof together, by any suitable route, including, but not limited to, oral or parenteral (by intravenous, intramuscular, topical or subcutaneous) route of administration.
  • the components of the pharmaceutical combinations of the present disclosure may be administered individually, or part or all thereof, together, orally or by injection (eg, intravenously or intraperitoneally).
  • the components in the pharmaceutical combination of the present disclosure may be formulated independently, or part or all thereof, together into suitable dosage forms, including but not limited to tablets, lozenges, pills, capsules (e.g., hard capsules, soft capsules, Enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal injection), granules, emulsions, suspensions, solutions, dispersions and for oral or parenteral use Dosage form of sustained-release formulation for administration.
  • suitable dosage forms including but not limited to tablets, lozenges, pills, capsules (e.g., hard capsules, soft capsules, Enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal injection), granules, emulsions, suspensions, solutions, dispersions and for oral or parenteral use
  • the components in the pharmaceutical combination of the present disclosure may be each independently, or some or all of them may together contain pharmaceutically acceptable auxiliary materials (including carriers and/or excipients).
  • the anti-PD-L1 antibody or antigen-binding fragment thereof and the chemotherapeutic drug are each in a pharmaceutical combination
  • the substances can be administered simultaneously, sequentially or at intervals.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof, a chemotherapeutic agent e.g., carboplatin and paclitaxel, doxorubicin, or, Docetaxel and gemcitabine
  • anlotinib or a pharmaceutically acceptable salt thereof are each in a pharmaceutical composition that can be administered simultaneously, sequentially or at intervals.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof and the chemotherapeutic drug are each administered at intervals. Medication.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof, a chemotherapeutic agent e.g., carboplatin and paclitaxel, doxorubicin, or docetaxel and gemcitabine
  • anlotinib or its The pharmaceutically acceptable salts are each administered at intervals.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof and the chemotherapeutic drug are administered in the same or different doses, respectively. Dosage according to the medication regimen.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof, a chemotherapeutic agent e.g., carboplatin and paclitaxel, doxorubicin, or docetaxel and gemcitabine
  • anlotinib or its The pharmaceutically acceptable salts may be administered in the same or different dosage regimens.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof and the chemotherapeutic agent are administered in different dosage regimens Give medication.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof, a chemotherapeutic agent e.g., carboplatin and paclitaxel, doxorubicin, or docetaxel and gemcitabine
  • anlotinib or its The pharmaceutically acceptable salts are each administered in different dosage regimens.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof can be administered every week (qlw), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w) once.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof is administered every 3 weeks.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of 600-2400 mg, 1200-2400 mg, 1200-1800 mg, or 1800-2400 mg each time.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of 600 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, 1600 mg, 1800 mg, 2000 mg, 2200 mg, or 2400 mg each time. In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of 1200 mg each time.
  • the anlotinib or pharmaceutically acceptable salt thereof is a treatment cycle every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks.
  • the anlotinib or a pharmaceutically acceptable salt thereof can be administered once a day at a dose of 6 mg, 8 mg, 10 mg or 12 mg each time for 2 weeks, with a 1-week pause. Medication. At this time, every 3 weeks is a treatment cycle.
  • the chemotherapeutic agent eg, carboplatin and paclitaxel, doxorubicin, or docetaxel and gemcitabine
  • the chemotherapeutic agent can be administered according to known administration methods.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof and the chemotherapeutic drug, and optionally anlotinib or a pharmaceutically acceptable salt thereof, respectively have the same or different treatment cycles.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof and the chemotherapeutic agent, and optionally anlotinib or a pharmaceutically acceptable salt thereof have the same treatment cycle, for example, every 1 week, every A treatment cycle is 2 weeks, every 3 weeks or every 4 weeks. In some embodiments, treatment cycles are every 3 weeks.
  • a pharmaceutical combination of the present disclosure, or a dosing regimen of a kit of the present disclosure the dosing regimen includes a first treatment phase, optionally including a second treatment phase.
  • the dosage regimen described in the present disclosure is suitable for the use in preparing a medicament for treating uterine malignant tumors, the method of treating uterine malignant tumors and the use of treating uterine malignant tumors according to the present disclosure.
  • the uterine malignant tumor is endometrial cancer and/or uterine sarcoma.
  • the uterine malignant tumor is endometrial cancer.
  • the uterine malignant tumor is uterine sarcoma.
  • the first treatment phase includes 1 to 14 treatment cycles, preferably 2 to 12 treatment cycles, further preferably 4 to 10 treatment cycles, for example: 4 to 10 treatment cycles, 5 to 10 Treatment cycles, 6 to 10 treatment cycles, 4 to 9 treatment cycles, 5 to 9 treatment cycles, 6 to 9 treatment cycles, 4 to 8 treatment cycles, 5 to 8 treatment cycles, or 6 to 8 Treatment cycles, most preferably 6 to 8 treatment cycles, for example: 6 treatment cycles, 7 treatment cycles, and/or 8 treatment cycles.
  • the second treatment phase follows the first treatment phase. In some embodiments of the present disclosure, the second treatment phase includes 2 to 20 treatment cycles. In some embodiments, the second treatment phase is continued from the end of the first treatment phase until clinical benefit is lost, toxicity is intolerable, efficacy is assessed as disease progression, and/or the investigator determines that continued treatment is not appropriate.
  • the treatment cycle is 14 days to 42 days; in some embodiments, the treatment cycle is 14 days days, 21 days, 28 days, 35 days, or 42 days; in some embodiments, the treatment period is 21 days.
  • the first treatment phase and the second treatment phase have the same treatment cycle. In some specific embodiments, the treatment cycles of the first treatment phase and the second treatment phase are both 21 days.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof is administered once on day 1, 2, 3, 4, 5, 6, or 7 of each treatment cycle, preferably every Administer once on the 1st day of each treatment cycle.
  • the anlotinib or a pharmaceutically acceptable salt thereof is administered on days 1-7, 8-14, 1-14, or 8 of each treatment cycle. -Continuous administration for 21 days, preferably on days 8-21 of each treatment cycle.
  • the chemotherapeutic agent e.g., carboplatin and paclitaxel, doxorubicin, or docetaxel and gemcitabine
  • the carboplatin is administered once on day 1, 2, 3, 4, 5, 6, or 7 of each treatment cycle, preferably once on day 1 of each treatment cycle.
  • the paclitaxel is administered once on day 1, 2, 3, 4, 5, 6, or 7 of each treatment cycle, preferably once on day 1 of each treatment cycle.
  • the doxorubicin is administered once on day 1, 2, 3, 4, 5, 6, or 7 of each treatment cycle, preferably on day 1 of each treatment cycle once.
  • the docetaxel is administered once on day 1, 2, 3, 4, 5, 6, 7, or 8 of each treatment cycle, preferably on day 8 of each treatment cycle. medicine once.
  • the gemcitabine is administered twice on days 1, 2, 3, 4, 5, 6, 7, or 8 of each treatment cycle, preferably on days 1 and 8 of each treatment cycle Each dose is administered once.
  • the present disclosure provides a method of treating uterine malignant tumors, comprising administering a first drug combination to a patient in need thereof during a first treatment phase; and optionally, administering a second drug combination to a patient in need thereof during a second treatment phase .
  • the present disclosure also provides the use of the pharmaceutical combination of the present disclosure in the preparation of a medicament for the treatment of uterine malignant tumors and the use of the pharmaceutical combination for the treatment of uterine malignant tumors, the pharmaceutical combination comprising administering to a patient in need during the first treatment phase
  • a first pharmaceutical combination, and optionally a second pharmaceutical combination are administered to a patient in need thereof during a second treatment phase.
  • the present disclosure provides a method for first-line treatment of uterine malignant tumors, which includes administering a first drug combination to a patient in need thereof during a first treatment phase; and optionally, administering a second drug to a patient in need thereof during a second treatment phase combination.
  • the present disclosure also provides the use of the pharmaceutical combination of the present disclosure in the preparation of a medicament for the first-line treatment of uterine malignant tumors and the use of the pharmaceutical combination for the first-line treatment of uterine malignant tumors, the pharmaceutical combination comprising administering to a patient in need in the first treatment phase A first drug combination is administered, and optionally, a second drug combination is administered to the patient in need thereof during a second treatment phase.
  • the uterine malignant tumors described in this disclosure are endometrial cancer and/or uterine sarcoma.
  • the uterine malignant tumor is endometrial cancer.
  • the uterine malignant tumor is uterine sarcoma.
