WO2023011631A1 - 治疗小细胞肺癌的药物组合 - Google Patents

治疗小细胞肺癌的药物组合 Download PDF

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WO2023011631A1
WO2023011631A1 PCT/CN2022/110539 CN2022110539W WO2023011631A1 WO 2023011631 A1 WO2023011631 A1 WO 2023011631A1 CN 2022110539 W CN2022110539 W CN 2022110539W WO 2023011631 A1 WO2023011631 A1 WO 2023011631A1
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Prior art keywords
antibody
seq
anlotinib
pharmaceutically acceptable
pharmaceutical composition
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English (en)
French (fr)
Inventor
张喜全
王训强
于鼎
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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 CA3227992A priority Critical patent/CA3227992A1/en
Priority to US18/292,655 priority patent/US20240343807A1/en
Priority to JP2024504984A priority patent/JP2024527974A/ja
Priority to AU2022321783A priority patent/AU2022321783A1/en
Priority to CN202280005896.5A priority patent/CN116209443A/zh
Priority to KR1020247006610A priority patent/KR20240046526A/ko
Priority to EP22852342.9A priority patent/EP4382123A4/en
Publication of WO2023011631A1 publication Critical patent/WO2023011631A1/zh
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
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2827—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the application belongs to the field of biomedicine, and relates to a drug combination, a kit and an application thereof for treating small cell lung cancer.
  • Tyrosine kinases are a group of enzymes that catalyze the phosphorylation of protein tyrosine residues. They play an important role in intracellular signal transduction. They are involved in the regulation, signal transmission and development of normal cells, and also with the tumor cells Proliferation, differentiation, migration and apoptosis are closely related. Many receptor tyrosine kinases are associated with the formation of tumors, and can be divided into epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor body (VEGFR), fibroblast growth factor receptor (FGFR) and so on.
  • EGFR epidermal growth factor receptor
  • PDGFR platelet-derived growth factor receptor
  • VEGFR vascular endothelial growth factor receptor body
  • FGFR fibroblast growth factor receptor
  • PD-L1 (Programmed death-ligand l), also known as CD247 and B7-H1, is a ligand of programmed death molecule 1 (Programmed death, PD-1).
  • PD-L1 is highly expressed on the surface of various tumor cells, and the malignancy and poor prognosis of tumors are closely related to the expression level of PD-L1.
  • PD-L1 on the surface of cancer cells binds to PD-1 or CD80 on the surface of T cells, inhibits the activation and proliferation of T cells, promotes effector T cells to enter a state of exhaustion or anergy, and induces the activation of T cells.
  • Apoptosis stimulates helper T cells to differentiate into regulatory T cells, thereby preventing T cells from killing tumor cells.
  • Anti-PD-L1 antibodies can block the interaction of PD-L1 with PD-1 and CD80, so that related negative regulatory signals cannot be initiated and transmitted, thereby avoiding the inhibition of the activity of effector T cells in the tumor microenvironment , so that T cells can play the role of killing and inhibiting tumor cells. Since the anti-PD-L1 antibody can directly act on tumor tissue, it has high specificity and safety.
  • Small cell lung cancer small cell lung cancer
  • SCLC small cell lung cancer
  • Etoposide combined with platinum-based antineoplastic drugs is the standard first-line treatment for extensive SCLC, but most patients have disease progression within 3 months, and there are still High relapse rate and drug resistance rate, so there are still many challenges in treatment.
  • WO2016022630 discloses a class of PD-L1 antibodies that have a high affinity for PD-L1, can significantly inhibit the interaction between PD-L1 and PD-1 on the cell surface, and significantly promote the secretion of IL-2 and INF- ⁇ by T cells .
  • cancers proliferative diseases
  • the present application provides a drug combination for treating small cell lung cancer, which includes an anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and further includes chemotherapy drugs.
  • the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain CDR1 region with at least 80% homology to the amino acid sequence shown in SEQ ID NO:1 or SEQ ID NO:4; and SEQ ID NO: 2 or a heavy chain CDR2 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO:5; having at least 80% homology to the amino acid sequence shown in SEQ ID NO:3 or SEQ ID NO:6
  • the heavy chain CDR3 region; the light chain CDR1 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO:7 or SEQ ID NO:10; the amino acid sequence shown in SEQ ID NO:8 or SEQ ID NO:11 A light chain CDR2 region with at least 80% homology in amino acid sequence; a light chain CDR3 region with at least 80% homology to the amino acid sequence shown in SEQ ID NO:9 or SEQ ID NO:12.
  • the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain CDR1 region selected from SEQ ID NO:1 or SEQ ID NO:4; a heavy chain CDR2 selected from SEQ ID NO:2 or SEQ ID NO:5 Region; heavy chain CDR3 region selected from SEQ ID NO:3 or SEQ ID NO:6; light chain CDR1 region selected from SEQ ID NO:7 or SEQ ID NO:10; selected from SEQ ID NO:8 or SEQ ID The light chain CDR2 region of NO: 11; the light chain CDR3 region selected from SEQ ID NO: 9 or SEQ ID NO: 12.
  • the anti-PD-L1 antibody comprises: a heavy chain CDR1 region having an amino acid sequence shown in SEQ ID NO:1, a heavy chain CDR2 region having an amino acid sequence shown in SEQ ID NO:2, having With the heavy chain CDR3 region of the amino acid sequence shown in SEQ ID NO:3; And have the light chain CDR1 region with the amino acid sequence shown in SEQ ID NO:7, have the light chain CDR1 region with the amino acid sequence shown in SEQ ID NO:8 chain CDR2 region, light chain CDR3 region having the amino acid sequence set forth in SEQ ID NO:9.
  • the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain variable region with at least 80% homology to the amino acid sequence shown in SEQ ID NO: 13 or SEQ ID NO: 14; and SEQ ID NO: 15 or a light chain variable region having at least 80% homology to the amino acid sequence shown in SEQ ID NO: 16.
  • the anti-PD-L1 antibody comprises: a variable heavy chain selected from hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4 humanized antibody, and a variable heavy chain selected from hu13C5-hIgG1, hu13C5-hIgG4 , hu5G11-hIgG1 or hu5G11-hIgG4 variable light chains of humanized antibodies.
  • the chemotherapeutic drug is selected from one or more of platinum-based antineoplastic drugs and topoisomerase inhibitors.
  • the platinum-based antineoplastic drugs include but are not limited to cisplatin, carboplatin, nedaplatin, dicycloplatin, picoplatin, oxaliplatin, miplatin or lobaplatin one or more of.
  • the platinum-based antitumor drug is selected from one or more of carboplatin, cisplatin, nedaplatin, picoplatin, miplatin or lobaplatin.
  • the platinum-based antineoplastic drug is selected from carboplatin.
  • the platinum-based antineoplastic drug is selected from cisplatin.
  • the topoisomerase inhibitors include but are not limited to topoisomerase I inhibitors, topoisomerase II inhibitors, topoisomerase I/II dual inhibitors; in some embodiments , the topoisomerase inhibitor is selected from topoisomerase II inhibitors.
  • the topoisomerase inhibitors include, but are not limited to, camptothecin, topotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone , irinotecan, topotecan, etoposide, or one or more of teniposide.
  • the topoisomerase inhibitor is one selected from topotecan, doxorubicin, epirubicin, mitoxantrone, irinotecan, topotecan, or etoposide one or more species.
  • the topoisomerase inhibitor is selected from etoposide.
  • the chemotherapeutic drug is selected from platinum-based antineoplastic drugs and etoposide.
  • the chemotherapeutic agent is selected from carboplatin and a topoisomerase inhibitor.
  • the chemotherapeutic drugs include: one or more selected from carboplatin, cisplatin, nedaplatin, picoplatin, miplatin or lobaplatin; and selected from topotecan, doxorubicin One or more of epirubicin, mitoxantrone, irinotecan, topotecan or etoposide.
  • the chemotherapeutic agent is selected from carboplatin and etoposide.
  • the pharmaceutical combination further includes a pharmaceutically acceptable carrier.
  • the present application provides a drug combination for treating small cell lung cancer, which includes a first drug combination, and optionally, a second drug combination.
  • the drug combination comprises a first drug combination administered to a patient in need thereof during a first treatment period, and optionally a second drug combination administered to a patient in need thereof during a second treatment period.
  • the treatment cycle of the first treatment phase is 1 to 10 treatment cycles, preferably 2 to 8 treatment cycles, most preferably 4 treatment cycles.
  • the first drug combination includes an anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and a chemotherapy drug.
  • the second pharmaceutical combination includes an anti-PD-L1 antibody, and anlotinib or a pharmaceutically acceptable salt thereof.
  • the drug combination comprises a first drug combination administered to a patient in need during a first treatment period, and optionally a second drug combination administered to a patient in need during a second treatment period , the first drug combination includes anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and chemotherapy drugs, and the second drug combination includes anti-PD-L1 antibody, and anlotinib or its pharmaceutically acceptable salt.
  • the treatment cycle of the first treatment phase is 1 to 10 treatment cycles, preferably 2 to 8 treatment cycles, most preferably 4 treatment cycles.
  • the pharmaceutical combination further includes a pharmaceutically acceptable carrier.
  • the pharmaceutical combination includes a pharmaceutical composition of anti-PD-L1 antibody, a pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition of chemotherapy drugs.
  • the above-mentioned drug combination of the present application is packaged in the same kit, and the kit also includes instructions for treating small cell lung cancer.
  • the kit for treating small cell lung cancer includes: anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and chemotherapy drugs.
  • the anti-PD-L1 antibody is contained in the first compartment
  • anlotinib or a pharmaceutically acceptable salt thereof is contained in the second compartment
  • the chemotherapy drug is contained in other compartments, optionally According to the type of chemotherapy drugs, the number of compartments in the kit can be increased according to the situation, and can be given to patients in need simultaneously, sequentially or sequentially.
  • the kit further comprises instructions for using anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof in combination with chemotherapy drugs to treat small cell lung cancer.
  • the kit includes: a pharmaceutical composition of an anti-PD-L1 antibody; and a pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof; and a pharmaceutical composition of a chemotherapy drug.
  • the above-mentioned kit is a kit suitable for administration in a single treatment cycle (for example, a treatment cycle of 21 days), including a pharmaceutical composition containing 600-2400 mg of anti-PD-L1 antibody and an anti-PD-L1 antibody containing 84-168 mg The pharmaceutical composition of Tini.
  • the treatment cycle is every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks.
  • the amount of anti-PD-L1 antibody administered can be determined according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health status of the patient.
  • the daily dose of anti-PD-L1 antibody can be 600-2400 mg, in some embodiments, the daily dose of anti-PD-L1 antibody can be 600, 800, 1000, 1200, 1400, 1600, 1800, 2000, 2200 or 2400mg.
  • the anti-PD-L1 antibody is administered parenterally.
  • the anti-PD-L1 antibody is administered intravenously.
  • the concentration of the pharmaceutical composition of anti-PD-L1 antibody is 10-60 mg/mL. In some embodiments, the concentration of the pharmaceutical composition of anti-PD-L1 antibody is 10, 20, 30, 40, 50 or 60 mg/mL.
  • the dosing regimen of the anti-PD-L1 antibody can be comprehensively determined according to the activity, toxicity, and tolerance of the patient.
  • the anti-PD-L1 antibody is used as a treatment cycle every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks.
  • the anti-PD-L1 antibody is administered weekly, every 2 weeks, every 3 weeks, or every 4 weeks.
  • the dose of anti-PD-L1 antibody is 600-2400 mg per treatment cycle.
  • the dose of anti-PD-L1 antibody is 1200 mg per treatment cycle.
  • the anti-PD-L1 antibody is administered once every 3 weeks, with a dose of 600-2400 mg each time.
  • the anlotinib or a pharmaceutically acceptable salt thereof is administered in a daily dose of 6 mg, 8 mg, 10 mg or 12 mg, administered continuously for 2 weeks and rested for 1 week.
  • the drug combination comprising anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and chemotherapy drugs described in this application includes a pharmaceutical composition of anti-PD-L1 antibody and anlotinib
  • the pharmaceutical composition of Tini wherein the pharmaceutical composition of anti-PD-L1 antibody is prepared as a unit dose or multiple doses of 600-2400 mg of anti-PD-L1 antibody suitable for the first administration, said Anluo
  • the pharmaceutical composition of Tini or its pharmaceutically acceptable salt is prepared to be suitable for 14 consecutive days, and the unit dose of 6mg, 8mg, 10mg and/or 12mg Anlotinib or its pharmaceutically acceptable salt is given to the patient every day .
  • the drug combination comprising anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and chemotherapy drugs described in this application includes: the concentration of anti-PD-L1 antibody is 10-60 mg/ A pharmaceutical composition of anti-PD-L1 antibody in mL, and a pharmaceutical composition with a unit dose of 6 mg, 8 mg, 10 mg and/or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof.
  • the drug combination comprising anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and chemotherapy drugs described in the present application includes: 1200 mg of anti-PD-L1 antibody in multiple doses
  • the provided pharmaceutical composition and the pharmaceutical composition with a unit dose of 8 mg, 10 mg and/or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof.
  • the drug combination containing anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and chemotherapy drugs described in this application is suitable for use in a single treatment cycle (for example, a treatment cycle of 21 days)
  • the preparations for internal administration include a pharmaceutical composition containing 600-2400 mg of anti-PD-L1 antibody and a pharmaceutical composition containing 84-168 mg of anlotinib.
  • the preparations described in the present application that are suitable for administration in a single treatment cycle (for example, a treatment cycle of 21 days) further include: a pharmaceutical composition containing 90 mg to 1800 mg, preferably 150 mg to 1800 mg of etoposide .
  • the preparation suitable for administration in a single treatment cycle (for example, a treatment cycle of 21 days) described in this application further includes: a pharmaceutical composition containing 50-800 mg of carboplatin.
  • the drug combination containing anti-PD-L1 antibody, anlotinib or its pharmaceutically acceptable salt, and chemotherapeutic drugs described in this application includes a weight ratio of (0.35-29):1, preferably (3.5- 29): 1, more preferably (3.5-14.5): 1, most preferably (7-14.5): 1 anti-PD-L1 antibody and anlotinib.
  • the anti-PD-L1 antibody and anlotinib can be packaged separately or packaged together.
  • anlotinib 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); the anti-PD-L1 antibody can be packaged in a single equal part or Multiple aliquots (eg, 2, 4 or more aliquots) are packaged.
  • the pharmaceutical combination described in this application comprises anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, carboplatin and etoposide, wherein, anti-PD-L1 antibody, anlotinib
  • the weight ratio of Tini or its pharmaceutically acceptable salt, carboplatin and etoposide is (300 ⁇ 1200):(42 ⁇ 84):(25 ⁇ 400):(45 ⁇ 900), for example (300 ⁇ 1200 ):(42 ⁇ 84):(25 ⁇ 400):(75 ⁇ 900).
  • the carboplatin and etoposide can be packaged in single or multiple aliquots (eg 3, 6 or more aliquots).
  • the present application also provides the use of the pharmaceutical combination of the present application, or the kit of the present application in the preparation of medicines for treating patients with small cell lung cancer.
  • the present application also provides a method for treating small cell lung cancer, comprising administering an effective amount of the drug combination of the present application, or the kit of the present application to a patient in need.
  • the application also provides the application of the drug combination of the application, or the kit of the application for treating small cell lung cancer in a patient.
  • the present application also provides the pharmaceutical combination of the present application, or the kit of the present application for treating small cell lung cancer in a patient.
  • the method for treating small cell lung cancer includes administering a therapeutically effective amount of anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and chemotherapy drugs to a patient in need.
  • the method of treatment comprises administering a first drug combination to a patient in need thereof during a first treatment period; and optionally, administering a second drug combination to a patient in need thereof during a second treatment period.
  • the first drug combination includes an anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and a chemotherapy drug.
  • the second pharmaceutical combination includes an anti-PD-L1 antibody, and anlotinib or a pharmaceutically acceptable salt thereof.
  • the treatment cycle of the first treatment phase is 1 to 10 treatment cycles, preferably 2 to 8 treatment cycles, most preferably 4 treatment cycles.