  • the dosing regimen of the first treatment phase includes: 1) anti-PD-L1 antibody or antigen-binding fragment thereof administered once a day within days 1-7 of each treatment cycle; 2) platinum The anti-tumor drug is administered once a day on days 1-7 of each treatment cycle; 3) the taxane anti-tumor drug is administered once a day on days 1-7 of each treatment cycle; and optionally 4) Anlotinib or its pharmaceutically acceptable salt is administered once a day on days 8-21 of each treatment cycle.
  • the dosing regimen of the first treatment phase includes: 1) anti-PD-L1 antibody or antigen-binding fragment thereof is administered once on the 1st day of each treatment cycle; 2) platinum anti-tumor drugs The drug is administered once on the first day of each treatment cycle; 3) Taxane anti-tumor drugs are administered once on the first day of each treatment cycle.
  • the dosing regimen of the first treatment phase includes: 1) anti-PD-L1 antibody or antigen-binding fragment thereof is administered once on the 1st day of each treatment cycle; 2) platinum anti-tumor drugs administered once on the first day of each treatment cycle; 3) taxane antitumor drugs administered once on the first day of each treatment cycle; 4) anlotinib or its pharmaceutically acceptable salts Administer once daily on days 8-21 of each treatment cycle.
  • the dosing regimen of the first treatment phase includes: 1) the anti-PD-L1 antibody or antigen-binding fragment thereof is administered once a day within days 1-7 of each treatment cycle; 2) the anti-PD-L1 antibody or antigen-binding fragment thereof is administered once a day; Platinum is administered once a day on days 1-7 of each treatment cycle; 3) Taxane alcohol is administered once a day on days 1-7 of each treatment cycle; and optionally, 4) anlotinib or a pharmaceutically acceptable salt thereof is administered daily on days 8-21 of each treatment cycle medicine once.
  • the dosing regimen of the first treatment phase includes: 1) anti-PD-L1 antibody or antigen-binding fragment thereof is administered once on day 1 of each treatment cycle; 2) carboplatin is administered every The drug is administered once on the first day of each treatment cycle; 3) Paclitaxel is administered once on the first day of each treatment cycle.
  • the dosing regimen of the first treatment phase includes: 1) anti-PD-L1 antibody or antigen-binding fragment thereof is administered once on day 1 of each treatment cycle; 2) carboplatin is administered every Dosed once on the 1st day of each treatment cycle; 3) Paclitaxel is administered once on the 1st day of each treatment cycle; 4) Anlotinib or its pharmaceutically acceptable salt is administered on days 8-21 of each treatment cycle Dosing once a day.
  • the dosing regimen for the first treatment phase includes administering an anti-PD-L1 antibody or antigen-binding fragment thereof, paclitaxel, and carboplatin on Day 1 of each treatment cycle. In some embodiments, the dosing regimen of the first treatment phase includes: administering an anti-PD-L1 antibody or antigen-binding fragment thereof, paclitaxel, and carboplatin on Day 1 of each treatment cycle; On days 8-21, administer anlotinib or its pharmaceutically acceptable salt daily.
  • the dosing regimen of the first treatment phase includes: 1) anti-PD-L1 antibody or antigen-binding fragment thereof is administered once on the first day of each treatment cycle; 2) anthracycline antibody Tumor drugs are administered once on the 1st day of each treatment cycle; 3) Anlotinib or its pharmaceutically acceptable salt is administered once a day on the 8th to 21st days of each treatment cycle.
  • the dosing regimen of the first treatment phase includes: 1) anti-PD-L1 antibody or antigen-binding fragment thereof is administered once on day 1 of each treatment cycle; 2) taxane-based anti-PD-L1 antibody or antigen-binding fragment thereof is administered once on day 1 of each treatment cycle; Tumor drugs are administered once on the 8th day of each treatment cycle; 3) Antimetabolite anti-tumor drugs are administered once on the 1st and 8th days of each treatment cycle; 4) Anlotinib or its pharmaceutical The above acceptable salt is administered once daily on days 8-21 of each treatment cycle.
  • the dosing regimen of the first treatment phase includes: 1) anti-PD-L1 antibody or antigen-binding fragment thereof is administered once on day 1 of each treatment cycle; 2) doxorubicin It is administered once on the 1st day of each treatment cycle; 3) Anlotinib or its pharmaceutically acceptable salt is administered once a day on the 8th to 21st days of each treatment cycle.
  • the dosing regimen of the first treatment phase includes: 1) anti-PD-L1 antibody or antigen-binding fragment thereof is administered once on day 1 of each treatment cycle; 2) docetaxel is administered It is administered once on the 8th day of each treatment cycle; 3) Gemcitabine is administered once on the 1st and 8th days of each treatment cycle; 4) Anlotinib or its pharmaceutically acceptable salt is administered once on each treatment cycle. Administer once daily on days 8-21 of the treatment cycle.
  • the dosing regimen of the second treatment phase includes: administering the anti-PD-L1 antibody or antigen-binding fragment thereof once a day on days 1-7 of each treatment cycle. In some embodiments, the dosing regimen of the second treatment phase includes: administering the anti-PD-L1 antibody or antigen-binding fragment thereof once on day 1 of each treatment cycle.
  • the dosing regimen for the second treatment phase includes: 1) administration of the anti-PD-L1 antibody or antigen-binding fragment thereof once a day on days 1-7 of each treatment cycle; and 2) Anlotinib or its pharmaceutically acceptable salt is administered once daily on days 8-21 of each treatment cycle.
  • the dosing regimen for the second treatment phase includes: 1) anti-PD-L1 antibody or antigen-binding fragment thereof administered once on Day 1 of each treatment cycle; and 2) anlotinib or a pharmaceutically acceptable salt thereof, administered once daily on days 8-21 of each treatment cycle.
  • an anti-PD-L1 antibody or antigen-binding fragment thereof e.g., hu5G11-hlgG1, paclitaxel, and carboplatin are administered to a patient in need thereof during the first treatment phase, and during the treatment phase,
  • the second treatment phase is to administer anti-PD-L1 antibodies or antigen-binding fragments thereof (such as hu5G11-hlgG1) to patients in need.
  • the first treatment phase includes 6 to 8 treatment cycles, with one treatment cycle every 3 weeks;
  • the dosage regimen of the first treatment phase includes: administering anti-PD-L1 antibody or its antigen-binding fragment, paclitaxel and carboplatin on the first day of each treatment cycle;
  • the dosage regimen of the second treatment phase includes: administering anti-PD-L1 antibody or antigen-binding fragment thereof on the first day of each treatment cycle.
  • an anti-PD-L1 antibody or antigen-binding fragment thereof e.g., hu5G11-hlgG1
  • paclitaxel paclitaxel
  • carboplatin carboplatin
  • ambroxol are administered to a patient in need thereof during the first treatment phase.
  • Anlotinib or a pharmaceutically acceptable salt thereof, and anlotinib or a pharmaceutically acceptable salt thereof is administered to patients in need in the second treatment phase with an anti-PD-L1 antibody or an antigen-binding fragment thereof (e.g., hu5G11-hlgG1) Salt
  • the first treatment phase includes 6 to 8 treatment cycles, with one treatment cycle every 3 weeks;
  • the dosage regimen of the first treatment phase includes: on the 1st day of each treatment cycle, administer anti-PD-L1 antibody or its antigen-binding fragment, paclitaxel and carboplatin; on the 8th to 21st days of each treatment cycle , daily administration of anlotinib or its pharmaceutically acceptable salt;
  • the dosage regimen of the second treatment phase includes: on the 1st day of each treatment cycle, administer anti-PD-L1 antibody or its antigen-binding fragment; on days 8-21 of each treatment cycle, administer amroxate every day or its pharmaceutically acceptable salt.
  • an anti-PD-L1 antibody or antigen-binding fragment thereof e.g., hu5G11-hlgG1
  • doxorubicin doxorubicin
  • ambroxol are administered to a patient in need thereof during the first treatment phase.
  • Anlotinib or a pharmaceutically acceptable salt thereof, and anlotinib or a pharmaceutically acceptable salt thereof is administered to patients in need in the second treatment phase with an anti-PD-L1 antibody or an antigen-binding fragment thereof (e.g., hu5G11-hlgG1) Salt
  • the first treatment phase includes 6 to 8 treatment cycles, with one treatment cycle every 3 weeks;
  • the dosage regimen of the first treatment phase includes: on day 1 of each treatment cycle, administer anti-PD-L1 antibody or antigen-binding fragment thereof and doxorubicin; on days 8-21 of each treatment cycle , daily administration of anlotinib or its pharmaceutically acceptable salt;
  • the dosage regimen of the second treatment phase includes: on the 1st day of each treatment cycle, administer anti-PD-L1 antibody or its antigen-binding fragment; on days 8-21 of each treatment cycle, administer amroxate every day or its pharmaceutically acceptable salt.
  • an anti-PD-L1 antibody or antigen-binding fragment thereof e.g., hu5G11-hlgG1, gemcitabine, docetaxel, and Anlotinib or a pharmaceutically acceptable salt thereof, and anlotinib or a pharmaceutically acceptable salt thereof is administered to patients in need in the second treatment phase with anti-PD-L1 antibodies or antigen-binding fragments thereof (e.g., hu5G11-hIgG1) and anlotinib or a pharmaceutically acceptable salt thereof.
  • the first treatment phase includes 6 to 8 treatment cycles, with one treatment cycle every 3 weeks;
  • the dosage regimen of the first treatment phase includes: on the 1st day of each treatment cycle, administer anti-PD-L1 antibody or its antigen-binding fragment, gemcitabine and docetaxel; on the 8th day of each treatment cycle , give gemcitabine; give anlotinib or its pharmaceutically acceptable salt every day on days 8-21 of each treatment cycle;
  • the dosage regimen of the second treatment phase includes: on the 1st day of each treatment cycle, administer anti-PD-L1 antibody or its antigen-binding fragment; on days 8-21 of each treatment cycle, administer amroxate every day or its pharmaceutically acceptable salt.
  • an anti-PD-L1 antibody or antigen-binding fragment thereof e.g., hu5G11-hlgG1, paclitaxel, and carboplatin are administered to a patient in need thereof during the first treatment phase, and during the treatment phase,
  • the second treatment phase is to administer anti-PD-L1 antibodies or antigen-binding fragments thereof (such as hu5G11-hlgG1) to patients in need.
  • the first treatment phase includes 6 to 8 treatment cycles, with one treatment cycle every 3 weeks;
  • the dosage regimen of the first treatment phase includes: on the first day of each treatment cycle, administer anti-PD-L1 antibody or its antigen-binding fragment, paclitaxel, and carboplatin; wherein, anti-PD-L1 antibody or its antigen-binding fragment Fragment was given at a daily dose of 1200 mg, paclitaxel was given at a daily dose of 175 mg/m 2 , and carboplatin was given at a daily dose with an AUC of 5 mg/mL/min;
  • the dosage regimen of the second treatment phase includes: on the first day of each treatment cycle, anti-PD-L1 antibody or antigen-binding fragment thereof is administered; wherein, anti-PD-L1 antibody or antigen-binding fragment thereof is administered at 1200 mg daily. dose given.
  • an anti-PD-L1 antibody or antigen-binding fragment thereof e.g., hu5G11-hlgG1
  • paclitaxel paclitaxel
  • carboplatin carboplatin
  • ambroxol are administered to a patient in need thereof during the first treatment phase.
  • Anlotinib or a pharmaceutically acceptable salt thereof, and anlotinib or a pharmaceutically acceptable salt thereof is administered to patients in need in the second treatment phase with an anti-PD-L1 antibody or an antigen-binding fragment thereof (e.g., hu5G11-hlgG1) Salt
  • the first treatment phase includes 6 to 8 treatment cycles, with one treatment cycle every 3 weeks;
  • the dosage regimen of the first treatment phase includes: on the 1st day of each treatment cycle, administer anti-PD-L1 antibody or its antigen-binding fragment, paclitaxel and carboplatin; on the 8th to 21st days of each treatment cycle , anlotinib or its pharmaceutically acceptable salt is administered daily; wherein, anti-PD-L1 The antibody or its antigen-binding fragment is administered at a daily dose of 1200 mg, paclitaxel is administered at a daily dose of 175 mg/ m2 , carboplatin is administered at a daily dose of AUC of 5 mg/mL/min, anlotinib or its pharmaceutically acceptable Salt is given in a daily dose of 8 mg;
  • the dosage regimen of the second treatment phase includes: on the 1st day of each treatment cycle, administer anti-PD-L1 antibody or its antigen-binding fragment; on days 8-21 of each treatment cycle, administer amroxate every day Anlotinib or a pharmaceutically acceptable salt thereof; wherein, the anti-PD-L1 antibody or its antigen-binding fragment is administered at a daily dose of 1200 mg, and anlotinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 10 mg.
  • an anti-PD-L1 antibody or antigen-binding fragment thereof e.g., hu5G11-hlgG1
  • doxorubicin doxorubicin
  • ambroxol are administered to a patient in need thereof during the first treatment phase.
  • Anlotinib or a pharmaceutically acceptable salt thereof, and anlotinib or a pharmaceutically acceptable salt thereof is administered to patients in need in the second treatment phase with an anti-PD-L1 antibody or an antigen-binding fragment thereof (e.g., hu5G11-hlgG1) Salt
  • the first treatment phase includes 6 to 8 treatment cycles, with one treatment cycle every 3 weeks;
  • the dosage regimen of the first treatment phase includes: on day 1 of each treatment cycle, administer anti-PD-L1 antibody or antigen-binding fragment thereof and doxorubicin; on days 8-21 of each treatment cycle , anlotinib or its pharmaceutically acceptable salt is administered every day; wherein, the anti-PD-L1 antibody or its antigen-binding fragment is administered at a daily dose of 1200 mg, doxorubicin is administered at a daily dose of 60 mg/ m2 , and Rotinib or its pharmaceutically acceptable salt is administered at a daily dose of 8 mg;
  • the dosage regimen of the second treatment phase includes: on the 1st day of each treatment cycle, administer anti-PD-L1 antibody or its antigen-binding fragment; on days 8-21 of each treatment cycle, administer amroxate every day Anlotinib or a pharmaceutically acceptable salt thereof; wherein, the anti-PD-L1 antibody or its antigen-binding fragment is administered at a daily dose of 1200 mg, and anlotinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 10 mg.
  • an anti-PD-L1 antibody or antigen-binding fragment thereof e.g., hu5G11-hlgG1, gemcitabine, docetaxel, and Anlotinib or a pharmaceutically acceptable salt thereof, and anlotinib or a pharmaceutically acceptable salt thereof is administered to patients in need in the second treatment phase with anti-PD-L1 antibodies or antigen-binding fragments thereof (e.g., hu5G11-hIgG1) and anlotinib or a pharmaceutically acceptable salt thereof.
  • the first treatment phase includes 6 to 8 treatment cycles, with one treatment cycle every 3 weeks;
  • the dosage regimen of the first treatment phase includes: on the 1st day of each treatment cycle, administer anti-PD-L1 antibody or its antigen-binding fragment, gemcitabine and docetaxel; on the 8th day of each treatment cycle , give gemcitabine; on days 8-21 of each treatment cycle, give anlotinib or its pharmaceutically acceptable salt every day; wherein, the anti-PD-L1 antibody or its antigen-binding fragment is given at a daily dose of 1200 mg, Gemcitabine is administered at a daily dose of 900 mg/ m2 , docetaxel is administered at a daily dose of 75 mg/ m2 , and anlotinib or its pharmaceutically acceptable salt is administered at a daily dose of 8 mg;
  • the dosage regimen of the second treatment phase includes: on the 1st day of each treatment cycle, administer anti-PD-L1 antibody or its antigen-binding fragment; on days 8-21 of each treatment cycle, administer amroxate every day Anlotinib or a pharmaceutically acceptable salt thereof; wherein, the anti-PD-L1 antibody or its antigen-binding fragment is administered at a daily dose of 1200 mg, and anlotinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 10 mg.
  • the second treatment phase follows the first treatment phase. In some embodiments, the second treatment phase is continued from the end of the first treatment phase until clinical benefit is lost, toxicity is intolerable, efficacy is assessed as disease progression, and/or the investigator determines that continued treatment is not appropriate.
  • the treatment is first-line treatment for uterine malignancy.
  • the uterine malignancy is endometrial cancer and/or uterine sarcoma.
  • the uterine malignant tumor is endometrial cancer. In other embodiments, the uterine malignant tumor is uterine sarcoma.
  • Embodiment 1 A pharmaceutical combination containing an anti-PD-L1 antibody or an antigen-binding fragment thereof and a chemotherapeutic drug for the treatment of uterine malignant tumors, wherein the anti-PD-L1 antibody or an antigen-binding fragment thereof comprises: Such as SEQ ID NO: The heavy chain CDR1 region shown in 1, the heavy chain CDR2 region shown in SEQ ID NO:2, the heavy chain CDR3 region shown in SEQ ID NO:3, the light chain CDR1 region shown in SEQ ID NO:7 , the light chain CDR2 region as shown in SEQ ID NO:8, and the light chain CDR3 region as shown in SEQ ID NO:9.