  • the chemotherapeutic drug is selected from one or more of platinum-based antineoplastic drugs and topoisomerase inhibitors. In some embodiments, the chemotherapeutic drug is selected from platinum-based antineoplastic drugs and etoposide. In some embodiments, the chemotherapeutic agent is selected from carboplatin and etoposide.
  • the anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and chemotherapy drugs are each in the form of a pharmaceutical composition, which can be administered simultaneously, sequentially or at intervals.
  • the anti-PD-L1 antibody is administered once every week, every 2 weeks, every 3 weeks, or every 4 weeks; preferably, the anti-PD-L1 antibody is administered at a dose of 600-2400 mg each time.
  • the anlotinib is administered in a dose of 6 mg, 8 mg, 10 mg or 12 mg once a day, with a regimen of continuous medication for 2 weeks and rest for 1 week.
  • anlotinib 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methanol Oxyquinolin-7-yl] oxygen group] methyl] cyclopropylamine, it has following structural formula:
  • the pharmaceutically acceptable salts of Anlotinib include but are not limited to salts formed by Anlotinib and acids selected from the following: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid , caproic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, Mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, p-toluenesulfonic acid, 3-phenylpropionic acid
  • anlotinib or a pharmaceutically acceptable salt thereof involved in this application is based on the molecular weight of anlotinib free base.
  • Anlotinib or a pharmaceutically acceptable salt thereof can be administered by various routes, including gastrointestinal administration and parenteral administration, including but not limited to oral, intravenous, intraarterial, transdermal , sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vaginal, intraocular, subcutaneous, intralipid, intraarticular, intraperitoneal, and intrathecal. In some specific embodiments, the administration is orally.
  • the amount of anlotinib or a pharmaceutically acceptable salt thereof to be administered can be determined according to the severity of the disease, the response of the disease, any treatment-related toxicity, 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, and in some embodiments, 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 can be administered once or more than once a day. In some embodiments, anlotinib or a pharmaceutically acceptable salt thereof is administered as an oral solid formulation once a day.
  • the dosing regimen of anlotinib or its pharmaceutically acceptable salt can be comprehensively determined according to the activity, toxicity and tolerance of the drug, etc.
  • anlotinib or a pharmaceutically acceptable salt thereof is administered at intervals.
  • the interval dosing includes a dosing period and a dosing period, and during the dosing period, anlotinib or a pharmaceutically acceptable salt thereof can be given once or more than once a day.
  • the ratio in days between the administration period and the withdrawal period is 2:(0.5-5), 2:(0.5-3), 2:(0.5-2), or 2:(0.5-1).
  • the administration is continued for 2 weeks and the administration is off for 2 weeks.
  • the administration is continued for 2 weeks with 1 week rest.
  • anlotinib or a pharmaceutically acceptable salt thereof can be administered orally at a dose of 6 mg, 8 mg, 10 mg or 12 mg once a day, continuously for 2 weeks, and administered in a manner of resting for 1 week.
  • composition of anlotinib or pharmaceutically acceptable salt thereof is provided.
  • the unit dose of the pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof includes 6 mg, 8 mg, 10 mg, or 12 mg of anlotinib.
  • the total dose of the pharmaceutical composition of anlotinib or its pharmaceutically acceptable salt administered in each cycle includes 84-168mg .
  • the total dose of the pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof includes a range selected from 84 mg, 112 mg, 140 mg, 168 mg or any of the above values.
  • the total dose of the pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof includes 112 mg to 168 mg.
  • the pharmaceutical composition includes but not limited to formulations suitable for oral, parenteral, and topical administration; in some embodiments, the pharmaceutical composition is a formulation suitable for oral administration; in some embodiments, The pharmaceutical composition is a solid preparation suitable for oral administration; in some embodiments, the pharmaceutical composition includes but not limited to tablets and capsules.
  • the chemotherapeutic drug is selected from one or more of platinum-based antineoplastic drugs and topoisomerase inhibitors.
  • the platinum-based antineoplastic drugs include but not limited to one of cisplatin, carboplatin, nedaplatin, dicycloplatin, picoplatin, oxaliplatin, miplatin or lobaplatin one or more species.
  • the platinum-based antineoplastic drug is selected from carboplatin.
  • the topoisomerase inhibitors include but are not limited to topoisomerase I inhibitors, topoisomerase II inhibitors, and topoisomerase I/II dual inhibitors; in some embodiments, the The topoisomerase inhibitors are selected from topoisomerase II inhibitors.
  • the topoisomerase inhibitors include, but are not limited to, camptothecin, topotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, rice One or more of toxantrone, irinotecan, topotecan, etoposide, or teniposide. In some embodiments of the present application, the topoisomerase inhibitor is selected from etoposide.
  • the chemotherapeutic drug is selected from platinum-based antineoplastic drugs and etoposide. In some embodiments, the chemotherapeutic agent is selected from carboplatin and a topoisomerase inhibitor. In some embodiments of the present application, the chemotherapeutic drug is selected from carboplatin, and/or etoposide. In some embodiments of the present application, the chemotherapeutic drug is selected from carboplatin and etoposide.
  • carboplatin is administered at a dose of AUC (drug-time curve) of 4-7 mg/ml/min, preferably at a dose of AUC of 5-7 mg/ml/min, more preferably at an AUC of 5 mg /ml/min dose administration.
  • AUC drug-time curve
  • etoposide is administered at a dose of 60-120 mg/m 2 , preferably at a dose of 60-100 mg/m 2 , more preferably at a dose of 100 mg/m 2 .
  • mg/ m2 refers to the dose of the drug used per square meter of body surface area of the subject.
  • the anti-PD-L1 antibody is the antibody in WO2016022630 or CN107001463A.
  • the anti-PD-L1 antibody comprises the following amino acid sequence: 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%) homologous heavy chain CDR1 region; at least 80% (e.g., 81%, 82%, 83%, 84%, 85%) to the amino acid sequence shown in SEQ ID NO: 2 or SEQ ID NO: 5 , 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homologous Heavy chain CDR2 region; at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%) of the amino acid sequence shown in SEQ ID NO:3 or SEQ ID NO:6 %
  • the anti-PD-L1 antibody comprises the following amino acid sequence: selected from the heavy chain CDR1 region of SEQ ID NO: 1 or SEQ ID NO: 4; selected from SEQ ID NO: 2 or SEQ ID The heavy chain CDR2 region of NO:5; the heavy chain CDR3 region selected from SEQ ID NO:3 or SEQ ID NO:6; the light chain CDR1 region selected from SEQ ID NO:7 or SEQ ID NO:10; selected from SEQ ID NO:7 or the light chain CDR1 region of SEQ ID NO:10; The light chain CDR2 region of ID NO:8 or SEQ ID NO:11; the light chain CDR3 region selected from SEQ ID NO:9 or SEQ ID NO:12.
  • the isolated anti-PD-L1 antibody described herein comprises: a heavy chain CDR1 region having the amino acid sequence set forth in SEQ ID NO:1, having a heavy chain CDR1 region set forth in SEQ ID NO:2
  • the heavy chain CDR2 region of the amino acid sequence has the heavy chain CDR3 region of the amino acid sequence shown in SEQ ID NO:3
  • the light chain CDR1 region having the amino acid sequence shown in SEQ ID NO:7 has the amino acid sequence shown in SEQ ID NO
  • the light chain CDR2 region with the amino acid sequence shown in SEQ ID NO:8 has the light chain CDR3 region with the amino acid sequence shown in SEQ ID NO:9.
  • Each of the CDR regions described herein and the above-mentioned variants can specifically recognize and bind to PD-L1, thereby effectively blocking the signal transduction between PD-L1 and PD-1.
  • the anti-PD-L1 antibody comprises the following amino acid sequence: 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%) homologous heavy chain variable region; at least 80% (eg, 81%, 82%, 83%, 84%, 85%) to 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 light chain variable region.
  • the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain variable region as shown in SEQ ID NO:13; a light chain variable region as shown in SEQ ID NO:15 .
  • the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain variable region as shown in SEQ ID NO:14; a light chain variable region as shown in SEQ ID NO:16 .
  • the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain amino acid sequence as shown in SEQ ID NO:17; a light chain amino acid sequence as shown in SEQ ID NO:18.
  • the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain amino acid sequence as shown in SEQ ID NO:19; a light chain amino acid sequence as shown in SEQ ID NO:20.
  • the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain amino acid sequence as shown in SEQ ID NO:21; a light chain amino acid sequence as shown in SEQ ID NO:18.
  • the anti-PD-L1 humanized monoclonal antibody provided by the application comprises SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO :5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, One of SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21 or multiple conservative substitution variants.
  • the anti-PD-L1 humanized monoclonal antibody comprising the conservative substitution variant retains the ability to specifically recognize and bind to PD-L1.
  • the anti-PD-L1 antibody can be an IgG1 or IgG4 antibody.
  • the anti-PD-L1 antibody is an IgG1 antibody. In some embodiments, the anti-PD-L1 antibody is a glycosylated IgG1 antibody.
  • the anti-PD-L1 antibody comprises a heavy chain complementarity determining region (CDR) selected from 13C5 or 5G11 antibody, and a light chain complementarity determining region selected from 13C5 or 5G11 antibody.
  • CDR heavy chain complementarity determining region
  • the anti-PD-L1 antibody described in the present application comprises a variable heavy chain selected from ch5G11-hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, ch13C5-hIgG4 chimeric antibodies, and selected from ch5G11- Variable light chains of hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, ch13C5-hIgG4 chimeric antibodies.
  • the anti-PD-L1 antibody described in the present application comprises a variable heavy chain selected from hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4 humanized antibody, and a variable heavy chain selected from hu13C5 - the variable light chain of a hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4 humanized antibody.
  • 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 ), the HCDR3 sequence is GYDSGFAY (SEQ ID NO:6), the LCDR1 sequence is ASQSVSTSSSSFMH (SEQ ID NO:10), the LCDR2 sequence is YASNLES (SEQ ID NO:11), and the LCDR3 sequence is QHSWEIPYT (SEQ ID NO:12);
  • the anti-PD-L1 antibody in the drug combination can be selected from one or more.
  • the term "plurality" may be more than one, eg, two, three, four, five or more.
  • the anti-PD-L1 antibody is selected from the group comprising a heavy chain variable region as shown in SEQ ID NO: 13 and a light chain variable region as shown in SEQ ID NO: 15 , or selected from comprising a heavy chain variable region as shown in SEQ ID NO: 14 and a light chain variable region as shown in SEQ ID NO: 16, or selected from a combination of the above.
  • the anti-PD-L1 antibody is selected from the heavy chain amino acid sequence shown in SEQ ID NO: 17 and the light chain amino acid sequence shown in SEQ ID NO: 18, or selected from the amino acid sequence shown in SEQ ID NO: 19 A heavy chain amino acid sequence and a light chain amino acid sequence as shown in SEQ ID NO:20, or selected from a heavy chain amino acid sequence as shown in SEQ ID NO:21 and a light chain amino acid sequence as shown in SEQ ID NO:18, or A combination of any of the above options.
  • the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain CDR1 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 4; A heavy chain CDR2 region with at least 80% homology to the amino acid sequence shown in :2 or SEQ ID NO: 5; at least 80% homology to the amino acid sequence shown in SEQ ID NO: 3 or SEQ ID NO: 6
  • the heavy chain CDR3 region; the light chain CDR1 region with at least 80% homology to the amino acid sequence shown in SEQ ID NO: 7 or SEQ ID NO: 10; the same as shown in SEQ ID NO: 8 or SEQ ID NO: 11 A light chain CDR2 region with at least 80% homology to the amino acid sequence; a light chain CDR3 region with at least 80% homology to the amino acid sequence shown in SEQ ID NO:9 or SEQ ID NO:12.
  • the pharmaceutical composition of anti-PD-L1 antibody contains 600-2400 mg of anti-PD-L1 antibody.
  • the pharmaceutical composition of the anti-PD-L1 antibody contains an anti-PD-L1 antibody selected from 600mg, 900mg, 1200mg, 1500mg, 1800mg, 2100mg, 2400mg, or the range formed by any of the above values.
  • the pharmaceutical composition of the anti-PD-L1 antibody contains 600-2100 mg, or 900 mg-1500 mg of the anti-PD-L1 antibody; wherein the pharmaceutical composition of the anti-PD-L1 antibody can be multi-dose or unit dose form exists.
  • the pharmaceutical composition of the anti-PD-L1 antibody contains 300 mg, 600 mg or 1200 mg of the anti-PD-L1 antibody;
  • the pharmaceutical composition of the anti-PD-L1 antibody is a solution for injection. In some embodiments, the pharmaceutical composition of the anti-PD-L1 antibody is an aqueous solution for injection. In some embodiments of the present application, the pharmaceutical composition of the anti-PD-L1 antibody comprises one or more of a buffer, an isotonic regulator, a stabilizer and/or a surfactant. In particular, the pharmaceutical composition of the anti-PD-L1 antibody comprises 1-150 mg/mL anti-PD-L1 antibody (such as monoclonal antibody), 3-50 mM buffer, 2-150 mg/mL isotonicity regulator/stabilizer and 0.01-0.8 mg/mL surfactant, and pH 4.5-6.8.
  • the pharmaceutical composition of the anti-PD-L1 antibody is calculated by w/v, and the concentration of the anti-PD-L1 monoclonal antibody is 5-150 mg/mL; in some embodiments, the concentration is 10 -60 mg/mL; in some embodiments the concentration is 10-30 mg/mL.
  • the mass volume concentration of anti-PD-L1 monoclonal antibody is 10mg/mL, 20mg/mL, 30mg/mL, 40mg/mL, 50mg/mL, 60mg/mL, 70mg/mL, 80mg/mL, 90mg/mL mL, 100 mg/mL, 110 mg/mL, or 120 mg/mL; in some embodiments, the concentration is 10 mg/mL, 20 mg/mL, 30 mg/mL, 40 mg/mL, 50 mg/mL, or 60 mg/mL; in some In embodiments, the concentration is 10 mg/mL, 20 mg/mL or 30 mg/mL.
  • the mass volume concentration of the anti-PD-L1 monoclonal antibody is 10 mg/mL. In other embodiments, the mass volume concentration of the anti-PD-L1 monoclonal antibody is 30 mg/mL. In other embodiments, the mass volume concentration of the anti-PD-L1 monoclonal antibody is 60 mg/mL.
  • the buffer is a histidine salt buffer.
  • the concentration of the histidine salt buffer is 5-30mM, in some embodiments, the concentration is 10-25mM; in some embodiments, the concentration is 10-20mM; in some embodiments, the The concentration is 10-15mM.
  • the concentration of the histidine salt buffer is 5mM, 10mM, 15mM, 20mM, 25mM or 30mM.
  • the concentration of the histidine salt buffer is 10 mM.
  • the concentration of the histidine salt buffer is 15 mM.
  • the concentration of the histidine salt buffer is 20 mM.
  • the histidine salt buffer contains histidine and hydrochloric acid.
  • the isotonic regulator/stabilizer is 20-150 mg/mL sucrose in w/v calculation; in some embodiments, the isotonic regulator/stabilizer is 40 mg/mL -100 mg/mL sucrose; in some embodiments, the isotonicity adjuster/stabilizer is 60-80 mg/mL sucrose. In some embodiments, the concentration of sucrose is 40 mg/mL, 50 mg/mL, 60 mg/mL, 70 mg/mL, 80 mg/mL, 90 mg/mL or 100 mg/mL. In some embodiments, the concentration of sucrose is 60 mg/mL. In some embodiments, the concentration of sucrose is 70 mg/mL. In some embodiments, the concentration of sucrose is 80 mg/mL. In some embodiments, the concentration of sucrose is 90 mg/mL.
  • the surfactant is selected from polysorbate 80, polysorbate 20, poloxamer 188; in some embodiments, the surfactant is selected from polysorbate 80 or Polysorbate 20; in some embodiments, the surfactant is selected from polysorbate 80.
  • the concentration of the surfactant is 0.05-0.6 mg/mL calculated by w/v; in some embodiments, the concentration is 0.1-0.4 mg/mL; in some embodiments, the Said concentration is 0.2 ⁇ 0.3mg/mL.
  • the surfactant is 0.01-0.8 mg/mL polysorbate 80 or polysorbate 20 calculated by w/v.
  • the surfactant is polysorbate 80 at 0.05-0.6 mg/mL; in some embodiments, the surfactant is polysorbate 80 at 0.1-0.4 mg/mL; in some In embodiments, the surfactant is 0.2-0.3 mg/mL polysorbate 80; in some embodiments, the surfactant is 0.2 mg/mL polysorbate 80.
  • the content of polysorbate 80 in the pharmaceutical composition is 0.1 mg/mL, 0.2 mg/mL, 0.3 mg/mL, 0.4 mg/mL, 0.5 mg/mL or 0.6 mg/mL; In some embodiments, the content of polysorbate 80 in the pharmaceutical composition is 0.2 mg/mL, 0.3 mg/mL, 0.4 mg/mL or 0.5 mg/mL; in some embodiments, polysorbate 80 in the pharmaceutical composition The content of polysorbate 80 is 0.2 mg/mL, 0.3 mg/mL or 0.4 mg/mL; in some embodiments, the content of polysorbate 80 in the pharmaceutical composition is 0.2 mg/mL.
  • the content of polysorbate 80 in the pharmaceutical composition is 0.1 mg/mL. In other embodiments, the content of polysorbate 80 in the pharmaceutical composition is 0.2 mg/mL. In some embodiments, the content of polysorbate 80 in the pharmaceutical composition is 0.3 mg/mL. In other embodiments, the content of polysorbate 80 in the pharmaceutical composition is 0.4 mg/mL. In some embodiments, the content of polysorbate 80 in the pharmaceutical composition is 0.5 mg/mL.
  • the pH value of the aqueous solution of the pharmaceutical composition is selected from 4.0 to 6.8; in some embodiments, the pH value is 4.5 to 6.5; in some embodiments, the pH value is 5.5 to 6.0; in some embodiments, the pH is 5.5. In some embodiments, the pH of the aqueous solution of the pharmaceutical composition is 4.5, 4.8, 5.0, 5.2, 5.4, 5.5, 5.6, 5.8, or 6.0, and in some embodiments, the pH is 5.0, 5.2, 5.4, 5.5 or 5.6; in some embodiments, the pH is 5.5. In some embodiments, the pH of the aqueous pharmaceutical composition is 5.0. In some embodiments, the pH of the aqueous pharmaceutical composition is 5.2.
  • the pH of the aqueous pharmaceutical composition is 5.4. In some embodiments, the pH of the aqueous pharmaceutical composition is 5.5. In some embodiments, the pH of the aqueous pharmaceutical composition is 5.6. In some embodiments, the pH of the aqueous pharmaceutical composition is 5.8. In some embodiments, the pH of the aqueous pharmaceutical composition is 6.0.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody with a mass volume concentration of 20 mg/mL, (b) sucrose with a mass volume concentration of 70 mg/mL, (c) Polysorbate 80 with a mass volume concentration of 0.1 mg/mL, (d) histidine with a molar concentration of 20 mM, and (e) an appropriate amount of hydrochloric acid to adjust the pH of the composition to 5.0.
  • the pharmaceutical composition comprises: (a) anti-PD-L1 monoclonal antibody with a mass volume concentration of 20 mg/mL, (b) sucrose with a mass volume concentration of 70 mg/mL, (c) Polysorbate 80 with a mass volume concentration of 0.1 mg/mL, (d) histidine with a molar concentration of 20 mM, and (e) an appropriate amount of hydrochloric acid to adjust the pH of the composition to 5.0.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody with a mass volume concentration of 10 mg/mL, (b) sucrose with a mass volume concentration of 80 mg/mL, (c ) polysorbate 80 with a mass volume concentration of 0.2 mg/mL, (d) histidine with a molar concentration of 10 mM, (e) optional hydrochloric acid in an appropriate amount, and adjust the pH value of the composition to 5.5.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody with a mass volume concentration of 50 mg/mL, (b) sucrose with a mass volume concentration of 80 mg/mL, (c ) polysorbate 80 with a mass volume concentration of 0.3 mg/ml, (d) histidine with a molar concentration of 10 mM, (e) an appropriate amount of hydrochloric acid, and adjust the pH of the composition to 5.5.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody with a mass volume concentration of 100 mg/mL, (b) sucrose with a mass volume concentration of 80 mg/mL, (c ) polysorbate 80 with a mass volume concentration of 0.5 mg/mL, (d) histidine with a molar concentration of 10 mM, (e) optional hydrochloric acid in an appropriate amount, and adjust the pH value of the composition to 5.5.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody with a mass volume concentration of 30 mg/mL, (b) sucrose with a mass volume concentration of 80 mg/mL, (c ) polysorbate 80 with a mass volume concentration of 0.2 mg/mL, (d) histidine with a molar concentration of 10 mM, (e) optional hydrochloric acid in an appropriate amount, and adjust the pH value of the composition to 5.5.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody with a mass volume concentration of 60 mg/mL, (b) sucrose with a mass volume concentration of 80 mg/mL, (c ) polysorbate 80 with a mass volume concentration of 0.2 mg/mL, (d) histidine with a molar concentration of 10 mM, (e) optional hydrochloric acid in an appropriate amount, and adjust the pH value of the composition to 5.5.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody with a mass volume concentration of 10 mg/mL, (b) sucrose with a mass volume concentration of 70 mg/mL, (c ) polysorbate 80 with a mass volume concentration of 0.4 mg/mL, (d) histidine with a molar concentration of 20 mM, (e) an appropriate amount of acetic acid, and adjust the pH of the composition to 6.5.
  • the pharmaceutical composition comprises: (a) anti-PD-L1 monoclonal antibody with a mass volume concentration of 10 mg/mL, (b) sucrose with a mass volume concentration of 80 mg/mL, ( c) polysorbate 80 with a mass volume concentration of 0.2 mg/mL, (d) histidine with a molar concentration of 20 mM, and (e) an appropriate amount of hydrochloric acid to adjust the pH of the composition to 5.5.
  • the pharmaceutical composition is a water-soluble injection; in some embodiments, the water-soluble injection includes but is not limited to non-lyophilized water-soluble preparations or lyophilized powder reconstituted water-soluble formulations.
  • the pharmaceutical composition is a lyophilized formulation.
  • the lyophilized preparation refers to a preparation in which an aqueous solution undergoes a freeze-drying process, in which the substance is first frozen, then the amount of solvent is reduced by sublimation (primary drying process), and then the amount of solvent is reduced by desorption (secondary drying process) until the amount of solvent reaches a value that no longer supports biological activity or chemical reaction.
  • the lyophilized formulations of the present application can also be dried by other methods known in the art, such as spray drying and bubble drying.
  • the present application provides a drug combination for treating small cell lung cancer, which includes an anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and chemotherapy drugs.
  • the drug combination includes anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and chemotherapy drugs.
  • the drug combination comprising anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and chemotherapy drugs is a fixed combination.
  • the fixed combination is in the form of a solid pharmaceutical composition or a liquid pharmaceutical composition.
  • the drug combination comprising anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and chemotherapy drugs is a non-fixed combination.
  • the anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and the chemotherapeutic agent in the non-fixed combination are each in the form of a pharmaceutical composition.
  • each active ingredient of the anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and the chemotherapy drug in the non-fixed combination is in the form of a pharmaceutical composition.
  • a pharmaceutical combination comprising a weight ratio of (0.35-29):1, preferably (3.5-29):1, more preferably (3.5-14.5):1, most preferably (7- 14.5): 1 anti-PD-L1 antibody and anlotinib.
  • the anti-PD-L1 antibody and anlotinib can be packaged separately or packaged together.
  • anlotinib can be packaged in multiple equal parts (for example, 2 equal parts, 7 equal parts, 14 equal parts, 28 equal parts or more equal parts).
  • the anti-PD-L1 antibody comprises a heavy chain complementarity determining region (CDR) selected from a 13C5 or 5G11 antibody, and a light chain complementarity determining region (CDR) selected from a 13C5 or 5G11 antibody region; in one embodiment, the anti-PD-L1 antibody comprises a variable heavy chain selected from the group consisting of ch5G11-hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, ch13C5-hIgG4 chimeric antibodies, and a variable heavy chain selected from the group consisting of ch5G11-hIgG1, ch5G11 - the variable light chain of a hIgG4, ch13C5-hIgG1, ch13C5-hIgG4 chimeric antibody; in one embodiment, the anti-PD-L1 antibody comprises a variable light chain selected from the group consisting of hu13
  • the HCDR1 sequence is SYGMS
  • the HCDR2 sequence is SISSGGSTYYPDSVYKG
  • the HCGDR3 sequence is GYDS
  • the sequence of LCDR1 is ASQSVSTSSSSFMH
  • the sequence of LCDR2 is YASNLES
  • the sequence of LCDR3 is QHSWEIPYT
  • the sequence of HCDR1 of 5G11, ch5G11-hIgG1, ch5G11-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4 is TYGVH
  • the sequence of HCDR2 is VIWRGVTTDYNAAFMS
  • the sequence of HCDR3 is LGRF1YNAFMS
  • the sequence is KASQSVSNDVA
  • the LCDR2 sequence is YAANRYT
  • the LCDR3 sequence is QQDYTSPYT
  • the LCDR2 sequence is YAANRYT
  • the LCDR3 sequence is QQDYTSP
  • the pharmaceutical combination containing anti-PD-L1 antibody and chemotherapy drugs includes a pharmaceutical composition containing 600-2400 mg of anti-PD-L1 antibody, a carboplatin pharmaceutical composition of 50-700 mg, and 20 ⁇ 200mg of etoposide pharmaceutical composition.
  • the pharmaceutical composition of the anti-PD-L1 antibody, the carboplatin pharmaceutical composition and the etoposide pharmaceutical composition are single-dose or multiple-dose.
  • the drug combination includes anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and chemotherapy drugs; or, it includes the above-mentioned anti-PD-L1 antibody, anlotinib A drug combination of nicillin or a pharmaceutically acceptable salt thereof and a chemotherapeutic drug.
  • the drug combination containing anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof and chemotherapy drugs includes anti-PD-L1 antibody pharmaceutical composition, anlotinib or a pharmaceutical composition and a chemotherapy pharmaceutical composition of a pharmaceutically acceptable salt thereof.
  • the drug combination is packaged in the same kit, and the kit also includes PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof and chemotherapy drugs for the treatment of small Illustration of cell lung cancer.
  • the drug combination containing anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and chemotherapy drugs includes a drug containing 600-2400 mg of anti-PD-L1 antibody Composition, single dose is 6mg, 8mg, 10mg and/or 12mg of anlotinib or its pharmaceutically acceptable salt, 50 ⁇ 800mg (for example 50 ⁇ 500mg) carboplatin pharmaceutical composition and 20 ⁇ 200mg Poside pharmaceutical composition.
  • the pharmaceutical composition of the anti-PD-L1 antibody, the pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof, the pharmaceutical composition of carboplatin and the pharmaceutical composition of etoposide are single dose or multiple doses.
  • the drug combination containing anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and chemotherapy drugs includes an anti-PD-L1 antibody containing 1200 mg provided in multiple doses.
  • the single dose is 6 mg, 8 mg, 10 mg and/or 12 mg of anlotinib, 200-400 mg of carboplatin pharmaceutical composition and 50-150 mg of etoposide pharmaceutical composition.
  • the drug combination containing anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and chemotherapy drugs includes an anti-PD-L1 antibody concentration of 10-60 mg/mL
  • the anti-PD-L1 antibody pharmaceutical composition, the single dose is 6 mg, 8 mg, 10 mg and/or 12 mg of anlotinib, 50-500 mg of carboplatin pharmaceutical composition and 20-200 mg of etoposide pharmaceutical composition.
  • the drug combination containing anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and chemotherapy drugs includes an anti-PD-L1 antibody concentration of 10 mg/mL
  • the PD-L1 antibody pharmaceutical composition, single dose is 8 mg, 10 mg and/or 12 mg of anlotinib, 200-400 mg of carboplatin pharmaceutical composition and 50-150 mg of etoposide pharmaceutical composition.
  • the pharmaceutical combination comprises a weight ratio of (0.35-29):1, preferably (3.5-29):1, more preferably (3.5-14.5):1, most preferably (7-14.5):1 anti-PD-L1 antibody and anlotinib.
  • the anti-PD-L1 antibody and anlotinib can be packaged separately or packaged together.
  • anlotinib can be packaged in multiple equal parts (for example, 2 equal parts, 7 equal parts, 14 equal parts, 28 equal parts or more equal parts).
  • the present application provides a drug combination for treating small cell lung cancer, which includes the first drug combination administered to patients in need during the first treatment phase, and optionally, the drug combination administered to patients in need during the second treatment phase.
  • the first drug combination may be selected from one or more of the above drug combinations.
  • the first drug combination includes an anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and a chemotherapy drug.
  • the second pharmaceutical combination includes an anti-PD-L1 antibody, and anlotinib or a pharmaceutically acceptable salt thereof.
  • the treatment cycle of the first treatment phase is 1 to 10 treatment cycles, preferably 2 to 8 treatment cycles, most preferably 4 treatment cycles.
  • the pharmaceutical combination further includes a pharmaceutically acceptable carrier.
  • the anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and the chemotherapeutic drug in the pharmaceutical combination are each in the form of a pharmaceutical composition.
  • each active ingredient of the anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and the chemotherapy drug in the pharmaceutical combination is in the form of a pharmaceutical composition.
  • the present application provides a kit for treating small cell lung cancer, the kit comprising an anti-PD-L1 antibody pharmaceutical composition, anlotinib or a pharmaceutically acceptable salt thereof, and further Including chemotherapeutic drugs, and instructions for using them in combination to treat small cell lung cancer; Tini or its pharmaceutically acceptable salt pharmaceutical composition, and/or carboplatin pharmaceutical composition and/or etoposide pharmaceutical composition, and instructions for combined use in the treatment of small cell lung cancer; or, the kit includes this The drug combination of the application, and the description of the combined use in the treatment of small cell lung cancer.
  • the present application also provides the use of the pharmaceutical combination of the present application, or the kit of the present application, in preparing a medicine for treating small cell lung cancer in a patient.
  • the present application also provides a method for treating small cell lung cancer in a patient, which includes administering an effective amount of the drug combination of the present application, or the kit of the present application to the patient in need.
  • the present application also provides the use of the drug combination of the present application or the kit of the present application for treating small cell lung cancer in a patient.
  • the pharmaceutical combination or kit is as described above.
  • the anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and chemotherapy drugs are each in the form of a pharmaceutical composition, which can be simultaneously or sequentially or interval administration.
  • the anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and chemotherapy drugs are each administered at intervals.
  • the anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and chemotherapy drugs are administered in the same or different dosage regimens.
  • the anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and chemotherapy drugs are administered in different dosage regimens.
  • the anti-PD-L1 antibody in the use or treatment method, can be used every week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w) ) is applied once. In a specific embodiment, the anti-PD-L1 antibody is administered every 3 weeks. In some embodiments, the anti-PD-L1 antibody is administered at a dose of 600-2400 mg each time.
  • the anlotinib or a pharmaceutically acceptable salt thereof can be administered once a day at a dosage of 6 mg, 8 mg, 10 mg or 12 mg, administered continuously for 2 weeks, followed by a regimen of 1 week off. medication. At this time, every 3 weeks is a dosing cycle.
  • the chemotherapeutic drugs can be administered according to known dosing regimens.
  • the anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and the chemotherapy drug have the same or different administration periods, respectively.
  • the anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof and the chemotherapy drug have the same administration cycle, for example, every 1 week, every 2 weeks, every 3 weeks or every 4 weeks is a dosing cycle.
  • 21 days is a dosing cycle
  • the PD-L1 antibody is administered on the first day of each dosing cycle , administering anlotinib or a pharmaceutically acceptable salt thereof, and chemotherapeutic drugs every day on days 1-14 of each cycle, wherein the chemotherapeutic drugs can be administered according to a known dosage regimen.
  • the PD-L1 antibody is administered once on the first day of each cycle, and anlotinib or a pharmaceutically acceptable salt thereof is administered once a day on days 1-14 of each cycle, and /or carboplatin on day 1 of each cycle, and/or etoposide on days 1, 2, and 3 of each cycle.