  • Embodiment 2 The use according to Embodiment 1, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof comprises: a heavy chain having at least 80% homology with the amino acid sequence shown in SEQ ID NO: 13 variable region, and is at least the same as the amino acid sequence shown in SEQ ID NO:15 80% homology to the light chain variable region.
  • Embodiment 3 The use according to embodiment 1 or 2, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof comprises: having at least 80% homology with the amino acid sequence shown in SEQ ID NO: 17 A heavy chain, and a light chain having at least 80% homology with the amino acid sequence shown in SEQ ID NO:18.
  • Embodiment 4 The use according to any one of embodiments 1-3, wherein the pharmaceutical combination further includes anlotinib or a pharmaceutically acceptable salt thereof.
  • Embodiment 5 The use according to any one of embodiments 1-4, wherein the drug combination includes a first drug combination, and optionally, a second drug combination; the first drug combination includes anti-PD- L1 antibodies or antigen-binding fragments thereof and chemotherapeutic drugs.
  • Embodiment 6 The use of embodiment 5, wherein the second pharmaceutical combination includes an anti-PD-L1 antibody or an antigen-binding fragment thereof.
  • Embodiment 7 The use according to embodiment 5, wherein the first pharmaceutical combination further includes anlotinib or a pharmaceutically acceptable salt thereof.
  • Embodiment 8 The use according to embodiment 7, wherein the second pharmaceutical combination includes an anti-PD-L1 antibody or an antigen-binding fragment thereof and anlotinib or a pharmaceutically acceptable salt thereof.
  • Embodiment 9 Use according to any one of embodiments 5-8, wherein the first pharmaceutical combination is administered to a patient in need thereof during a first treatment phase, and optionally, the second pharmaceutical combination is administered during A second treatment phase is administered to a patient in need; said first treatment phase includes 1 to 14 treatment cycles, 2 to 12 treatment cycles, preferably 4 to 10 treatment cycles, and most preferably 6 to 8 treatment cycles.
  • Embodiment 10 The use according to Embodiment 9, wherein every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks is a treatment cycle, preferably every 3 weeks is a treatment cycle.
  • Embodiment 11 The use according to any one of embodiments 1-10, wherein the chemotherapeutic drug is selected from the group consisting of platinum anti-tumor drugs, taxane anti-tumor drugs, anthracycline anti-tumor drugs, and antimetabolites.
  • the chemotherapeutic drug is selected from the group consisting of platinum anti-tumor drugs, taxane anti-tumor drugs, anthracycline anti-tumor drugs, and antimetabolites.
  • the chemotherapeutic drug is selected from the group consisting of platinum anti-tumor drugs, taxane anti-tumor drugs, anthracycline anti-tumor drugs, and antimetabolites.
  • the chemotherapeutic drug is selected from the group consisting of platinum anti-tumor drugs, taxane anti-tumor drugs, anthracycline anti-tumor drugs, and antimetabolites.
  • One or more anti-tumor drugs is selected from the group consisting of platinum anti-tumor
  • the platinum anti-tumor drug is selected from the group consisting of cisplatin, carboplatin, nedaplatin, bicycloplatin, picoplatin, oxaliplatin, imiplatin, loplatin, leplatin, triplatinum tetranitrate, phenanplatin , one or more of saplatin;
  • the taxane anti-tumor drug is selected from one or more of paclitaxel, paclitaxel liposome, albumin-bound paclitaxel, and docetaxel;
  • the anthracycline anti-tumor drug is selected from doxorubicin, doxorubicin liposome, epirubicin, pirarubicin, amrubicin, arubicin, idarubicin One or more of doxorubicin, daunorubicin, mitoxantrone, idarubicin, valrubicin, zorubicin, pixantron, and liposomal doxorubicin;
  • the antimetabolite anti-tumor drug is selected from the group consisting of carmofur, 5-fluorouracil, tegafur, capecitabine, tegio, furfururacil, deoxyfluridine, and trifluridine, One or more of cytarabine, gemcitabine, azacitidine, amcitabine, mercaptopurine, fludarabine, methotrexate, and pemetrexed.
  • Embodiment 12 The use according to any one of embodiments 1-11, wherein the chemotherapeutic drug is selected from carboplatin and paclitaxel, or the chemotherapeutic drug is selected from doxorubicin, or the chemotherapeutic drug is selected from doxorubicin. Cetaxel and gemcitabine.
  • Embodiment 13 The use according to embodiment 12, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof, paclitaxel and carboplatin is administered to a patient in need thereof during the first treatment phase, and the patient in need thereof is administered during the second treatment phase.
  • the patient is administered anti-PD-L1 antibody or antigen-binding fragment thereof, and the first treatment phase includes 6 to 8 treatment cycles, with one treatment cycle every 3 weeks;
  • the dosage regimen of the first treatment phase includes: administering anti-PD-L1 antibody or its antigen-binding fragment, paclitaxel and carboplatin on the first day of each treatment cycle;
  • the dosage regimen of the second treatment phase includes: administering anti-PD-L1 antibody or antigen-binding fragment thereof on the first day of each treatment cycle.
  • Embodiment 14 The use according to embodiment 12, wherein an anti-PD-L1 antibody or antigen-binding fragment thereof, paclitaxel, carboplatin and anlotinib or a pharmaceutical agent thereof is administered to a patient in need thereof during the first treatment phase.
  • Acceptable salts to be given to patients in need during the second treatment phase Administering anti-PD-L1 antibody or antigen-binding fragment thereof and anlotinib or a pharmaceutically acceptable salt thereof, the first treatment phase includes 6 to 8 treatment cycles, with one treatment cycle every 3 weeks;
  • the dosage regimen of the first treatment phase includes: on the 1st day of each treatment cycle, administer anti-PD-L1 antibody or its antigen-binding fragment, paclitaxel and carboplatin; on the 8th to 21st days of each treatment cycle , daily administration of anlotinib or its pharmaceutically acceptable salt;
  • the dosage regimen of the second treatment phase includes: on the 1st day of each treatment cycle, administer anti-PD-L1 antibody or its antigen-binding fragment; on days 8-21 of each treatment cycle, administer amroxate every day or its pharmaceutically acceptable salt.
  • Embodiment 15 The use according to embodiment 12, wherein an anti-PD-L1 antibody or an antigen-binding fragment thereof, doxorubicin and anlotinib or a pharmaceutically acceptable drug thereof is administered to a patient in need thereof during the first treatment phase.
  • the dosage regimen of the first treatment phase includes: on day 1 of each treatment cycle, administer anti-PD-L1 antibody or antigen-binding fragment thereof and doxorubicin; on days 8-21 of each treatment cycle , daily administration of anlotinib or its pharmaceutically acceptable salt;
  • the dosage regimen of the second treatment phase includes: on the 1st day of each treatment cycle, administer anti-PD-L1 antibody or its antigen-binding fragment; on days 8-21 of each treatment cycle, administer amroxate every day or its pharmaceutically acceptable salt.
  • Embodiment 16 The use according to embodiment 12, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof, gemcitabine, docetaxel and anlotinib or its Pharmaceutically acceptable salts, administering an anti-PD-L1 antibody or antigen-binding fragment thereof and anlotinib or a pharmaceutically acceptable salt thereof to a patient in need in a second treatment phase, the first treatment phase comprising 6 Up to 8 treatment cycles, one treatment cycle every 3 weeks;
  • the dosage regimen of the first treatment phase includes: on the 1st day of each treatment cycle, administer anti-PD-L1 antibody or its antigen-binding fragment, gemcitabine and docetaxel; on the 8th day of each treatment cycle , give gemcitabine; give anlotinib or its pharmaceutically acceptable salt every day on days 8-21 of each treatment cycle;
  • the dosage regimen of the second treatment phase includes: on the 1st day of each treatment cycle, administer anti-PD-L1 antibody or its antigen-binding fragment; on days 8-21 of each treatment cycle, administer amroxate every day or its pharmaceutically acceptable salt.
  • Embodiment 17 The use according to any one of embodiments 1-16, wherein the uterine malignant tumor is endometrial cancer or uterine sarcoma.
  • Embodiment 18 Use according to any one of embodiments 1-17, wherein the treatment is first-line treatment of endometrial cancer or uterine sarcoma.
  • Embodiment 19 Use according to embodiment 17 or 18, wherein the endometrial cancer is advanced, recurrent, and/or metastatic endometrial cancer, or the endometrial cancer is stage III or stage IV or recurrent endometrial cancer.
  • Embodiment 20 The use according to any one of embodiments 17-19, wherein the endometrial cancer or uterine sarcoma is an endometrial cancer or uterine sarcoma that has not previously received first-line systemic anti-tumor treatment, and /or Endometrial cancer or uterine sarcoma that is not suitable for treatment other than systemic therapy.