  • the anti-PD-L1 antibody may comprise a /kg, 0.1 to 10mg/kg, 1 to 15mg/kg, 1 to 20mg/kg, 1 to 3mg/kg, 3 to 10mg/kg, 3 to 15mg/kg, 3 to 20mg/kg, 3 to 30mg/kg , 10 to 20 mg/kg, or 15 to 20 mg/kg; or 60 mg to 2400 mg, 90 mg to about 1800 mg, 120 mg to 1500 mg, 300 mg to 900 mg, 600 mg to 900 mg, 300 mg to 1200 mg, 600 mg to 1200 mg, or 900 mg Doses up to 1200 mg are administered to patients.
  • 21 days is a dosing cycle
  • 1200 mg of PD-L1 antibody is administered on the first day of each cycle
  • 6 mg is administered every day on the 1st-14th day of each cycle , 8mg, 10mg and/or 12mg of anlotinib.
  • the dosing regimen of the drug combination, or the use or treatment method includes, in repeated cycles, administering anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt, and chemotherapy drugs for the first treatment phase; then, optionally, in repeated cycles, anti-PD-L1 antibody, and anlotinib or a pharmaceutically acceptable salt thereof is administered for the second treatment phase.
  • both the first treatment period and the second treatment period are 21 days as a dosing cycle.
  • the PD-L1 antibody is administered on the first day of each dosing cycle
  • anlotinib or its pharmaceutical form is administered daily on the 1-14th day of each cycle.
  • the chemotherapeutic drugs can be administered according to known dosing regimens.
  • the chemotherapeutic drug is selected from one or more of platinum-based antineoplastic drugs and/or topoisomerase inhibitors.
  • the chemotherapeutic agent is selected from carboplatin and etoposide.
  • the PD-L1 antibody is administered once on the first day of each cycle, and anlotinib or a pharmaceutically acceptable salt thereof is administered once a day on days 1-14 of each cycle, and /or carboplatin on day 1 of each cycle, and/or etoposide on days 1, 2, and 3 of each cycle.
  • the treatment cycle of the first treatment phase is 1 to 10 treatment cycles, preferably 2 to 8 treatment cycles, most preferably 4 treatment cycles.
  • carboplatin is administered with an AUC of 4-7 mg/ml/min, preferably with an AUC of 5-7 mg/ml/min, more preferably with an AUC of 5 mg/ml/min. Dosing.
  • etoposide is administered at a dose of 60-120 mg/m 2 , preferably at a dose of 60-100 mg/m 2 , more preferably at a dose of 100 mg/m 2 .
  • the PD-L1 antibody in the second treatment phase, is administered on the first day of each dosing cycle, and anlotinib or its pharmaceutical drug is administered daily on days 1-14 of each cycle. acceptable salt.
  • the small cell lung cancer includes limited-stage and extensive-stage small cell lung cancer. According to the common sense of those skilled in the art, it can be understood that the term "extensive-stage small cell lung cancer” includes but not limited to untreated (ie, initially treated) extensive-stage small cell lung cancer.
  • the small cell lung cancer is advanced and/or refractory and/or recurrent and/or metastatic small cell lung cancer. In some embodiments, the small cell lung cancer includes sensitive relapsed and/or refractory relapsed small cell lung cancer. In some embodiments, the small cell lung cancer is small cell lung cancer with brain metastases.
  • the small cell lung cancer patient is a small cell lung cancer patient who has received surgery, chemotherapy and/or radiotherapy.
  • the chemotherapy is selected from chemotherapy comprising a platinum-based antineoplastic agent.
  • the platinum-based antitumor drugs include but not limited to cisplatin and carboplatin.
  • the small cell lung cancer is small cell lung cancer that has not received prior systemic therapy. In some embodiments, the small cell lung cancer is small cell lung cancer that has not previously received systemic therapy for extensive-stage small cell lung cancer. In some embodiments, the small cell lung cancer is extensive-stage small cell lung cancer that has not received prior systemic therapy.
  • the small cell lung cancer patient is a patient who has previously received radiation and/or chemotherapy for limited-stage small cell lung cancer.
  • the chemotherapeutic drugs include but are not limited to one or more of platinum-based antitumor drugs, podophyllin, alkylating agents, camptothecins, taxanes, antimetabolites, and antibiotic anti-tumor drugs; Examples that can be cited include, but are not limited to, platinum-based antineoplastic drugs (such as cisplatin, carboplatin, nedaplatin, miplatin, oxaliplatin), etoposide, irinotecan, topotecan, paclitaxel, doxyl One or more of taxel, temozolomide, vinorelbine, gemcitabine, cyclophosphamide, adriamycin, vincristine, bendamustine, epirubicin, methotrexate, and amrubicin .
  • platinum-based antineoplastic drugs such as cisplatin, carboplatin, nedaplatin, miplatin, oxalip
  • the components in the pharmaceutical composition of the present application can be administered independently, or some or all of them can be administered in suitable various ways, including but not limited to oral or parenteral (by intravenous, intramuscular, topical or subcutaneous route) ) application.
  • the components of the pharmaceutical combination of the present application can be administered independently or part or all of them together orally or by injection, such as intravenous injection or intraperitoneal injection.
  • the components in the pharmaceutical composition of the present application can be each independently, or some or all of them are suitable dosage forms together, including but not limited to tablets, buccal tablets, pills, capsules (such as hard capsules, soft capsules, enteric capsules, etc.) capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and for oral or parenteral administration
  • suitable dosage forms together including but not limited to tablets, buccal tablets, pills, capsules (such as hard capsules, soft capsules, enteric capsules, etc.) capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and for oral or parenteral administration
  • suitable dosage forms together including but not limited to tablets, buccal
  • the components in the pharmaceutical combination of the present application may each independently, or part or all of them jointly contain pharmaceutically acceptable carriers and/or excipients.
  • the pharmaceutical combinations of the present application may also contain additional therapeutic agents.
  • the additional therapeutic agent may be a small cell cancer therapeutic known in the art.
  • the dosing regimen includes a first treatment phase, optionally a second treatment phase.
  • the dosage regimen described in the present application is also applicable to the use of the medicine for treating small cell lung cancer in a patient, the method for treating small cell lung cancer in a patient, and the use for treating small cell lung cancer in a patient described in this application.
  • the first treatment period includes 1-10 treatment cycles, preferably 2-8 treatment cycles, most preferably 4 treatment cycles.
  • the second treatment period comprises 2-20 treatment cycles. In some embodiments, the second treatment period continues until the clinical benefit is lost or the toxicity is intolerable or the efficacy evaluation is PD or the investigator considers it inappropriate to continue the drug.
  • the treatment cycle is 14 days to 42 days; in some embodiments, the treatment cycle is 14 days, 21 days, 28 days, 35 days or 42 days; in some embodiments In, the treatment cycle is 21 days.
  • the first treatment period has the same treatment period as the second treatment period.
  • the treatment cycles (eg, a single treatment cycle) of the first treatment period and the second treatment period are both 21 days.
  • the dosing regimen of the first treatment stage includes: 1) anti-PD-L1 antibody is administered once a day within days 1-7 of each treatment cycle; and 2) Anluo Tini or a pharmaceutically acceptable salt thereof is administered continuously on days 1-28 of each treatment cycle; optionally, 3) platinum-based antineoplastic drugs are given on one day within days 1-7 of each treatment cycle and optionally, 4) the topoisomerase inhibitor is administered continuously on days 1-7 of each treatment cycle.
  • every 21 days is a treatment cycle
  • the dosing regimen of the first treatment phase includes: 1) the anti-PD-L1 antibody is administered once on the first day of each treatment cycle; and 2) anlotinib Cosmeticlin or a pharmaceutically acceptable salt thereof is administered continuously on the 1st-14th day of each treatment cycle; optionally, 3) platinum-based antineoplastic drugs are administered once on the 1st day of each treatment cycle; optionally Alternatively, 4) the topoisomerase inhibitor is administered continuously on days 1-3 of each cycle.
  • the dosing regimen of the first treatment stage includes: 1) the anti-PD-L1 antibody is administered once a day within days 1-7 of each treatment cycle; and 2) anlotinib Cosmeticlin or a pharmaceutically acceptable salt thereof is administered continuously on days 1-28 of each treatment cycle; and 3) platinum-based antineoplastic drugs are administered once a day within days 1-7 of each treatment cycle; and 4) Topoisomerase inhibitors are administered continuously on the first 1-7 days of each treatment cycle.
  • every 21 days is a treatment cycle
  • the dosing regimen of the first treatment phase includes: 1) the anti-PD-L1 antibody is administered once on the first day of each treatment cycle; and 2) Anlotinib or a pharmaceutically acceptable salt thereof is administered continuously on days 1-14 of each treatment cycle; and 3) platinum-based antineoplastic drugs are administered once on day 1 of each treatment cycle; and 4 ) Topoisomerase inhibitors are administered continuously on days 1-3 of each cycle.
  • the dosing regimen of the first treatment stage includes: 1) the anti-PD-L1 antibody hu5G11-hIgG1 is given once on the first day of each treatment cycle; Hydrochloride is administered continuously on days 1-14 of each treatment cycle; and 3) platinum-based antineoplastic drugs are administered once on day 1 of each treatment cycle; and 4) topoisomerase inhibitors are administered once on day 1 of each treatment cycle The first 1-3 days of each cycle are administered continuously.
  • the dosing regimen of the first treatment stage includes: 1) the anti-PD-L1 antibody hu5G11-hIgG1 is given once on the first day of each treatment cycle; Hydrochloride was administered continuously on days 1-14 of each treatment cycle; and 3) carboplatin was administered once on day 1 of each treatment cycle; and 4) etoposide was administered once on days 1-14 of each cycle. 3 consecutive days of administration.
  • the dosing regimen of the second treatment stage includes: 1) the anti-PD-L1 antibody is administered once a day within the 1st-7th day of each treatment cycle; optionally, 2 ) Anlotinib or a pharmaceutically acceptable salt thereof is administered continuously on days 1-28 of each treatment cycle.
  • the dosage regimen of the second treatment stage includes: 1) anti-PD-L1 antibody is administered once on the first day of each treatment cycle; and 2) anlotinib or its The pharmaceutically acceptable salt is administered continuously on the 1st-14th day of each treatment cycle.
  • the dosage regimen of the second treatment stage includes: 1) the anti-PD-L1 antibody hu5G11-hIgG1 is administered once on the first day of each treatment cycle; 2) Anlotinib Dihydrochloride was administered continuously on days 1-14 of each treatment cycle.
  • the anti-PD-L1 antibody is administered once on the 1st, 2nd, 3rd, 4th, 5th, 6th, or 7th day of each treatment cycle, preferably on the 1st day of each treatment cycle. 1 dose once a day.
  • the anlotinib or a pharmaceutically acceptable salt thereof is administered on day 1-7, day 7-14, day 1-14, or day 7 of each treatment cycle. - Continuous administration for 21 days, preferably on days 1-14 of each treatment cycle.
  • the platinum-based antineoplastic drug is administered once on the 1st, 2nd, 3rd, 4th, 5th, 6th, or 7th day of each treatment cycle, preferably on the 1st day of each treatment cycle. 1 dose once a day.
  • the topoisomerase inhibitor is administered on days 1-3, days 1-4, days 1-5, days 1-6, days 1- 7 days, 2-4 days, 2-5 days, 2-6 days, 2-7 days, 3-5 days, 3-6 days, 3-7 days, 4-6 days , day 4-7, or day 5-7, preferably on day 1-3 of each treatment cycle.
  • the drug combination of the application can safely and effectively treat small cell lung cancer.
  • the drug combination of the present application can safely and effectively treat extensive-stage small cell lung cancer.
  • the drug combination of the present application can provide treatment with higher tolerance in patients, and its anti-tumor effect is better than that of any drug or any two drugs in the combination alone, and/or or fewer adverse reactions and/or complications.
  • the drug combination of the present application exhibits a more excellent anti-tumor synergistic effect in the treatment of small cell lung cancer.
  • the median PFS progression-free survival period
  • median OS progression-free survival period
  • OS median OS of the patient
  • the median OS of the patients are significantly prolonged (overall survival).
  • the median PFS of the patients reaches 5-10 months; in some specific embodiments, the median PFS of the patients even exceeds 10 months.
  • the median OS of the patients reaches 13-20 months; in some specific embodiments, the median OS of the patients even exceeds 20 months.
  • the objective response rate (ORR) and disease control rate (DCR) of the patient are significantly improved.
  • a 57-year-old patient clinically diagnosed as extensive-stage small cell lung cancer in the right lower lung, accompanied by double hilar, mediastinal, double supraclavicular lymph nodes, and right middle lobe metastasis, received the anti-inflammatory drug described in the present application.
  • the target lesion The sum of (right lower lobe mass lesion, lung middle lobe mass lesion and left hilar lymph node) was 21mm, which was reduced by 65%.
  • the overall curative effect evaluation was partial response (PR).
  • PR partial response
  • the patient continued to receive the above regimen for 2 cycles, and then received anti-PD-L1 antibody hu5G11-hIgG1 injection and anlotinib hydrochloride capsules for maintenance treatment.
  • the target lesions further shrunk or disappeared, and the efficacy evaluation continued to be partial response (PR ).
  • the progression-free survival (PFS) was more than 27 months, and the patient was still receiving treatment.
  • a 69-year-old patient clinically diagnosed as small cell lung cancer of the left lower lung, with metastasis of the left lower lung hilum and left lower lobe, received the anti-PD-L1 antibody hu5G11-hIgG1 injection described in this application, After 2 cycles (42 days, every 3 weeks as a treatment cycle) of the research protocol of Anlotinib Hydrochloride Capsules, Carboplatin Injection and Etoposide Injection, the target lesions (including: left lower hilar mass lesions, mediastinum The sum of lymph nodes and left lower pulmonary nodular lesions) was 21mm, shrinking by 79.4%, and the overall curative effect evaluation was partial response (PR).
  • PR partial response
  • the patient continued to receive the above regimen for 2 cycles, and then received anti-PD-L1 antibody hu5G11-hIgG1 injection and anlotinib hydrochloride capsules for maintenance treatment.
  • the target lesions further shrunk or disappeared, and the efficacy evaluation continued to be partial response (PR ), the progression-free survival (PFS) of the patients exceeded 20 months.
  • PR partial response
  • PFS progression-free survival
  • a 55-year-old patient is clinically diagnosed as left hilar small cell lung cancer with mediastinal lymph node and bone metastasis.
  • the research program was treated for 2 cycles (42 days, every 3 weeks for After one treatment cycle), the sum of the target lesions (including: left pulmonary hilar mass lesions, mediastinal lymph nodes) was 41mm, shrinking by 39.7%, and the overall curative effect evaluation was partial response (PR).
  • the patient continued to receive the above regimen for 2 cycles, and then received anti-PD-L1 antibody hu5G11-hIgG1 injection and anlotinib hydrochloride capsules for maintenance treatment.
  • the target lesions further shrunk or disappeared, and the efficacy evaluation continued to be partial response (PR ).
  • PR partial response
  • the progression-free survival (PFS) was more than 26 months, and the patients were still receiving treatment.
  • the amount of anlotinib or a pharmaceutically acceptable salt thereof refers to the amount of the active ingredient anlotinib free base.
  • dose refers to the dose administered to a patient regardless of the patient's weight or body surface area (BSA).
  • BSA body surface area
  • a 60kg person and a 100kg person will receive the same dose of antibody (eg, 240mg anti-PD-1 antibody).
  • the term "pharmaceutical combination” refers to two or more active ingredients administered simultaneously or sequentially (administered in the form of the respective active ingredients themselves, or in the form of their respective pharmaceutically acceptable salts or esters, etc. administration in the form of derivatives, prodrugs or compositions).
  • the active substances may be administered to the subject simultaneously, each as a single formulation, or sequentially, each as a single formulation, in any order.
  • antibody refers to a binding protein having at least one antigen binding domain.
  • Antibodies and fragments thereof of the present application may be whole antibodies or any fragments thereof. Accordingly, the antibodies and fragments of the present application include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof, as well as immunoconjugates. Examples of antibody fragments include Fab fragments, Fab' fragments, F(ab)' fragments, Fv fragments, isolated CDR regions, single chain Fv molecules (scFv), Fd fragments, and other antibody fragments known in the art. Antibodies and fragments thereof may also include recombinant polypeptides, fusion proteins and bispecific antibodies.
  • the anti-PD-L1 antibodies and fragments thereof disclosed herein can be of the IgG1, IgG2, IgG3 or IgG4 isotype.
  • the term "isotype" refers to the antibody class encoded by the heavy chain constant region genes.
  • the anti-PD-L1 antibodies and fragments thereof disclosed herein are of the IgG1 or IgG4 isotype.
  • the PD-L1 antibodies and fragments thereof of the present application may be derived from any species, including but not limited to mice, rats, rabbits, primates, llamas and humans.
  • PD-L1 antibodies and fragments thereof can be chimeric antibodies, humanized antibodies or fully human antibodies.
  • the anti-PD-L1 antibody is an antibody produced by a hybridoma cell line derived from mice.
  • the anti-PD-L1 antibody is a murine antibody.
  • the anti-PD-L1 antibody is a chimeric antibody.
  • the chimeric antibody is a mouse-human chimeric antibody.
  • the antibody is a humanized antibody.
  • the antibody is derived from a murine antibody and is humanized.
  • a “humanized antibody” is an antibody that contains complementarity determining regions (CDRs) derived from a non-human antibody; and framework and constant regions derived from a human antibody.
  • the anti-PD-L1 antibodies provided herein can comprise CDRs derived from one or more murine antibodies as well as human framework and constant regions.
  • a humanized antibody provided herein binds to the same epitope on PD-L1 as the murine antibody from which the CDRs of the antibody are derived.
  • Exemplary humanized antibodies are provided herein. Additional anti-PD-L1 antibodies or variants thereof comprising the heavy and light chain CDRs provided herein can be generated using any human framework sequences and are also encompassed in this application.
  • framework sequences suitable for use in the present application include those framework sequences that are structurally similar to the framework 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 revert mutations to residues in the original germline sequence. In some embodiments, such modifications include those corresponding to mutations exemplified herein, including back mutations to germline sequences. For example, in one embodiment, one or more amino acids in the human framework regions of the VH and/or VL of the humanized antibodies provided herein are backmutated to the corresponding amino acid in the parental murine antibody.
  • amino acids at positions 53 and/or 60 and/or 67 of the light chain variable region are backmutated to the corresponding amino acids found at said positions in the mouse 5G11 or 13C5 light chain variable region. amino acid.
  • amino acids at positions 24 and/or 28 and/or 30 and/or 49 and/or 73 and/or 83 and/or 94 of the heavy chain variable region are backmutated to be in mouse 5G11 or the corresponding amino acid found at said position in the 13C5 heavy chain variable region.
  • the humanized 5G11 antibody comprises a light chain variable region in which the amino acid at position 60 is mutated from Ser(S) to Asp(D), and the amino acid at position 67 is mutated from Ser(S) is Tyr (Y); and the heavy chain variable region, wherein the amino acid at position 24 is mutated from Phe (F) to Val (V), and the amino acid at position 49 is mutated from Ala (A) to Gly (G), The amino acid at position 73 was mutated from Thr(T) to Asn(N), and the amino acid at position 83 was mutated from Thr(T) to Asn(N).
  • the humanized 13C5 antibody comprises a light chain variable region in which the amino acid at position 53 is mutated from Tyr (Y) to Lys (K); and a heavy chain variable region in which the amino acid at position 28 is the amino acid is mutated from Thr (T) to Ile (I), the amino acid at position 30 is mutated from Ser (S) to Arg (R), the amino acid at position 49 is mutated from Ser (S) to Ala (A), and The amino acid at position 94 was mutated from Tyr (Y) to Asp (D). Additional or alternative backmutations can be made in the framework regions of the humanized antibodies provided herein to improve the properties of the antibodies.
  • the present application also includes humanized antibodies that bind PD-L1 and that comprise framework modifications corresponding to the exemplary modifications described herein with respect to any suitable framework sequence, as well as otherwise improving antibodies Additional framework decorations for features.
  • the application provides an isolated antibody or fragment thereof that binds PD-L1, wherein said antibody is produced by a hybridoma selected from the group consisting of hybridomas referred to herein as 13C5, 5G11. Accordingly, the present application also includes hybridomas 13C5, 5G11, and any hybridoma that produces an antibody disclosed herein.
  • the application also provides isolated polynucleotides encoding the antibodies and fragments thereof provided herein.
  • the present application also includes expression vectors comprising the isolated polynucleotides, and host cells comprising the expression vectors.
  • Isolated antibody means an antibody that is substantially free of other antibodies that have a different antigen specificity (e.g., an isolated antibody that specifically binds PD-1 is substantially free of antibodies that specifically bind other than PD-1). Antibodies to antigens). However, an isolated antibody that specifically binds PD-1 may have cross-reactivity with other antigens, such as PD-1 molecules from different species. Furthermore, an isolated antibody can be substantially free of other cellular material and/or chemicals.
  • mAb refers to an antibody molecule of single molecular composition (i.e., an antibody molecule whose basic sequence is substantially identical and which exhibits a single binding specificity and affinity for a particular epitope ) non-naturally occurring preparations.
  • a mAb is an example of an isolated antibody.
  • mAbs can be produced by hybridoma, recombinant, transgenic or other techniques known to those skilled in the art.
  • the antibodies and antigen-binding fragments thereof disclosed herein are specific for PD-L1.
  • the antibody or fragment thereof is specific for PD-L1.
  • the antibodies and fragments provided herein bind human or primate PD-L1, but do not bind PD-L1 from any other mammal.
  • the antibody or fragment thereof does not bind mouse PD-L1.
  • the terms "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. "Specific for” means that the antibody and fragments thereof bind PD-L1 with greater affinity than any other target.
  • 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 side effects due to the disease.
  • treatment encompasses any treatment of a disease in a patient, including: (a) inhibiting the symptoms of the disease, ie arresting its development; or (b) relieving the symptoms of the disease, ie causing regression of the disease or symptoms.
  • the term "effective amount” means (i) treating a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) delaying any of the symptoms described herein
  • the amount of a compound of the application for the onset of one or more symptoms of a particular disease, condition or disorder may vary depending on factors such as the individual's disease state, age, sex, and weight, and the effect of the therapeutic agent or combination of therapeutic agents on the individual. Ability to answer required. Effective amounts can also be routinely determined by those skilled in the art based on their own knowledge and this disclosure.
  • administration or “administration” are used interchangeably to refer to the physical introduction into a subject of a composition comprising a therapeutic agent using any of a variety of methods and delivery systems known to those skilled in the art.
  • Routes of administration of immune checkpoint inhibitors include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, such as by injection or infusion .
  • parenteral administration refers to modes of administration other than enteral and topical administration, usually by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, Intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injections and infusions, and in vivo electroporation.
  • the immune checkpoint inhibitor eg, anti-PD-1 antibody or anti-PD-L1 antibody
  • non-parenteral routes include topical, epidermal or mucosal routes of administration, eg, intranasally, vaginally, rectally, sublingually or topically. Administration can also be performed, eg, once, multiple times, and/or over one or more extended periods of time.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts of alkali ions and free acids or salts of acid ions and free bases including, for example, hydrochloride, hydrobromide, nitrate, sulfate, phosphate, formazan salt, acetate, trifluoroacetate, fumarate, oxalate, maleate, citrate, succinate, methanesulfonate, benzenesulfonate or p-toluenesulfonate Acid salts, preferably hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, methanesulfonate, p-toluenesulfonate salt, sodium salt, potassium salt, ammonium salt, amino acid salt, etc.
  • the molar ratio of the free acid to the base ion is about 1:0.5 to 1:5, preferably 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7 or 1:8.
  • the molar ratio of the free base to the acid radical ion is about 1:0.5 to 1:5, preferably 1:0.5, 1:1, 1:2, 1 :3, 1:4, 1:5, 1:6, 1:7 or 1:8.
  • the term “subject” or “patient” is used interchangeably herein.
  • the term “subject” or “patient” is a mammal.
  • the subject or patient is a mouse.
  • the subject or patient is a human.
  • “combination” or “combined use” means that two or more active substances may be administered to a patient each as a single formulation simultaneously, or each as a single formulation sequentially in any order.
  • single dose refers to the smallest packaging unit containing a certain amount of medicine.
  • a box of medicine has seven capsules, and each capsule is a single dose; or each bottle of injection is a single dose.
  • multiple dose consists of a number of single doses.
  • fixed combination means that the active components (such as anti-PD-L1 antibody and anlotinib) are simultaneously administered to patients in a fixed total dose or dose ratio, or in the form of a single entity, pharmaceutical composition or preparation.
  • active components such as anti-PD-L1 antibody and anlotinib
  • non-fixed combination refers to the simultaneous, concurrent or sequential administration of two or more active ingredients to a patient as separate entities (e.g. pharmaceutical composition, formulation) without specific time limitation, wherein the active ingredients administered to the patient achieve a therapeutic effect. effective level.
  • examples of non-fixed combinations are cocktail therapy, eg administration of 3 or more active ingredients.
  • the individual active ingredients may be packaged, sold or administered as entirely separate pharmaceutical compositions.
  • the "non-fixed combination” also includes the combined use of "fixed combinations" or independent entities of any one or more active components.
  • pharmaceutical composition refers to a mixture of one or more active ingredients of the present application or its pharmaceutical combination and pharmaceutically acceptable excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration of a compound of the present application, or a pharmaceutical combination thereof, to a patient.
  • the anti-PD-L1 antibody in the example was prepared according to the method described in WO2016022630, and after affinity chromatography, the eluate containing the antibody was obtained according to a conventional antibody purification method.
  • Embodiment 1 clinical trial
  • Eligible subjects will be randomly entered into experimental group 1, experimental group 2 or control group. Treatment is divided into an induction therapy phase and a maintenance phase. Efficacy was evaluated every 2 cycles. Patients with disease control (CR+PR+SD) and tolerable adverse reactions can continue to use the drug until the end of the study when the clinical benefit is lost, the toxicity is intolerable, the efficacy evaluation is PD, and the investigator thinks it is not suitable to continue the drug.
  • CR+PR+SD disease control
  • tolerable adverse reactions can continue to use the drug until the end of the study when the clinical benefit is lost, the toxicity is intolerable, the efficacy evaluation is PD, and the investigator thinks it is not suitable to continue the drug.
  • Anti-PD-L1 antibody injection hu5G11-hIgG1 or anti-PD-L1 antibody blank injection 1200 mg or 0 mg anti-PD-L1 antibody injection is diluted to 250 mL with normal saline, and the infusion time is 60 ⁇ 10 minutes. After the infusion is completed, follow the hospital routine Physiological saline flushing is required, and every 21 days is a treatment cycle, and the drug is administered on the first day of each cycle. Specifications: 100mg/10mL, 300mg/10mL.
  • Anlotinib Hydrochloride Capsules (active ingredient is Anlotinib Dihydrochloride) or Anlotinib Hydrochloride Blank Capsules: Take Anlotinib Hydrochloride Capsules (12mg) or Blank Capsules (0mg) on an empty stomach once a day. One tablet at a time, taken orally for 2 consecutive weeks and then stopped for 1 week, that is, 21 days is a treatment cycle, and the drug is administered on the 1st-14th day of each cycle. Specifications: 12mg, 10mg, 8mg.
  • Carboplatin injection dissolve this product with 5% glucose injection, the concentration is 10mg/ml, then add the solution of this concentration to 5% glucose injection 250-500mL for intravenous infusion, every 21 days is a treatment cycle, Dose on day 1 of each cycle.
  • Dose (mg) 5(AUC)(mg/mL/min) ⁇ [creatinine clearance rate (mL/min)+25 within 7 days before medication).
  • Etoposide injection After calculating the dosage by the calculation formula, dilute this product with sodium chloride injection, the concentration per milliliter should not exceed 0.25 mg, every 21 days is a treatment cycle, and the first, second, and third days of each cycle Continuous dosing. Dose: 100 mg/m 2 .
  • Treatment is divided into an induction treatment phase (ie, the first treatment phase) and a maintenance phase (ie, the second treatment phase).
  • the first treatment phase consists of 4 treatment cycles:
  • Test group 1 Every 21 days is a treatment cycle.
  • Anti-PD-L1 antibody injection 1200mg/time, once every 21 days, intravenous infusion;
  • Anlotinib Hydrochloride Capsules 12mg/time, for 2 consecutive weeks and 1 week off, orally;
  • Carboplatin for injection administered on the first day, AUC 5mg/mL/min, intravenous infusion (maximum dosage is 800mg);
  • Etoposide injection administered continuously on the 1st, 2nd, and 3rd day, 100mg/m 2 , intravenous infusion.
  • Test group 2 Every 21 days is a treatment cycle.
  • Anti-PD-L1 antibody blank injection 0mg/time, administered once every 21 days, intravenous infusion;
  • Anlotinib Hydrochloride Capsules 12mg/time, for 2 consecutive weeks and 1 week off, orally;
  • Carboplatin for injection administered on the first day, AUC 5mg/mL/min, intravenous infusion (maximum dosage is 800mg);
  • Etoposide injection administered continuously on the 1st, 2nd, and 3rd day, 100mg/m 2 , intravenous infusion.
  • Control group every 21 days is a treatment cycle.
  • Anti-PD-L1 antibody blank injection 0mg/time, administered once every 21 days, intravenous infusion;
  • Anlotinib hydrochloride blank capsules 0 mg/time, for 2 consecutive weeks and 1 week off, orally;
  • Carboplatin for injection administered on the first day, AUC 5mg/mL/min, intravenous infusion (maximum dosage is 800mg);
  • Etoposide injection administered continuously on the 1st, 2nd, and 3rd day, 100mg/m 2 , intravenous infusion.
  • Test group 1 Every 21 days is a treatment cycle.
  • Anti-PD-L1 antibody injection 1200mg/time, once every 21 days, intravenous infusion;
  • Anlotinib Hydrochloride Capsules 12mg/time, for 2 consecutive weeks and 1 week off, orally;
  • Experimental group 2 Every 21 days is a treatment cycle.
  • Anti-PD-L1 antibody blank injection 0mg/time, administered once every 21 days, intravenous infusion;
  • Anlotinib Hydrochloride Capsules 12mg/time, for 2 consecutive weeks and 1 week off, orally;
  • Control group every 21 days is a treatment cycle.
  • Anti-PD-L1 antibody blank injection 0mg/time, administered once every 21 days, intravenous infusion;
  • Anlotinib Hydrochloride Blank Capsules 0 mg/time, for 2 consecutive weeks and 1 week off, orally.
  • PFS progression-free survival
  • OS overall survival
  • ORR objective response rate
  • DCR CR + PR + stable disease
  • PFS progression-free survival
  • OS overall survival
  • DOR duration of response
  • AEs adverse events
  • SAEs serious adverse events
  • the regimens in the experimental group 1 and experimental group 2 are expected to achieve significant clinical benefits.
  • the improvement of the current overall efficacy data indicates that the median PFS of the subjects receiving the regimen in the trial group 1 has been significantly improved; the median OS is expected to exceed 14 months. It shows that anti-PD-L1 antibody combined with anlotinib or its pharmaceutically acceptable salt and chemotherapy drugs can be used as a more effective first-line treatment for small cell lung cancer, especially for extensive stage small cell lung cancer.