  • Embodiment 21 The use according to any one of embodiments 17-20, wherein the endometrial cancer or uterine sarcoma is an endometrial cancer or uterine sarcoma that has previously undergone non-radical surgical treatment, or the uterine sarcoma Endometrial cancer or uterine sarcoma is an endometrial cancer or uterine sarcoma that has recurred after at least one previous treatment, or the endometrial cancer or uterine sarcoma has been previously treated with surgery, or surgery combined with adjuvant therapy and/or new Endometrial cancer or uterine sarcoma with disease recurrence after adjuvant therapy.
  • Embodiment 22 The use according to any one of embodiments 17-21, wherein the endometrial cancer is microsatellite unstable endometrial cancer, high microsatellite instability (MSI-H) endometrial cancer Cancer, low-grade microsatellite instability (MSI-L) endometrial cancer, microsatellite stable (MSS) endometrial cancer, MSS/MSI-L endometrial cancer, mismatch repair deficiency (dMMR) intrauterine uterine cancer, or non-mismatch repair deficient (non-dMMR) endometrial cancer.
  • MSI-H microsatellite instability
  • MSI-L microsatellite instability
  • MSS microsatellite stable endometrial cancer
  • dMMR mismatch repair deficiency
  • non-dMMR non-mismatch repair deficient endometrial cancer.
  • Embodiment 23 A drug combination for treating uterine malignant tumors, which includes: an anti-PD-L1 antibody or an antigen-binding fragment thereof and a chemotherapy drug,
  • the anti-PD-L1 antibody or antigen-binding fragment thereof includes: a heavy chain CDR1 region as shown in SEQ ID NO: 1, a heavy chain CDR2 region as shown in SEQ ID NO: 2, as shown in SEQ ID NO: 3
  • Embodiment 24 The pharmaceutical combination according to embodiment 23, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof comprises: an amino acid sequence having at least 80% homology with the amino acid sequence shown in SEQ ID NO: 13. chain variable region, and a light chain variable region having at least 80% homology with the amino acid sequence shown in SEQ ID NO:15.
  • Embodiment 25 The pharmaceutical combination according to embodiment 23 or 24, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof comprises: at least 80% homology with the amino acid sequence shown in SEQ ID NO: 17 The heavy chain, and the light chain having at least 80% homology with the amino acid sequence shown in SEQ ID NO:18.
  • Embodiment 26 The pharmaceutical combination according to any one of embodiments 23-25, wherein the pharmaceutical combination further includes anlotinib or a pharmaceutically acceptable salt thereof.
  • Embodiment 27 The pharmaceutical combination according to any one of embodiments 23-26, wherein the pharmaceutical combination includes a first pharmaceutical combination, and optionally, a second pharmaceutical combination, wherein the first pharmaceutical combination includes an anti- PD-L1 antibodies or antigen-binding fragments thereof and chemotherapy drugs.
  • Embodiment 28 The pharmaceutical combination of embodiment 27, wherein the second pharmaceutical combination includes an anti-PD-L1 antibody or an antigen-binding fragment thereof.
  • Embodiment 29 The pharmaceutical combination according to Embodiment 27, wherein the first pharmaceutical combination further includes anlotinib or a pharmaceutically acceptable salt thereof.
  • Embodiment 30 The pharmaceutical combination according to Embodiment 29, wherein the second pharmaceutical combination includes an anti-PD-L1 antibody or an antigen-binding fragment thereof and anlotinib or a pharmaceutically acceptable salt thereof.
  • Embodiment 31 The pharmaceutical combination of any one of embodiments 27-30, wherein the first pharmaceutical combination is administered to a patient in need thereof during a first treatment phase, and optionally, the second pharmaceutical combination It is administered to a patient in need thereof during a second treatment phase; said first treatment phase includes 1 to 14 treatment cycles, 2 to 12 treatment cycles, preferably 4 to 10 treatment cycles, and most preferably 6 to 8 treatment cycles.
  • Embodiment 32 The pharmaceutical combination according to embodiment 31, wherein every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks is a treatment cycle, preferably every 3 weeks is a treatment cycle.
  • Embodiment 33 The drug combination according to any one of embodiments 23-32, wherein the chemotherapy drug is selected from the group consisting of platinum anti-tumor drugs, taxane anti-tumor drugs, anthracycline anti-tumor drugs, and antimetabolites. One or more anti-tumor drugs;
  • the platinum anti-tumor drug is selected from the group consisting of cisplatin, carboplatin, nedaplatin, bicycloplatin, picoplatin, oxaliplatin, imiplatin, loplatin, leplatin, triplatinum tetranitrate, phenanplatin , one or more of saplatin;
  • the taxane anti-tumor drug is selected from one or more of paclitaxel, paclitaxel liposome, albumin-bound paclitaxel, and docetaxel;
  • the anthracycline anti-tumor drug is selected from doxorubicin, doxorubicin liposome, epirubicin, pirarubicin, amrubicin, arubicin, idarubicin One or more of doxorubicin, daunorubicin, mitoxantrone, idarubicin, valrubicin, zorubicin, pixantron, and liposomal doxorubicin;
  • the antimetabolite anti-tumor drug is selected from the group consisting of carmofur, 5-fluorouracil, tegafur, capecitabine, tegio, furfururacil, deoxyfluridine, and trifluridine, One or more of cytarabine, gemcitabine, azacitidine, amcitabine, mercaptopurine, fludarabine, methotrexate, and pemetrexed.
  • Embodiment 34 The drug combination according to any one of embodiments 23-33, wherein the chemotherapy drug is selected from carboplatin and paclitaxel, or the chemotherapy drug is selected from doxorubicin, or the chemotherapy drug is selected from Docetaxel and gemcitabine.
  • Embodiment 35 The pharmaceutical combination according to any one of embodiments 23-34, wherein the uterine malignant tumor is endometrial cancer or uterine sarcoma.
  • Embodiment 36 The pharmaceutical combination according to any one of embodiments 23-35, wherein the treatment is for endometrial cancer or uterine sarcoma. first-line treatment of tumors.
  • Embodiment 37 The pharmaceutical combination according to embodiment 35 or 36, wherein the endometrial cancer is advanced, recurrent, and/or metastatic endometrial cancer, or the endometrial cancer is III Stage or stage IV or recurrent endometrial cancer.
  • Embodiment 38 The pharmaceutical combination according to any one of embodiments 35-37, wherein the endometrial cancer or uterine sarcoma is an endometrial cancer or uterine sarcoma that has not received first-line systemic anti-tumor treatment in the past, and /or Endometrial cancer or uterine sarcoma that is not suitable for treatment other than systemic therapy.
  • Embodiment 39 The pharmaceutical combination according to any one of embodiments 35-38, wherein the endometrial cancer or uterine sarcoma is an endometrial cancer or uterine sarcoma that has previously received non-radical surgical treatment, or the Endometrial cancer or uterine sarcoma is an endometrial cancer or uterine sarcoma that has recurred after at least one previous treatment, or the endometrial cancer or uterine sarcoma has been previously treated with surgery, or surgery combined with adjuvant treatment and/or Endometrial cancer or uterine sarcoma with disease recurrence after neoadjuvant therapy.
  • Embodiment 40 The pharmaceutical combination according to any one of embodiments 35 to 39, wherein the endometrial cancer is microsatellite instability endometrial cancer, high microsatellite instability (MSI-H) intrauterine cancer.
  • MSI-H microsatellite instability
  • MSI-L low-grade microsatellite instability
  • MSS microsatellite stable
  • MSS/MSI-L mismatch repair-deficient
  • dMMR mismatch repair-deficient
  • non-dMMR non-mismatch repair deficient endometrial cancer.
  • the drug combinations of the present disclosure have one or more of the following effects: (1) Producing better efficacy in reducing tumor growth or even eliminating tumors than either drug in the combination administered alone; (2) ) provides for administration of smaller amounts than either drug in the combination when administered alone; (3) is a treatment that is well tolerated in patients and has fewer adverse effects and/or effects than either drug administered alone; or fewer complications; (4) better disease control rates among treated patients; (5) longer survival (e.g., median survival, progression-free survival, or overall survival among treated patients) survival); (6) compared with standard chemotherapy, the treated patients have longer survival (such as median survival, progression-free survival, or overall survival); (7) have longer Duration of disease response (DOR); and/or (8) Compared with any drug in the combination administered alone, it has good activity in treating tumors or proliferative diseases and shows a more excellent anti-tumor synergistic effect.