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Abstract

提供了治疗小细胞肺癌的药物组合，其包括抗PD-L1抗体、安罗替尼或其药学上可接受的盐和化疗药物。还提供了含抗PD-L1抗体、安罗替尼或其药学上可接受的盐和化疗药物的药物组合物或试剂盒在制备用于治疗小细胞肺癌的药物中的用途。还提供了治疗小细胞肺癌的方法，向有需要的患者给予治疗有效量的抗PD-L1抗体、安罗替尼或其药学上可接受的盐、和化疗药物。

Description

治疗小细胞肺癌的药物组合 技术领域
本申请属于生物医药领域，涉及治疗小细胞肺癌的药物组合、试剂盒及其用途。
背景技术
酪氨酸激酶是一组催化蛋白质酪氨酸残基磷酸化的酶，在细胞内的信号转导中起着重要的作用，它参与正常细胞的调节、信号传递和发育，也与肿瘤细胞的增殖、分化、迁移和凋亡密切相关。许多受体酪氨酸激酶都与肿瘤的形成相关，根据其细胞外区域结构的不同可分为表皮生长因子受体(EGFR)、血小板衍化生长因子受体(PDGFR)、血管内皮细胞生长因子受体(VEGFR)、成纤维细胞生长因子受体(FGFR)等等。
PD-L1(Programmed death-ligand l)又称为CD247和B7-H1，是程序性死亡分子l(Programmed death,PD-1)的一个配体。PD-L1在多种肿瘤细胞表面高表达，而且肿瘤的恶性程度以及不良预后与PD-L1的表达水平密切相关。在肿瘤微环境中，癌症细胞表面的PD-L1通过与T细胞表面的PD-1或CD80的结合，抑制T细胞的激活和增殖，促进效应T细胞进入衰竭或无反应状态，诱导T细胞的凋亡，刺激辅助T细胞分化成为调节性T细胞，从而阻止T细胞对肿瘤细胞的杀伤作用。抗PD-L1抗体可以通过阻断PD-L1与PD-1及CD80的相互作用，使得相关的负调控信号不能被启动与传导，从而避免了在肿瘤微环境中的效应T细胞的活性被抑制，使T细胞可以发挥杀伤和抑制肿瘤细胞的功能。由于抗PD-L1抗体能够直接作用于肿瘤组织，因而具有较高的特异性和安全性。
小细胞肺癌(small cell lung cancer,SCLC)是肺癌中恶性程度最高的一种类型，具有进展快、转移早、易复发等特点，约占新发肺癌15％-20％，其发生与长期吸烟有密切关系；SCLC侵袭性高，预后较差，5年生存率不足5％，不治疗的患者平均生存期仅2-4个月。同其它类型肺癌相比，SCLC对化疗和放疗比较敏感，依托泊苷联合铂类抗肿瘤药物是治疗广泛期SCLC标准的一线治疗方案，但多数患者在3个月内出现病情进展，并且还存在高复发率和耐药率，因此在治疗方面仍然面临诸多挑战。
WO2016022630公开了一类PD-L1抗体，对PD-L1具有较高的亲和力，能够显著抑制细胞表面的PD-L1和PD-1的相互作用，并显著促进T细胞分泌IL-2和INF-γ。
尽管对增殖性疾病(癌症)患者而言有许多治疗选择，仍需要更为有效的治疗剂以供临床使用，尤其是一种以上药物的组合使用。
发明内容
一方面，本申请提供用于治疗小细胞肺癌的药物组合，其包括抗PD-L1抗体、安罗替尼或其药学上可接受的盐、以及进一步包括化疗药物。
进一步地，所述抗PD-L1抗体包含如下氨基酸序列：与SEQ ID NO:1或SEQ ID NO:4所示的氨基酸序列有至少80％同源性的重链CDR1区；与SEQ ID NO:2或SEQ ID NO:5所示的氨基酸序列有至少80％同源性的重链CDR2区；与SEQ ID NO:3或SEQ ID NO:6所示的氨基酸序列有至少80％同源性的重链CDR3区；与SEQ ID NO:7或SEQ ID NO:10所示的氨基酸序列有至少80％同源性的轻链CDR1区；与SEQ ID NO:8或SEQ ID NO:11所示的氨基酸序列有至少80％同源性的轻链CDR2区；与SEQ ID NO:9或SEQ ID NO:12所示的氨基酸序列有至少80％同源性的轻链CDR3区。更进一步地，抗PD-L1抗体包含如下氨基酸序列：选自SEQ ID NO:1或SEQ ID NO:4的重链CDR1区；选自SEQ ID NO:2或SEQ ID NO:5的重链CDR2区；选自SEQ ID NO:3或SEQ ID NO:6的重链CDR3区；选自SEQ ID NO:7或SEQ ID NO:10的轻链CDR1区；选自SEQ ID NO:8或SEQ ID NO:11的轻链CDR2区；选自SEQ ID NO:9或SEQ ID NO:12的轻链CDR3区。更进一步地，所述抗PD-L1抗体包含：具有以SEQ ID NO:1示出的氨基酸序列的重链CDR1区，具有以SEQ ID NO:2示出的氨基酸序列的重链CDR2区，具有以SEQ ID NO:3示出的氨基酸序列的重链CDR3区；以及具有以SEQ ID NO:7示出的氨基酸序列的轻链CDR1区，具有以SEQ ID NO:8示出的氨基酸序列的轻链CDR2区，具有以SEQ ID NO:9示出的氨基酸序列的轻链CDR3区。更进一步地，抗PD-L1抗体包含如下氨基酸序列：与SEQ ID NO:13或SEQ ID NO:14所示的氨基酸序列有至少80％同源性的重链可变区；与SEQ ID NO:15或SEQ ID NO:16所示的氨基酸序列有至少80％同源性的轻链可变区。更进一步 地，所述抗PD-L1抗体包含：选自hu13C5-hIgG1、hu13C5-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4人源化抗体的可变重链，和选自hu13C5-hIgG1、hu13C5-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4人源化抗体的可变轻链。
进一步地，所述化疗药物选自铂类抗肿瘤药物和拓扑异构酶抑制剂中的一种或多种。在一些实施方案中，所述铂类抗肿瘤药物包括但不限于顺铂、卡铂、奈达铂、双环铂(dicycloplatin)、吡铂(picoplatin)、奥沙利铂、米铂或洛铂中的一种或者多种。在一些具体实施方案中，所述铂类抗肿瘤药物选自卡铂、顺铂、奈达铂、吡铂、米铂或洛铂中的一种或者多种。在一些具体实施方案中，所述铂类抗肿瘤药物选自卡铂。在一些具体实施方案中，所述铂类抗肿瘤药物选自顺铂。在一些实施方案中，所述拓扑异构酶抑制剂包括但不限于拓扑异构酶I抑制剂、拓扑异构酶II抑制剂、拓扑异构酶I/II双重抑制剂；在一些实施方案中，所述的拓扑异构酶抑制剂选自拓扑异构酶II抑制剂。在一些实施方案中，所述拓扑异构酶抑制剂包括但不限于喜树碱、托泊替康、阿霉素、柔红霉素、表柔比星、伊达比星、米托蒽醌、伊立替康、拓扑替康、依托泊苷、或替尼泊苷中的一种或者多种。在一些实施方案中，所述拓扑异构酶抑制剂为选自托泊替康、阿霉素、表柔比星、米托蒽醌、伊立替康、拓扑替康或依托泊苷中的一种或者多种。在一些具体实施方案中，所拓扑异构酶抑制剂选自依托泊苷。在一些实施方案中，所述化疗药物选自铂类抗肿瘤药物和依托泊苷。在一些实施方案中，所述化疗药物选自卡铂和拓扑异构酶抑制剂。在一些实施方案中，所述化疗药物包括：选自卡铂、顺铂、奈达铂、吡铂、米铂或洛铂中的一种或者多种；以及选自托泊替康、阿霉素、表柔比星、米托蒽醌、伊立替康、拓扑替康或依托泊苷中的一种或者多种。在一些实施方案中，所述化疗药物选自卡铂和依托泊苷。
在一些实施方案中，所述的药物组合还进一步包括药学上可接受的载体。
另一方面，本申请提供用于治疗小细胞肺癌的药物组合，其包括第一药物组合，以及任选地，第二药物组合。在一些实施方案中，所述药物组合包括在第一治疗阶段向有需要的患者给予的第一药物组合，以及任选地，在第二治疗阶段向有需要的患者给予的第二药物组合。在一些实施方案中，所述第一治疗阶段的治疗周期为1到10个治疗周期，优选2到8个治疗周期，最优选4个治疗周期。
在一些实施方案中，所述第一药物组合包括抗PD-L1抗体、安罗替尼或其药学上可接受的盐、和化疗药物。
在一些实施方案中，所述第二药物组合包括抗PD-L1抗体、和安罗替尼或其药学上可接受的盐。
在一具体实施方案中，所述药物组合包括在第一治疗阶段向有需要的患者给予的第一药物组合，以及任选地，在第二治疗阶段向有需要的患者给予的第二药物组合，所述第一药物组合包括抗PD-L1抗体、安罗替尼或其药学上可接受的盐、和化疗药物，所述第二药物组合包括抗PD-L1抗体、和安罗替尼或其药学上可接受的盐。在一些实施方案中，所述第一治疗阶段的治疗周期为1到10个治疗周期，优选2到8个治疗周期，最优选4个治疗周期。
在一些实施方案中，所述的药物组合还进一步包括药学上可接受的载体。
在一些实施方案中，对于本申请所述的含抗PD-L1抗体、安罗替尼或其药学上可接受的盐和化疗药物的药物组合，其中所述抗PD-L1抗体、安罗替尼或其药学上可接受的盐和化疗药物各自呈药物组合物的形式，可同时、先后或依次给药。在一些实施方案中，所述药物组合包括抗PD-L1抗体的药物组合物、安罗替尼或其药学上可接受的盐的药物组合物、和化疗药物的药物组合物。
进一步地，本申请的上述药物组合包装于同一试剂盒中，所述试剂盒还包括治疗小细胞肺癌的说明。
在一些实施方案中，本申请提供的用于治疗小细胞肺癌的试剂盒，其包括：抗PD-L1抗体、安罗替尼或其药学上可接受的盐、和化疗药物。在一些实施方案中，抗PD-L1抗体包含在第一隔室中，安罗替尼或其药学上可接受的盐包含在第二隔室中，化疗药物包含在其他隔室中，可选地根据化疗药物的种类可视情况增加试剂盒中隔室的数量，可同时、先后或者依次序给予有需要的患者。在一些实施方案中，该试剂盒进一步包含抗PD-L1抗体、安罗替尼或其药学上可接受的盐和化疗药物联合使用治疗小细胞肺癌的说明。在一些实施方案中，所述试剂盒包括：抗PD-L1抗体的药物组合物；和安罗替尼或其药学上可接受的盐的药物组合物；和化疗药物的药物组合物。
进一步地，上述试剂盒为适用于在单个治疗周期(例如21天的一个治疗周期)内施用的试剂盒，包括含600～2400mg的抗PD-L1抗体的药物组合物和含84～168mg安罗替尼的药物组合物。在一些实施方案中，每1周、每2周、每3周、或者每4周为一个治疗周期。
给予抗PD-L1抗体的量可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄和健康状态来确定。例如，给予抗PD-L1抗体的日剂量可为600～2400mg，在一些实施方案中，给予抗PD-L1抗体的日剂量可为600、800、1000、1200、1400、1600、1800、2000、2200或2400mg。在一些实施方案中，抗PD-L1抗体以胃肠外给药的方式给药。在一些实施方案中，抗PD-L1抗体以静脉内给药的方式给药。在一些实施方案中，抗PD-L1抗体的药物组合物的浓度为10～60mg/mL。在一些实施方案中，抗PD-L1抗体的药物组合物的浓度为10、20、30、40、50或者60mg/mL。
抗PD-L1抗体的给药方案可根据药物的活性、毒性以及患者的耐受性等来综合确定。在一些实施方案中，抗PD-L1抗体每1周、每2周、每3周、或者每4周为一个治疗周期。在一些实施方案中，抗PD-L1抗体每周、每2周、每3周、或者每4周施用一次。在一些实施方案中，在每个治疗周期抗PD-L1抗体的剂量为600～2400mg。在一些具体实施方案中，每个治疗周期抗PD-L1抗体的剂量为1200mg。在一些实施方案中，所述抗PD-L1抗体每3周给药一次，每次以600～2400mg的剂量施用。在一些实施方案中，所述安罗替尼或其药学上可接受的盐以6mg、8mg、10mg或者12mg的日剂量，连续用药2周，停1周的给药方案给药。
在一些实施方案中，本申请所述的含抗PD-L1抗体、安罗替尼或其药学上可接受的盐、和化疗药物的药物组合包括抗PD-L1抗体的药物组合物和安罗替尼的药物组合物，其中抗PD-L1抗体的药物组合物被制备为适合第一次给药时向患者给予600～2400mg的抗PD-L1抗体的单位剂量或多剂量，所述安罗替尼或其药学上可接受的盐的药物组合物被制备为适合连续14天，每天向患者给予6mg、8mg、10mg和/或12mg安罗替尼或其药学上可接受的盐的单位剂量。
在一些实施方案中，本申请所述的含抗PD-L1抗体、安罗替尼或其药学上可接受的盐、和化疗药物的药物组合包括：抗PD-L1抗体浓度为10～60mg/mL的抗PD-L1抗体的药物组合物，和单位剂量为6mg、8mg、10mg和/或12mg安罗替尼或其药学上可接受的盐的药物组合物。
在一些实施方案中，本申请所述的含抗PD-L1抗体、安罗替尼或其药学上可接受的盐、和化疗药物的药物组合包括：1200mg的抗PD-L1抗体以多剂量形式提供的药物组合物，和单位剂量为8mg、10mg和/或12mg安罗替尼或其药学上可接受的盐的药物组合物。
进一步地，本申请所述的含抗PD-L1抗体、安罗替尼或其药学上可接受的盐、和化疗药物的药物组合为适用于在单个治疗周期(例如21天的一个治疗周期)内施用的制剂，包括含600～2400mg的抗PD-L1抗体的药物组合物和含84～168mg安罗替尼的药物组合物。在一些实施方式中，本申请所述的适用于在单个治疗周期(例如21天的一个治疗周期)内施用的制剂还包括：含90mg～1800mg、优选150mg～1800mg的依托泊苷的药物组合物。在一些实施方式中，本申请所述的适用于在单个治疗周期(例如21天的一个治疗周期)内施用的制剂还包括：含50～800mg的卡铂的药物组合物。
进一步地，本申请所述的含抗PD-L1抗体、安罗替尼或其药学上可接受的盐、和化疗药物的药物组合包括重量比为(0.35-29):1、优选(3.5-29):1、更优选(3.5-14.5):1、最优选(7-14.5):1的抗PD-L1抗体和安罗替尼。其中，抗PD-L1抗体和安罗替尼可分开地包装或者包装在一起。并且其中，安罗替尼能够以多个等份(例如2等份、7等份、14等份、28等份或更多等份)进行包装；抗PD-L1抗体能够以单等份或多个等份(例如2等份、4等份或更多等份)进行包装。在一些实施方案中，本申请所述的药物组合包含抗PD-L1抗体、安罗替尼或其药学上可接受的盐、卡铂和依托泊苷，其中，抗PD-L1抗体、安罗替尼或其药学上可接受的盐、卡铂和依托泊苷的重量比为(300～1200):(42～84):(25～400):(45～900)，例如(300～1200):(42～84):(25～400):(75～900)。优选地，所述卡铂和依托泊苷能够以单等份或多个等份(例如3等份、6等份或更多等份)进行包装。
再一方面，本请还提供本申请的药物组合、或本申请的试剂盒在制备用于治疗患者的小细胞肺癌的药物的用途。或者，本申请还提供治疗小细胞肺癌的方法，包括向有需要的患者给予有效量的本申请的药物组合、或本申请的试剂盒。或者，本申请还提供本申请的药物组合、或本申请的试剂盒用于治疗患者的小 细胞肺癌的用途。或者，本申请还提供用于治疗患者的小细胞肺癌的本申请的药物组合、或本申请的试剂盒。
在一些实施方案中，本申请提供的治疗小细胞肺癌的方法包括向有需要的患者给予治疗有效量的抗PD-L1抗体、安罗替尼或其药学上可接受的盐、和化疗药物。在一些实施方案中，所述治疗方法包括，在第一治疗阶段向有需要的患者给予第一药物组合；以及任选地，在第二治疗阶段向有需要的患者给予第二药物组合。在一些实施方案中，所述第一药物组合包括抗PD-L1抗体、安罗替尼或其药学上可接受的盐、和化疗药物。在一些实施方案中，所述第二药物组合包括抗PD-L1抗体、和安罗替尼或其药学上可接受的盐。
在一些实施方案中，所述第一治疗阶段的治疗周期为1到10个治疗周期，优选2到8个治疗周期，最优选4个治疗周期。
在一些实施方案中，所述化疗药物选自铂类抗肿瘤药物和拓扑异构酶抑制剂中的一种或多种。在一些实施方案中，所述化疗药物选自铂类抗肿瘤药物和依托泊苷。在一些实施方案中，所述化疗药物选自卡铂和依托泊苷。
进一步地，所述抗PD-L1抗体、安罗替尼或其药学上可接受的盐和化疗药物各自呈药物组合物的形式，可同时、顺序或间隔给药。更进一步地，所述抗PD-L1抗体每周、每2周、每3周、或者每4周施用一次；优选地，所述抗PD-L1抗体每次以600～2400mg的剂量施用。更进一步地，所述安罗替尼以每日一次6mg、8mg、10mg或者12mg的剂量，连续用药2周、停1周的给药方案给药。
安罗替尼
如本申请所用，所述安罗替尼的自由碱的化学名为1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺，其具有如下的结构式：