  • longer survival e.g., median survival, progression-free survival, or overall survival among treated patients
  • DOR Duration of disease response
  • the disclosed drug combination and its treatment plan have good curative effect in the treatment of uterine malignant tumors. It has a beneficial effect in at least one of ORR, DCR, DoR, PFS, OS, tolerability and side effects.
  • the drug combination provided by the present disclosure including hu5G11-hlgG1, carboplatin and paclitaxel can safely and effectively treat uterine malignant tumors.
  • Patients with uterine malignant tumors have beneficial effects on at least one of ORR, DCR, DOR, PFS, OS, tolerability and side effects after receiving a treatment plan.
  • the treatment plan is: to patients in the first treatment phase.
  • hu5G11-hIgG1, carboplatin and paclitaxel were given;
  • hu5G11-hIgG1 was given to patients in the second treatment phase.
  • the drug combination provided by the present disclosure including hu5G11-hlgG1, carboplatin, paclitaxel and anlotinib hydrochloride can safely and effectively treat uterine malignant tumors.
  • Patients with uterine malignant tumors have beneficial effects on at least one of ORR, DCR, DOR, PFS, OS, tolerability and side effects after receiving a treatment plan.
  • the treatment plan is: to patients in the first treatment phase. hu5G11-hIgG1, carboplatin, paclitaxel and anlotinib hydrochloride were given; in the second treatment phase, some patients were given hu5G11-hIgG1 and anlotinib hydrochloride.
  • the pharmaceutical combination provided by the present disclosure including hu5G11-hlgG1, doxorubicin and anlotinib hydrochloride can safely and effectively treat uterine malignant tumors.
  • Patients with uterine malignant tumors have beneficial effects on at least one of ORR, DCR, DOR, PFS, OS, tolerability and side effects after receiving a treatment plan.
  • the treatment plan is: to patients in the first treatment phase. hu5G11-hIgG1, doxorubicin and anlotinib hydrochloride were given; in the second treatment phase, some patients were given hu5G11-hIgG1 and anlotinib hydrochloride.
  • the drug combination provided by the present disclosure including hu5G11-hlgG1, gemcitabine, docetaxel and anlotinib hydrochloride can safely and effectively treat uterine malignant tumors.
  • Patients with uterine malignant tumors have beneficial effects on at least one of ORR, DCR, DOR, PFS, OS, tolerability and side effects after receiving a treatment plan.
  • the treatment plan is: to patients in the first treatment phase. hu5G11-hIgG1, gemcitabine, docetaxel and anlotinib hydrochloride were given; in the second treatment phase, some patients were given hu5G11-hIgG1 and anlotinib hydrochloride.
  • the treatment is first-line treatment for uterine malignancy.
  • the uterine malignancy is endometrial cancer and/or uterine sarcoma.
  • the first treatment phase includes 6 to 8 treatment cycles. In some embodiments, treatment cycles are every 3 weeks.
  • anlotinib or its pharmaceutically acceptable salt refers to the amount of the active ingredient anlotinib free base.
  • flat dose refers to the dose administered to a patient without regard to the patient's weight or body surface area (BSA).
  • BSA body surface area
  • the unified dose is therefore specified as the absolute amount of pharmaceutical agent rather than as mg/kg dose. For example, a 60kg person and a 100kg person will receive the same dose of antibody (eg, 1200mg anti-PD-L1 antibody).
  • partial response refers to a reduction of more than 30% in the total diameter of the target lesion compared with the baseline total diameter.
  • disease progression means that the total diameter of the target lesion increases by 20% or more compared with the minimum total diameter appearing in the study (including the baseline total diameter, if it is the minimum value in the study), and The absolute value of the total diameter must be increased by more than 5mm. The appearance of one or more new lesions should also be considered disease progression.
  • stable disease refers to the shrinkage of lesions, but not enough for PR; or the enlargement of lesions, but not enough for PD. The smallest diameter is used as a reference in the test.
  • best efficacy refers to the best efficacy at all time points from the first evaluation to the last evaluation.
  • recurrent cancer is a cancer that reappears at the original site or at a distant site after responding to initial treatment, such as surgery.
  • metalstatic cancer refers to cancer that has spread from one part of the body, such as the uterus, to another part of the body.
  • the term "pharmaceutical combination” refers to two or more active substances administered simultaneously or sequentially (either in the form of the respective active ingredients themselves, or in their respective pharmaceutically acceptable salts or esters, etc. derivatives, prodrugs or compositions).
  • the active substances may be administered to the patient simultaneously, each as a single preparation, or each as a single preparation, sequentially in any order.
  • antibody refers to an antigen-binding protein having at least one antigen-binding domain.
  • Antibodies and fragments thereof of the present disclosure may be whole antibodies or any fragments thereof.
  • the antibodies and fragments thereof of the present disclosure include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof.
  • Examples of antibodies and antigen-binding fragments thereof of the present disclosure include monospecific antibodies, bispecific antibodies, multispecific antibodies, Fab fragments, Fab' fragments, F(ab)'2 fragments, Fv fragments, isolated CDR regions, Single chain Fv molecules (scFv), Fd fragments and other antibody fragments known in the art.
  • PD-L1 antibodies or antigen-binding fragments thereof of the present disclosure may be of IgG1, IgG2, IgG3, or IgG4 isotype.
  • the term "isotype" refers to the class of antibody encoded by the heavy chain constant region genes.
  • the PD-L1 antibodies or antigen-binding fragments thereof of the disclosure are of the IgG1 or IgG4 isotype.
  • PD-L1 antibodies or antigen-binding fragments thereof of the present disclosure can be derived from any species, including but not limited to mouse, rat, rabbit, primate, llama, and human.
  • the PD-L1 antibody or antigen-binding fragment thereof of the present disclosure may be a murine antibody, a chimeric antibody, a humanized antibody, or a fully human antibody.
  • 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 antibodies are derived from murine antibodies and are 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.
  • an anti-PD-L1 antibody described herein may comprise CDRs derived from one or more murine antibodies and human framework and constant regions.
  • the humanized antibodies described herein bind to 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 chain CDRs and light chain CDRs provided herein can be generated using any human framework sequences and are also included in the present disclosure.
  • Frame sequences used in this disclosure include those that are structurally similar to the frame sequences 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 remove T cell epitopes; or mutations back to residues in the original germline sequence.
  • such modifications include those corresponding to mutations exemplified herein, including back mutations to germline sequences.
  • 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 parent murine antibody.
  • “antibodies” in this disclosure include entire antibodies and any antigen-binding fragments (or “antigen-binding portions”) or single chains thereof.
  • a conventional "whole antibody” is a glycoprotein containing two heavy (H) chains and two light (L) chains linked by disulfide bonds.
  • Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (CH).
  • the heavy chain constant region consists of three domains, namely CH1, CH2 and CH3.
  • Each light chain consists of a light chain variable region (VL) and a light chain constant region (CL).
  • the light chain constant region consists of one domain, CL.
  • the VH and VL regions can also be divided into hypervariable regions, namely complementarity determining regions (CDR), and framework regions (FR) with relatively conserved sequences.
  • Each VH and VL are composed of three CDRs and four FRs respectively, from the amino end to the carboxyl end: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the variable regions of the heavy and light chains contain binding domains that interact with the antigen.
  • the constant region of an antibody can mediate binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (eg, effector cells) and the first component (Clq) of the classical complement system.
  • special “whole antibodies” such as Nanobodies, have only heavy (H) chains and no light (L) chains.
  • an “antigen-binding fragment” or “antibody-binding portion” of an antibody refers to one or more fragments of an antibody that retain the function of specifically binding an antigen (eg, PD-L1). It has been demonstrated that the antigen-binding function of an antibody can be performed by fragments of the entire antibody.
  • Examples encompassed by the term "antigen-binding portion/fragment" of an antibody include: (i) Fab fragments: monovalent fragments consisting of VL, VH, CL and CH1 domains; (ii) F(ab') 2 fragments, including A bivalent fragment of two Fab fragments connected by a disulfide bridge in the hinge region; (iii) an Fd fragment consisting of VH and CH1 domains; (iv) an Fv fragment consisting of the VL and VH domains of an antibody single arm; ( v) dAb fragments consisting of VH domains (see Ward et al., Nature.
  • the heavy chain variable region contains a single variable domain and two constant domains.
  • the two domains VL and VH of the Fv fragment are encoded by different genes, recombinant methods can be used to connect VH and VL into a single protein chain through synthetic linkers, in which VL and VH pair to form a monovalent molecule (called a single-chain Fv (scFv); see, for example, Bird et al., Science. 242:423-426 (1988); Huston et al., Proc. Natl. Acad. Sci. 85:5879-5883 (1988)).