Figure PCTCN2022110539-appb-000001
安罗替尼的药学上可接受的盐包括但不限于安罗替尼与选自以下的酸所形成的盐：盐酸、氢溴酸、硫酸、硝酸、磷酸、乙酸、三氟乙酸、丙酸、己酸、庚酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、对氯苯磺酸、对甲苯磺酸、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、羟基萘甲酸、水杨酸、硬脂酸；在一些实施方案中，所述药学上可接受的盐为盐酸盐和马来酸盐；在一些实施方案中，所述药学上可接受的盐为二盐酸盐。
本申请中涉及的安罗替尼或其药学上可接受的盐的剂量，除非另有说明，均基于安罗替尼游离碱的分子量。
安罗替尼或其药学上可接受的盐可通过多种途径给药，该途径包括经胃肠道给药以及肠胃外给药途径，包括但不限于口服、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、吸入、阴道、眼内、皮下、脂肪内、关节内、腹膜内和鞘内。在一些特定的实施方案中，通过口服给药。给予安罗替尼或其药学上可接受的盐的量可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄和健康状态来确定。例如，给予安罗替尼或其药学上可接受的盐的日剂量可为2毫克至20毫克，在一些实施方案中，给予安罗替尼或其药学上可接受的盐的日剂量可为2、3、4、5、6、7、8、9、10、11、12、13、14、15和16毫克。安罗替尼或其药学上可接受的盐可以每日施用一次或多次。在一些实施方案中，安罗替尼或其药学上可接受的盐以口服固体制剂每天给药一次。
安罗替尼或其药学上可接受的盐的给药方案可根据药物的活性、毒性以及患者的耐受性等来综合确 定。优选地，以间隔给药的方式给予安罗替尼或其药学上可接受的盐。所述的间隔给药包括给药期和停药期，在给药期内可以每天一次或多次给予安罗替尼或其药学上可接受的盐。例如给药期和停药期的以天数计的比值为2:(0.5～5)、2:(0.5～3)、2:(0.5～2)、或者2:(0.5～1)。在一些实施方案中，连续给药2周停药2周。在一些实施方案中，连续给药2周停药1周。在一些实施方案中，连续给药5天停药2天。例如安罗替尼或其药学上可接受的盐可以每日一次6mg、8mg、10mg或者12mg的剂量口服给药，连续用药2周，停1周的给药方式给药。
安罗替尼或其药学上可接受的盐的药物组合物
在本申请的一些实施方案中，所述安罗替尼或其药学上可接受的盐的药物组合物的单位剂量包括6mg、8mg、10mg、或12mg的安罗替尼。
在本申请的一些实施方案中，按照给药2周停1周的治疗周期，每个周期给予所述安罗替尼或其药学上可接受的盐的药物组合物的总剂量包括84～168mg。在部分方案中，所述安罗替尼或其药学上可接受的盐的药物组合物的总剂量包括选自84mg、112mg、140mg、168mg或上述任意值形成的范围。在部分方案中，所述安罗替尼或其药学上可接受的盐的药物组合物的总剂量包括112mg～168mg。
在一些实施方案中，所述药物组合物包括但不限于适合口服、肠道外、局部给药的制剂；在一些实施方案中，所述药物组合物为适合口服的制剂；在一些实施方案中，所述药物组合物为适合口服的固体制剂；在一些实施方案中，所述药物组合物包括但不限于片剂、胶囊。
化疗药物
在本申请的一些实施方案中，所述化疗药物选自铂类抗肿瘤药物和拓扑异构酶抑制剂中的一种或多种。
本申请中，所述铂类抗肿瘤药物包括但不限于顺铂、卡铂、奈达铂、双环铂(dicycloplatin)、吡铂(picoplatin)、奥沙利铂、米铂或洛铂中的一种或者多种。在本申请的一些实施方案中，所述铂类抗肿瘤药物选自卡铂。
本申请中，所述拓扑异构酶抑制剂包括但不限于拓扑异构酶I抑制剂、拓扑异构酶II抑制剂、拓扑异构酶I/II双重抑制剂；在一些实施方案中，所述的拓扑异构酶抑制剂选自拓扑异构酶II抑制剂。在本申请的一些实施方案中，所述拓扑异构酶抑制剂包括但不限于喜树碱、托泊替康、阿霉素、柔红霉素、表柔比星、伊达比星、米托蒽醌、伊立替康、拓扑替康、依托泊苷、或替尼泊苷中的一种或者多种。本申请的一些实施方案中，所拓扑异构酶抑制剂选自依托泊苷。
在本申请的一些实施方案中，所述化疗药物选自铂类抗肿瘤药物和依托泊苷。在一些实施方案中，所述化疗药物选自卡铂和拓扑异构酶抑制剂。在本申请的一些实施方案中，所述化疗药物选自卡铂、和/或依托泊苷。在本申请的一些实施方案中，所述化疗药物选自卡铂和依托泊苷。
在一些实施方案中，卡铂以AUC(药时曲线)为4～7mg/ml/min的剂量给药，优选以AUC为5～7mg/ml/min的剂量给药，进一步优选以AUC为5mg/ml/min的剂量给药。
在一些实施方案中，依托泊苷以60～120mg/m 2的剂量给药，优选以60～100mg/m 2的剂量给药，进一步优选100mg/m 2的剂量给药。其中，根据本领域技术人员的常识，可以理解的是，mg/m 2是指受试者每平方米体表面积所用的药物的剂量。
抗PD-L1抗体
在本申请的一些实施方案中，所述抗PD-L1抗体为WO2016022630或CN107001463A中的抗体。
在本申请的一些实施方案中，所述抗PD-L1抗体包含如下氨基酸序列：与SEQ ID NO:1或SEQ ID NO:4所示的氨基酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性的重链CDR1区；与SEQ ID NO:2或SEQ ID NO:5所示的氨基酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性的重链CDR2区；与SEQ ID NO:3或SEQ ID NO:6所示的氨基酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性的重链CDR3 区；与SEQ ID NO:7或SEQ ID NO:10所示的氨基酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性的轻链CDR1区；与SEQ ID NO:8或SEQ ID NO:11所示的氨基酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性的轻链CDR2区；与SEQ ID NO:9或SEQ ID NO:12所示的氨基酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性的轻链CDR3区。
在本申请的一些实施方案中，所述抗PD-L1抗体包含如下氨基酸序列：选自SEQ ID NO:1或SEQ ID NO:4的重链CDR1区；选自SEQ ID NO:2或SEQ ID NO:5的重链CDR2区；选自SEQ ID NO:3或SEQ ID NO:6的重链CDR3区；选自SEQ ID NO:7或SEQ ID NO:10的轻链CDR1区；选自SEQ ID NO:8或SEQ ID NO:11的轻链CDR2区；选自SEQ ID NO:9或SEQ ID NO:12的轻链CDR3区。
在本申请的一些实施方案中，本文所述的分离的抗PD-L1抗体包含：具有以SEQ ID NO:1示出的氨基酸序列的重链CDR1区，具有以SEQ ID NO:2示出的氨基酸序列的重链CDR2区，具有以SEQ ID NO:3示出的氨基酸序列的重链CDR3区；以及具有以SEQ ID NO:7示出的氨基酸序列的轻链CDR1区，具有以SEQ ID NO:8示出的氨基酸序列的轻链CDR2区，具有以SEQ ID NO:9示出的氨基酸序列的轻链CDR3区。
本文所述的各CDR区及其上述的各种变体能够特异性地识别并结合PD-L1，从而有效地阻断PD-L1和PD-1之间的信号传导。
在本申请的一些实施方案中，所述抗PD-L1抗体包含如下氨基酸序列：与SEQ ID NO:13或SEQ ID NO:14所示的氨基酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性的重链可变区；与SEQ ID NO:15或SEQ ID NO:16所示的氨基酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性的轻链可变区。
在本申请的一些实施方案中，所述抗PD-L1抗体包含如下氨基酸序列：如SEQ ID NO:13所示的重链可变区；如SEQ ID NO:15所示的轻链可变区。
在本申请的一些实施方案中，所述抗PD-L1抗体包含如下氨基酸序列：如SEQ ID NO:14所示的重链可变区；如SEQ ID NO:16所示的轻链可变区。
在本申请的一些实施方案中，所述抗PD-L1抗体包含如下氨基酸序列：如SEQ ID NO:17所示的重链氨基酸序列；如SEQ ID NO:18所示的轻链氨基酸序列。
在本申请的一些实施方案中，所述抗PD-L1抗体包含如下氨基酸序列：如SEQ ID NO:19所示的重链氨基酸序列；如SEQ ID NO:20所示的轻链氨基酸序列。
在本申请的一些实施方案中，所述抗PD-L1抗体包含如下氨基酸序列：如SEQ ID NO:21所示的重链氨基酸序列；如SEQ ID NO:18所示的轻链氨基酸序列。
在一个具体实施方案中，本申请提供的抗PD-L1人源化单抗包含选自SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21中的一个或多个的保守置换变体。包含所述保守置换变体的抗PD-L1人源化单抗保留了特异性地识别并结合PD-L1的能力。
在本申请的一些实施方案中，所述抗PD-L1抗体可为IgG1或IgG4抗体。
在本申请的一些实施方案中，所述抗PD-L1抗体为IgG1抗体。在部分实施方案中，所述抗PD-L1抗体为糖基化的IgG1抗体。
在本申请的一些实施方案中，所述抗PD-L1抗体包含选自13C5或5G11抗体的重链互补决定区(CDR)，和选自13C5或5G11抗体的轻链互补决定区。在一个实施方案中，本申请所述的抗PD-L1抗体，其包含选自ch5G11-hIgG1、ch5G11-hIgG4、ch13C5-hIgG1、ch13C5-hIgG4嵌合抗体的可变重链，和选自 ch5G11-hIgG1、ch5G11-hIgG4、ch13C5-hIgG1、ch13C5-hIgG4嵌合抗体的可变轻链。在一个实施方案中，本申请所述的抗PD-L1抗体，其包含选自hu13C5-hIgG1、hu13C5-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4人源化抗体的可变重链，和选自hu13C5-hIgG1、hu13C5-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4人源化抗体的可变轻链。可以参考专利文献WO2016022630或CN107001463A的记载：13C5、ch13C5-hIgG1、ch13C5-hIgG4、hu13C5-hIgG1或hu13C5-hIgG4的HCDR1序列为SYGMS(SEQ ID NO:4)，HCDR2序列为SISSGGSTYYPDSVKG(SEQ ID NO:5)，HCDR3序列为GYDSGFAY(SEQ ID NO:6)，LCDR1序列为ASQSVSTSSSSFMH(SEQ ID NO:10)，LCDR2序列为YASNLES(SEQ ID NO:11)，LCDR3序列为QHSWEIPYT(SEQ ID NO:12)；5G11、ch5G11-hIgG1、ch5G11-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4的HCDR1序列为TYGVH(SEQ ID NO:1)，HCDR2序列为VIWRGVTTDYNAAFMS(SEQ ID NO:2)，HCDR3序列为LGFYAMDY(SEQ ID NO:3)，LCDR1序列为KASQSVSNDVA(SEQ ID NO:7)，LCDR2序列为YAANRYT(SEQ ID NO:8)，LCDR3序列为QQDYTSPYT(SEQ ID NO:9)。
在本申请的一些实施方案中，所述药物组合中的抗PD-L1抗体可以选自一种或多种。如本申请所用，术语“多种”可以是多于一种，例如，两种、三种、四种、五种或更多种。例如，在本申请的一些实施方案中，所述抗PD-L1抗体选自包含如SEQ ID NO:13所示的重链可变区和如SEQ ID NO:15所示的轻链可变区，或选自包含如SEQ ID NO:14所示的重链可变区和如SEQ ID NO:16所示的轻链可变区，或选自上述的组合。又例如，所述抗PD-L1抗体选自如SEQ ID NO:17所示的重链氨基酸序列和如SEQ ID NO:18所示的轻链氨基酸序列，或选自如SEQ ID NO:19所示的重链氨基酸序列和如SEQ ID NO:20所示的轻链氨基酸序列，或选自如SEQ ID NO:21所示的重链氨基酸序列和如SEQ ID NO:18所示的轻链氨基酸序列，或选自上述任选多种的组合。
在一些实施方案中，抗PD-L1抗体包含如下氨基酸序列：与SEQ ID NO:1或SEQ ID NO:4所示的氨基酸序列有至少80％同源性的重链CDR1区；与SEQ ID NO:2或SEQ ID NO:5所示的氨基酸序列有至少80％同源性的重链CDR2区；与SEQ ID NO:3或SEQ ID NO:6所示的氨基酸序列有至少80％同源性的重链CDR3区；与SEQ ID NO:7或SEQ ID NO:10所示的氨基酸序列有至少80％同源性的轻链CDR1区；与SEQ ID NO:8或SEQ ID NO:11所示的氨基酸序列有至少80％同源性的轻链CDR2区；与SEQ ID NO:9或SEQ ID NO:12所示的氨基酸序列有至少80％同源性的轻链CDR3区。
抗PD-L1抗体的药物组合物
在本申请的一些实施方案中，所述抗PD-L1抗体的药物组合物含有600～2400mg的抗PD-L1抗体。在部分方案中，所述抗PD-L1抗体的药物组合物含有选自600mg、900mg、1200mg、1500mg、1800mg、2100mg、2400mg、或上述任意值形成的范围的抗PD-L1抗体。在部分方案中，所述抗PD-L1抗体的药物组合物含有600～2100mg、或900mg～1500mg的抗PD-L1抗体；其中所述抗PD-L1抗体的药物组合物可以多剂量或者单位剂量形式存在。
在本申请的一些实施方案中，所述抗PD-L1抗体的药物组合物中含300mg、600mg或者1200mg的抗PD-L1抗体；在本申请的一些实施方案中，提供了一种配制成单位剂量的抗PD-L1抗体的药物组合物，其含有300mg、600mg或1200mg的抗PD-L1抗体。
在一些实施方案中，所述抗PD-L1抗体的药物组合物为注射用溶液剂。在一些实施方案中，所述抗PD-L1抗体的药物组合物为注射用水溶液。在本申请的一些实施方案中，所述抗PD-L1抗体的药物组合物包含缓冲液、等渗调节剂、稳定剂和/或表面活性剂中的一种或多种。特别地，所述抗PD-L1抗体的药物组合物包含1～150mg/mL抗PD-L1抗体(例如单抗)、3～50mM缓冲液、2～150mg/mL等渗调节剂/稳定剂和0.01～0.8mg/mL表面活性剂，且pH为4.5～6.8。
在本申请的一些实施方案中，所述抗PD-L1抗体的药物组合物以w/v计算，抗PD-L1单抗浓度为5～150mg/mL；在一些实施方案中所述浓度为10～60mg/mL；在一些实施方案中所述浓度为10～30mg/mL。在一些具体方案中，抗PD-L1单抗质量体积浓度为10mg/mL、20mg/mL、30mg/mL、40mg/mL、50mg/mL、60mg/mL、70mg/mL、80mg/mL、90mg/mL、100mg/mL、110mg/mL或120mg/mL；在一些实施方案中，所述浓度为10mg/mL、20mg/mL、30mg/mL、40mg/mL、50mg/mL或60mg/mL；在一些实施方案中，所述浓度为10mg/mL、20mg/mL或30mg/mL。在一些实施方案中，抗PD-L1单抗质量体积浓度为10 mg/mL。在另一些实施方案中，抗PD-L1单抗质量体积浓度为30mg/mL。在另一些实施方案中，抗PD-L1单抗质量体积浓度为60mg/mL。