  • scFv single-chain Fv
  • antigen-binding portion/fragment single chain antibodies are also encompassed by the term antigen-binding portion/fragment.
  • recombinant polypeptides, fusion proteins and immunoconjugates comprising such antigen-binding portions/fragments are also encompassed by the term antigen-binding portions/fragments.
  • isolated antibody means an antibody that is substantially free of other antibodies with different antigenic specificities (e.g., an isolated antibody that specifically binds PD-L1 is substantially free of antibodies that specifically bind other than PD-L1 Antibodies to the antigen). However, an isolated antibody that specifically binds PD-L1 may have cross-reactivity with other antigens, such as PD-L1 molecules from different species. Furthermore, the isolated antibodies are essentially free of other cellular material and/or chemicals.
  • human PD-L1, hPD-L1, and “huPD-L1,” etc. are used interchangeably herein and refer to human PD-L1 and variants or isoforms of human PD-L1.
  • Identity refers to the similarity between two reference sequences, and percent identity refers to the percentage obtained by comparing sequences or designated regions of sequences using sequence comparison algorithms well known to those skilled in the art.
  • treatment 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 symptoms due to the disease.
  • treatment encompasses any treatment of a patient's disease that: (a) inhibits the symptoms of the disease, i.e., prevents their progression; or (b) alleviates the symptoms of the disease, i.e., causes the disease or disease state to resolve.
  • first-line treatment refers to the first or standard choice of drug treatment based on the patient's condition.
  • prevention means preventing a disease or one or more symptoms associated with said disease and includes preventing the occurrence of a disease or disease state in a mammal, in particular where such mammal is susceptible to the disease state, but When the disease state has not yet been diagnosed.
  • systemic treatment refers to treatment in which drug substances are delivered through the bloodstream to reach and affect cells throughout the body.
  • systemic treatment refers to systemic chemotherapy, systemic or local radiation therapy.
  • first-line systemic therapy refers to the systemic therapy that can be selected first or as a standard option based on the patient's condition.
  • adjuvant therapy refers to any treatment given after initial treatment (i.e., surgery) to increase the chance of long-term survival
  • adjeoadjuvant therapy refers to treatment given before initial treatment (i.e., surgery).
  • treatment failure is defined as disease progression during treatment or after the last treatment; or due to intolerable side effects during treatment.
  • the term "effective amount” means (i) treating a specified disease, condition, or disorder, (ii) reducing, ameliorating, or eliminating one or more symptoms of a specified disease, condition, or disorder, or (iii) preventing or delaying the symptoms described herein.
  • the amount of an active agent (e.g., an antibody or compound of the present disclosure) that constitutes a "therapeutically effective amount” may vary depending on factors such as the disease state, age, sex, and weight of the individual, as well as the therapeutic agent or combination of therapeutic agents elicited in the individual. The ability to respond required. Effective amounts can also be routinely determined by those skilled in the art based on their own knowledge and this disclosure.
  • administering means the physical introduction of 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 anti-PD-L1 antibodies or antigen-binding fragments thereof include parenteral routes of administration (including, but not limited to, intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration), such as by injection or infusion. Note.
  • 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, intracystic, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intraarticular, subcapsular , subarachnoid, intraspinal, epidural and intrasternal injections and infusions, and in vivo electroporation.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof is administered by a non-parenteral route; in certain embodiments, oral administration; other non-parenteral routes include topical, epidermal or mucosal administration , for example, intranasal, intravaginal, rectal, sublingual or topical administration. Administration may also be performed, eg, once, multiple times, and/or over one or more extended time periods.
  • 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, or allergic reactions or other problems or complications.
  • salts includes salts formed by a free base and an acid or a salt formed by an acid and a free base, including, for example, hydrochloride, hydrobromide, nitrate, sulfate, phosphate, and formate.
  • it is a hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, methanesulfonate, p- Toluene sulfonate, sodium salt, potassium salt, ammonium salt, amino acid salt, etc.
  • the molar ratio of the acid to the free base is 1:0.2-1:5; in some embodiments, it is 1:0.5, 1:1, 1 :2, 1:3, 1:4, 1:5, 1:6, 1:7 or 1:8.
  • a "patient” or “subject” is a mammal, such as rodents, felines, canines, and primates.
  • the patient is a human.
  • the subject is human.
  • “Subject” includes any human or non-human animal.
  • Non-human animals include, but are not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs.
  • the terms "patient,” “subject,” and “subject” are used interchangeably in certain contexts herein.
  • chemotherapy regimen includes one or more chemotherapy drugs.
  • single dose refers to the smallest packaging unit containing a certain amount of medicine. For example, if a box of medicine contains seven tablets, one tablet is a single dose; or a bottle of injection is a single dose. “Unit dose” refers to the dose of active ingredient contained in the smallest packaging unit containing a certain amount of medicine. For example, the dose of antibody contained in a bottle of antibody injection is a unit dose.
  • multiple doses consists of a plurality of single doses.
  • pharmaceutical composition refers to a mixture of one or more active ingredients of the present disclosure or a pharmaceutical combination thereof and pharmaceutically acceptable excipients.
  • the purpose of pharmaceutical compositions is to facilitate administration to a patient of a compound of the present disclosure or a pharmaceutical combination thereof.
  • pharmaceutical composition and “preparation” have the same meaning and are used interchangeably.
  • the terms “about,” “approximately,” or “substantially comprise” mean a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined or composition, that is, the limitations of the measurement system. For example, “about,” “approximately,” or “substantially including” may mean within 1 or more than 1 standard deviation as is practiced in the art. Alternatively, “about” or “substantially comprising” may refer to a range that differs by up to 10% or 20% (ie, ⁇ 10% or ⁇ 20%) from the parameter or value modified thereby.
  • about 3 mg may include any number between 2.7 mg and 3.3 mg (for 10%) or between 2.4 mg and 3.6 mg (for 20%).
  • the term may refer up to an order of magnitude or up to 5 times a numerical value.
  • any concentration range, percentage range, ratio range or integer range should be understood to include the value of any integer within the recited range and, where appropriate, fractions thereof (such as tenths and One percent) unless otherwise stated.
  • “combination” or “used in combination” means that two or more active substances may be administered to a subject together in a mixture, simultaneously as a single formulation, or sequentially in any order as a single formulation.
  • Chronic benefits include, but are not limited to: prolongation of progression-free survival (PFS), prolongation of overall survival (OS), improvement of objective response rate (ORR), and disease control rate (DCR) of clinical patients. ) is improved, objective time to response (TTR) is prolonged, and the number and/or severity of adverse reactions is reduced.
  • PFS progression-free survival
  • OS prolongation of overall survival
  • ORR objective response rate
  • DCR disease control rate
  • stage endometrial cancer is the FIGO (International Federation of Gynecology and Obstetrics) system. Endometrial cancer is classified based on three factors: the extent of the tumor and whether the cancer has spread to the lymph nodes and whether the cancer has spread to distant sites. Information about the tumor, lymph nodes, and any spreading cancer is then combined to determine the stage of the disease, a process called stage grouping. Roman numerals from I to IV describe these Period. Some periods are divided into subperiods (indicated by letters and numbers).
  • the anti-PD-L1 antibody hu5G11-hlgG1 (the heavy chain amino acid sequence is shown in SEQ ID NO: 17, and the light chain amino acid sequence is shown in SEQ ID NO: 18) can be prepared according to the method described in WO2016022630, or You can refer to the amino acid sequence of benmelstobart disclosed in WHO Drug Information, Vol. 36, No. 4, 2022 for preparation.
  • the treatment process is divided into the first treatment phase and the maintenance treatment phase (ie, the second treatment phase). Every 3 weeks (21 days) is a treatment cycle. Patients first receive the first treatment phase of 6 to 8 treatment cycles, and then enter the maintenance treatment phase, which continues until clinical benefit is lost, toxicity is intolerable, and the efficacy is evaluated as disease. progress, or until the researcher deems it unsuitable to continue taking the medication.
  • Age ⁇ 18 years old (when signing the informed consent form); ECOG PS score: 0-1 points; expected survival time is more than 3 months; body mass index (BMI) >18.5 and weight >40kg.
  • Newly diagnosed subjects those who still have residual lesions visible on imaging after non-radical surgery or who have not undergone surgery (those who have not undergone surgery are those who are not suitable for surgery and radical radiotherapy);
  • Subjects with first recurrence The time of recurrence is more than 12 months from the end of initial treatment (complete remission after surgery or surgery + adjuvant therapy); or the subject receives systemic platinum adjuvant and/or neoadjuvant chemotherapy (single use) Chemotherapy, concurrent chemoradiotherapy or as sequential therapy, complete remission after treatment), and the disease relapses more than 6 months after the last chemotherapy;
  • Newly diagnosed subjects who did not receive postoperative radiotherapy can start receiving experimental drug treatment within 8 weeks after surgery; those who received postoperative radiotherapy can start receiving experimental drug treatment within 8 weeks after surgery; adjuvant treatment includes external beam radiotherapy (EBRT), vaginal post-loading radiotherapy, radiotherapy + chemotherapy; sarcoma overgrowth is defined as pathological report indicating that high-grade sarcomatoid components account for more than 25% of the total tumor.
  • EBRT external beam radiotherapy
  • vaginal post-loading radiotherapy radiotherapy + chemotherapy
  • sarcoma overgrowth is defined as pathological report indicating that high-grade sarcomatoid components account for more than 25% of the total tumor.
  • Tumor tissue samples can be provided for testing MSI/MMR status or traceable test reports.
  • Biochemical examinations must meet the following standards: total bilirubin (TBIL) ⁇ 1.5 times the upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ⁇ 2.5 ⁇ ULN , if accompanied by liver metastasis, ALT and AST ⁇ 5 ⁇ ULN; serum creatinine (Cr) ⁇ 1.5 ⁇ ULN or creatinine clearance (Ccr) ⁇ 60mL/min; serum albumin (ALB) > 30g/L;
  • Routine urine examination standards Routine urine examination indicates urine protein ⁇ ++; if urine protein ⁇ ++, it is necessary to confirm that the 24-hour urine protein quantification is ⁇ 1.0g;
  • Coagulation function or thyroid function tests must meet the following standards: prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio (INR) ⁇ 1.5 ⁇ ULN (no anticoagulant treatment has been received); Thyroid-stimulating hormone (TSH) ⁇ ULN. If abnormal, triiodothyronine (T3) and thyroxine (T4) levels should be examined. If T3 and T4 levels are normal, you can be selected;
  • LVEF left ventricular ejection fraction
  • Female subjects should agree to use contraceptive measures (such as intrauterine devices or condoms) during the study and within 6 months after the end of the study; the serum pregnancy test must be negative within 7 days before study enrollment, and must be Non-lactating subjects.
  • contraceptive measures such as intrauterine devices or condoms
  • Anti-PD-L1 antibody hu5G11-hIgG1 injection (specification: 600mg/20mL): According to the dose of 1200mg hu5G11-hIgG1, intravenous infusion is administered, and the infusion time is 60 ⁇ 10 minutes.
  • hu5G11-hlgG1 injection was administered on the 1st day (d1) of each treatment cycle and once every 3 weeks (21 days) (d1/Q3W). Every 3 weeks (21 days) is a treatment cycle.
  • Anlotinib hydrochloride capsule active ingredient is anlotinib dihydrochloride (specifications: 12mg/capsule, 10mg/capsule, 8mg/capsule, 6mg/capsule): once a day (oral before breakfast), every 1 tablet at a time (10mg or 8mg). It is taken orally continuously for 2 weeks and then stopped for 1 week, that is, a treatment cycle is 21 days, and it is administered on days 8-21 of each treatment cycle. Unless there are special circumstances, it is recommended to take it at a fixed time every day. If a dose is missed during the medication, and it is confirmed that the time before the next dose is less than 12 hours, no more supplementary doses will be taken (i.e.
  • anlotinib hydrochloride capsules 10mg/qd or 8mg/qd, d8-21/Q3W.
  • researchers can adjust the dosage of anlotinib hydrochloride capsules according to the disease status and safety, for example: 12mg/qd, 10mg/qd, 8mg/qd, 6mg/qd.
  • Paclitaxel injection 175mg/ m2 dose (calculated as paclitaxel), administered by intravenous infusion, the infusion time is greater than 3 hours, administered on the 1st day (d1) of each treatment cycle, and administered every 3 weeks (21 days) Take medicine once (d1/Q3W). Every 3 weeks (21 days) is a treatment cycle.
  • the dosage of carboplatin injection needs to be calculated based on the area under the plasma concentration-time curve (AUC) and endogenous creatinine clearance.
  • AUC plasma concentration-time curve
  • Carboplatin dose (mg) set AUC (mg/mL/min) ⁇ [creatinine clearance (mL/min) + 25]
  • Doxorubicin hydrochloride for injection intravenously administered at a dose of 60 mg/ m2 (calculated as doxorubicin hydrochloride), intravenous bolus injection for 5-10 minutes, intravenous infusion for 90-120 minutes, each treatment cycle Administer on day 1 (d1) and once every 3 weeks (21 days) (d1/Q3W). Every 3 weeks (21 days) is a treatment cycle.
  • Gemcitabine hydrochloride for injection 900mg/ m2 dose (calculated as gemcitabine), administered by intravenous infusion, the infusion time is 30 minutes, and administered on the 1st day (d1) and the 8th day (d8) of each treatment cycle. Once, administered on the 1st and 8th day every 3 weeks (d1, d8/Q3W). Every 3 weeks (21 days) is a treatment cycle.
  • Docetaxel injection at a dose of 75 mg/m 2 (calculated as docetaxel), administered by intravenous infusion, the infusion time is 60 minutes, administered once on the 8th day (d8) of each treatment cycle, every Administer once every 3 weeks (21 days) (d1/Q3W). Every 3 weeks (21 days) is a treatment cycle.
  • the 1st day of each treatment cycle is d1
  • the 8th day of each treatment cycle is d8
  • the 21st day of each treatment cycle is d21.
  • the treatment process is divided into the first treatment phase and the maintenance treatment phase (i.e. the second treatment phase), of which the first treatment phase (6-8 treatment cycles) and the maintenance treatment phase (continuing from the end of the first treatment phase) Until the clinical benefit is lost, the toxicity is intolerable, the efficacy is evaluated as PD, and the researcher believes that it is not suitable to continue using the drug).
  • researchers can adjust the dosage of anlotinib hydrochloride capsules according to the disease status and safety, for example: 12mg/qd, 10mg/qd, 8mg/qd, 6mg/qd.
  • the second treatment stage hu5G11-hIgG1 injection 1200mg, d1/Q3W.
  • the second treatment phase hu5G11-hIgG1 injection 1200 mg, d1/Q3W; and anlotinib hydrochloride capsule 10 mg/qd, d8-21/Q3W.
  • the first treatment phase hu5G11-hIgG1 injection 1200 mg, d1/Q3W; anlotinib hydrochloride capsule 8 mg/qd, d8-21/Q3W; and chemotherapy regimen (doxorubicin hydrochloride injection 60 mg/m 2 , d1/ Q3W; or gemcitabine hydrochloride for injection 900mg/ m2 , d1, d8/Q3W + docetaxel injection 75mg/ m2 , d1/Q3W)
  • the second treatment phase hu5G11-hIgG1 injection 1200 mg, d1/Q3W; and anlotinib hydrochloride capsule 10 mg/qd, d8-21/Q3W.
  • Effectiveness evaluation criteria RECIST 1.1 and iRECIST standards are used to determine disease status. Mainly based on RECIST 1.1 standard evaluation, the iRECIST standard is also used to confirm the efficacy.
  • Safety evaluation standard NCI-CTC AE 5.0 standard is used to judge the severity of adverse events.
  • PFS progression-free survival
  • OS overall survival
  • DCR disease control rate
  • DOR duration of response
  • AEs adverse events
  • SAEs serious adverse events
  • a total of 28 patients are currently recruited, including 10 patients in cohort 1 and 18 patients in cohort 2.

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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une combinaison pharmaceutique pour le traitement d'une tumeur utérine maligne, qui comprend un anticorps anti-PD-L1 ou un fragment de liaison à l'antigène de celui-ci et un agent chimiothérapeutique, et comprend en outre éventuellement de l'Anlotinib ou un sel pharmaceutiquement acceptable de celui-ci. L'invention concerne en outre une utilisation de la combinaison pharmaceutique dans le traitement d'une tumeur utérine maligne.
PCT/CN2023/097702 2022-06-02 2023-06-01 Combinaison pharmaceutique pour le traitement d'une tumeur utérine maligne Ceased WO2023232100A1 (fr)

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WO2025140324A1 (fr) * 2023-12-26 2025-07-03 百奥泰生物制药股份有限公司 Utilisation d'un anticorps anti-pd-1 combiné à un agent chimiothérapeutique dans le traitement de tumeurs

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WO2025140324A1 (fr) * 2023-12-26 2025-07-03 百奥泰生物制药股份有限公司 Utilisation d'un anticorps anti-pd-1 combiné à un agent chimiothérapeutique dans le traitement de tumeurs

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