在本申请的一些实施方案中，所述缓冲液为组氨酸盐缓冲液。所述组氨酸盐缓冲液浓度为5～30mM，在一些实施方案中，所述浓度为10～25mM；在一些实施方案中，所述浓度为10～20mM；在一些实施方案中，所述浓度为10～15mM。在一些具体方案中，所述组氨酸盐缓冲液浓度为5mM、10mM、15mM、20mM、25mM或30mM。在一些实施方案中，所述组氨酸盐缓冲液浓度为10mM。在另一些实施方案中，所述组氨酸盐缓冲液浓度为15mM。在另一些实施方案中，所述组氨酸盐缓冲液浓度为20mM。其中，所述组氨酸盐缓冲液包含组氨酸和盐酸。
在本申请的一些实施方案中，以w/v计算，所述等渗调节剂/稳定剂为20～150mg/mL的蔗糖；在一些实施方案中，所述等渗调节剂/稳定剂为40～100mg/mL的蔗糖；在一些实施方案中，所述等渗调节剂/稳定剂为60～80mg/mL的蔗糖。在一些具体方案中，所述蔗糖的浓度为40mg/mL、50mg/mL、60mg/mL、70mg/mL、80mg/mL、90mg/mL或100mg/mL。在一些具体实施方案中，所述蔗糖的浓度为60mg/mL。在一些具体实施方案中，所述蔗糖的浓度为70mg/mL。在一些具体实施方案中，所述蔗糖的浓度为80mg/mL。在一些具体实施方案中，所述蔗糖的浓度为90mg/mL。
在本申请的一些实施方案中，所述表面活性剂选自聚山梨酯80、聚山梨酯20、泊洛沙姆188；在一些实施方案中，所述表面活性剂选自聚山梨酯80或聚山梨酯20；在一些实施方案中，所述表面活性剂选自聚山梨酯80。在一些方案中，以w/v计算，所述表面活性剂的浓度为0.05～0.6mg/mL；在一些实施方案中，所述浓度为0.1～0.4mg/mL；在一些实施方案中，所述浓度为0.2～0.3mg/mL。
在本申请的一些实施方案中，以w/v计算，所述表面活性剂为0.01～0.8mg/mL的聚山梨酯80或聚山梨酯20。在一些具体方案中，所述表面活性剂为0.05～0.6mg/mL的聚山梨酯80；在一些实施方案中，所述表面活性剂为0.1～0.4mg/mL的聚山梨酯80；在一些实施方案中，所述表面活性剂为0.2～0.3mg/mL的聚山梨酯80；在一些实施方案中，所述表面活性剂为0.2mg/mL的聚山梨酯80。在一些实施方案中，所述药物组合物中聚山梨酯80含量为0.1mg/mL、0.2mg/mL、0.3mg/mL、0.4mg/mL、0.5mg/mL或0.6mg/mL；在一些实施方案中，所述药物组合物中聚山梨酯80含量为0.2mg/mL、0.3mg/mL、0.4mg/mL或0.5mg/mL；在一些实施方案中，所述药物组合物中聚山梨酯80含量为0.2mg/mL、0.3mg/mL或0.4mg/mL；在一些实施方案中，所述药物组合物中聚山梨酯80含量为0.2mg/mL。在一些实施方案中，所述药物组合物中聚山梨酯80含量为0.1mg/mL。在另一些实施方案中，所述药物组合物中聚山梨酯80含量为0.2mg/mL。在一些实施方案中，所述药物组合物中聚山梨酯80含量为0.3mg/mL。在另一些实施方案中，所述药物组合物中聚山梨酯80含量为0.4mg/mL。在一些实施方案中，所述药物组合物中聚山梨酯80含量为0.5mg/mL。
在本申请的一些实施方案中，所述药物组合物的水溶液pH值选自4.0～6.8；在一些实施方案中，所述pH值为4.5～6.5；在一些实施方案中，所述pH值为5.5～6.0；在一些实施方案中，所述pH值为5.5。在一些实施方案中，药物组合物水溶液的pH值为4.5、4.8、5.0、5.2、5.4、5.5、5.6、5.8或6.0，在一些实施方案中，所述pH值为5.0、5.2、5.4、5.5或5.6；在一些实施方案中，所述pH值为5.5。在一些实施方案中，药物组合物水溶液的pH值为5.0。在一些实施方案中，药物组合物水溶液的pH值为5.2。在一些实施方案中，药物组合物水溶液的pH值为5.4。在一些实施方案中，药物组合物水溶液的pH值为5.5。在一些实施方案中，药物组合物水溶液的pH值为5.6。在一些实施方案中，药物组合物水溶液的pH值为5.8。在一些实施方案中，药物组合物水溶液的pH值为6.0。
在本申请的一些具体实施方案中，所述药物组合物包含：(a)质量体积浓度为20mg/mL的抗PD-L1抗体，(b)质量体积浓度为70mg/mL的蔗糖，(c)质量体积浓度为0.1mg/mL的聚山梨酯80，(d)摩尔浓度为20mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为5.0。本申请的一个具体实施方案中，所述药物组合物包含：(a)质量体积浓度为20mg/mL的抗PD-L1单抗，(b)质量体积浓度为70mg/mL的蔗糖，(c)质量体积浓度为0.1mg/mL的聚山梨酯80，(d)摩尔浓度为20mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为5.0。
在本申请的另一个具体实施方案中，所述药物组合物包含：(a)质量体积浓度为10mg/mL的抗PD-L1抗体，(b)质量体积浓度为80mg/mL的蔗糖，(c)质量体积浓度为0.2mg/mL的聚山梨酯80，(d)摩尔 浓度为10mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为5.5。
在本申请的另一个具体实施方案中，所述药物组合物包含：(a)质量体积浓度为50mg/mL的抗PD-L1抗体，(b)质量体积浓度为80mg/mL的蔗糖，(c)质量体积浓度为0.3mg/ml的聚山梨酯80，(d)摩尔浓度为10mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为5.5。
在本申请的另一个具体实施方案中，所述药物组合物包含：(a)质量体积浓度为100mg/mL的抗PD-L1抗体，(b)质量体积浓度为80mg/mL的蔗糖，(c)质量体积浓度为0.5mg/mL的聚山梨酯80，(d)摩尔浓度为10mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为5.5。
在本申请的另一个具体实施方案中，所述药物组合物包含：(a)质量体积浓度为30mg/mL的抗PD-L1抗体，(b)质量体积浓度为80mg/mL的蔗糖，(c)质量体积浓度为0.2mg/mL的聚山梨酯80，(d)摩尔浓度为10mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为5.5。
在本申请的另一个具体实施方案中，所述药物组合物包含：(a)质量体积浓度为60mg/mL的抗PD-L1抗体，(b)质量体积浓度为80mg/mL的蔗糖，(c)质量体积浓度为0.2mg/mL的聚山梨酯80，(d)摩尔浓度为10mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为5.5。
在本申请的另一个具体实施方案中，所述药物组合物包含：(a)质量体积浓度为10mg/mL的抗PD-L1抗体，(b)质量体积浓度为70mg/mL的蔗糖，(c)质量体积浓度为0.4mg/mL的聚山梨酯80，(d)摩尔浓度为20mM的组氨酸，(e)任选醋酸适量，调节组合物的pH值为6.5。
在本申请的另一个具体实施方案中，所述药物组合物包含：(a)质量体积浓度为10mg/mL的抗PD-L1单抗，(b)质量体积浓度为80mg/mL的蔗糖，(c)质量体积浓度为0.2mg/mL的聚山梨酯80，(d)摩尔浓度为20mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为5.5。
在本申请的另一个具体实施方案中，药物组合物为水溶性注射液；在一些实施方案中，所述水溶性注射液包括但不限于未经冻干的水溶性制剂或冻干粉重构的水溶性制剂。在另一些方案中，药物组合物为冻干制剂。所述冻干制剂是指水溶液经历冻干过程制备的制剂，在该过程中物质首先被冷冻，然后先通过升华降低溶剂数量(初级干燥过程)，然后通过脱附作用降低溶剂数量(二级干燥过程)，直到溶剂数量为不再支持生物学活性或化学反应的值。本申请的冻干制剂还可以通过本领域已知的其它方法干燥，如喷雾干燥和鼓泡干燥(bubble drying)。
药物组合
一方面，本申请提供用于治疗小细胞肺癌的药物组合，其包括抗PD-L1抗体、安罗替尼或其药学上可接受的盐、和化疗药物。
在本申请的一些实施方案中，所述药物组合包括抗PD-L1抗体、安罗替尼或其药学上可接受的盐和化疗药物。在本申请的一些实施方案中，所述包括抗PD-L1抗体、安罗替尼或其药学上可接受的盐和化疗药物的药物组合是固定组合。在一些方案中，所述固定组合呈固体药物组合物形式或液体药物组合物形式。在本申请的一些实施方案中，所述包括抗PD-L1抗体、安罗替尼或其药学上可接受的盐和化疗药物的药物组合是非固定组合。在一些方案中，所述非固定组合中的抗PD-L1抗体、安罗替尼或其药学上可接受的盐和化疗药物各自呈药物组合物形式。在一些方案中，所述非固定组合中的抗PD-L1抗体、安罗替尼或其药学上可接受的盐和化疗药物中的每一种活性成分各自呈药物组合物形式。
在一些实施方案中，提供了一种药物组合，其包括重量比为(0.35-29):1、优选(3.5-29):1、更优选(3.5-14.5):1、最优选(7-14.5):1的抗PD-L1抗体和安罗替尼。其中，抗PD-L1抗体和安罗替尼可分开地包装或者包装在一起。并且其中，安罗替尼能够以多个等份(例如2等份、7等份、14等份、28等份或更多等份)进行包装。
在本申请的一些实施方案中，所述包括抗PD-L1抗体、安罗替尼或其药学上可接受的盐和化疗药物的药物组合包括：
i)抗PD-L1抗体；在一个实施方案中，所述抗PD-L1抗体包含选自13C5或5G11抗体的重链互补决定区(CDR)，和选自13C5或5G11抗体的轻链互补决定区；在一个实施方案中，所述抗PD-L1抗体包含选自ch5G11-hIgG1、ch5G11-hIgG4、ch13C5-hIgG1、ch13C5-hIgG4嵌合抗体的可变重链，和选自 ch5G11-hIgG1、ch5G11-hIgG4、ch13C5-hIgG1、ch13C5-hIgG4嵌合抗体的可变轻链；在一个实施方案中，所述抗PD-L1抗体包含选自hu13C5-hIgG1、hu13C5-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4人源化抗体的可变重链，和选自hu13C5-hIgG1、hu13C5-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4人源化抗体的可变轻链；在一个实施方案中，所述抗PD-L1抗体选自包括如下的互补决定区，如专利文献WO2016022630或CN107001463A记载的13C5、ch13C5-hIgG1、ch13C5-hIgG4、hu13C5-hIgG1或hu13C5-hIgG4的HCDR1序列为SYGMS，HCDR2序列为SISSGGSTYYPDSVKG，HCDR3序列为GYDSGFAY，LCDR1序列为ASQSVSTSSSSFMH，LCDR2序列为YASNLES，LCDR3序列为QHSWEIPYT；5G11、ch5G11-hIgG1、ch5G11-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4的HCDR1序列为TYGVH，HCDR2序列为VIWRGVTTDYNAAFMS，HCDR3序列为LGFYAMDY，LCDR1序列为KASQSVSNDVA，LCDR2序列为YAANRYT，LCDR3序列为QQDYTSPYT；
ii)安罗替尼或其药学上可接受的盐；
iii)铂类抗肿瘤药物、和/或依托泊苷。
在本申请的一些实施方案中，所述含抗PD-L1抗体和化疗药物的药物组合包括含600～2400mg的抗PD-L1抗体的药物组合物、50～700mg的卡铂药物组合物和20～200mg的依托泊苷药物组合物。其中抗PD-L1抗体的药物组合物、卡铂药物组合物和依托泊苷药物组合物为单剂量或者多剂量。
在本申请的一些实施方案中，所述药物组合包括抗PD-L1抗体、安罗替尼或其药学上可接受的盐和化疗药物；或者，其包括上述抗PD-L1抗体、安罗替尼或其药学上可接受的盐和化疗药物的药物组合。
在本申请的一些实施方案中，所述含抗PD-L1抗体、安罗替尼或其药学上可接受的盐和化疗药物的药物组合包括抗PD-L1抗体药物组合物、安罗替尼或其药学上可接受的盐的药物组合物和化疗药物组合物。在本申请的一些实施方案中，所述药物组合包装于同一试剂盒中，所述试剂盒还包括PD-L1抗体、安罗替尼或其药学上可接受的盐和化疗药物联合使用治疗小细胞肺癌的说明。
在本申请的一些实施方案中，所述含抗PD-L1抗体、安罗替尼或其药学上可接受的盐、和化疗药物的药物组合包括含600～2400mg的抗PD-L1抗体的药物组合物、单剂量是6mg、8mg、10mg和/或12mg的安罗替尼或其药学上可接受的盐、50～800mg(例如50～500mg)的卡铂药物组合物和20～200mg的依托泊苷药物组合物。其中抗PD-L1抗体的药物组合物、安罗替尼或其药学上可接受的盐的药物组合物、卡铂药物组合物和依托泊苷药物组合物为单剂量或者多剂量。
在本申请的一些实施方案中，所述含抗PD-L1抗体、安罗替尼或其药学上可接受的盐、化疗药物的药物组合包括含1200mg的抗PD-L1抗体以多剂量形式提供的药物组合物、单剂量是6mg、8mg、10mg和/或12mg的安罗替尼、200～400mg的卡铂药物组合物和50～150mg的依托泊苷药物组合物。
在本申请的一些实施方案中，所述含抗PD-L1抗体、安罗替尼或其药学上可接受的盐、和化疗药物的药物组合包括抗PD-L1抗体浓度为10-60mg/mL的抗PD-L1抗体药物组合物、单剂量是6mg、8mg、10mg和/或12mg的安罗替尼、50～500mg的卡铂药物组合物和20～200mg的依托泊苷药物组合物。
在本申请的一些实施方案中，所述含抗PD-L1抗体、安罗替尼或其药学上可接受的盐、和化疗药物的药物组合包括抗PD-L1抗体浓度为10mg/mL的抗PD-L1抗体药物组合物、单剂量是8mg、10mg和/或12mg的安罗替尼、200～400mg的卡铂药物组合物和50～150mg的依托泊苷药物组合物。
在一些实施方案中，所述药物组合包括重量比为(0.35-29):1、优选(3.5-29):1、更优选(3.5-14.5):1、最优选(7-14.5):1的抗PD-L1抗体和安罗替尼。其中，抗PD-L1抗体和安罗替尼可分开地包装或者包装在一起。并且其中，安罗替尼能够以多个等份(例如2等份、7等份、14等份、28等份或更多等份)进行包装。
另一方面，本申请提供用于治疗小细胞肺癌的药物组合，其包括在第一治疗阶段向有需要的患者给予的第一药物组合，以及任选地，在第二治疗阶段向有需要的患者给予的第二药物组合，在本申请的一些实施方案中，所述第一药物组合可选自上述药物组合中的一种或多种。
在一些实施方案中，所述第一药物组合包括抗PD-L1抗体、安罗替尼或其药学上可接受的盐、和化疗药物。
在一些实施方案中，所述第二药物组合包括抗PD-L1抗体、和安罗替尼或其药学上可接受的盐。
在一些实施方案中，所述第一治疗阶段的治疗周期为1到10个治疗周期，优选2到8个治疗周期，最优选4个治疗周期。
在一些实施方案中，所述的药物组合还进一步包括药学上可接受的载体。
在一些实施方案中，所述药物组合中的抗PD-L1抗体、安罗替尼或其药学上可接受的盐、和化疗药物各自呈药物组合物形式。在一些方案中，所述药物组合中的抗PD-L1抗体、安罗替尼或其药学上可接受的盐、和化疗药物中的每一种活性成分各自呈药物组合物形式。
试剂盒
又一方面，本申请提供用于治疗小细胞肺癌的试剂盒，所述试剂盒包括抗PD-L1抗体药物组合物、安罗替尼或其药学上可接受的盐的药物组合物、和进一步包括化疗药物，以及联合使用治疗小细胞肺癌的说明；在一些实施方案中，提供了一种用于治疗小细胞肺癌的试剂盒，所述试剂盒包括抗PD-L1抗体药物组合物、安罗替尼或其药学上可接受的盐药物组合物、和/或卡铂药物组合物和/或依托泊苷药物组合物，以及联合使用治疗小细胞肺癌的说明；或者，所述试剂盒包括本申请的药物组合，以及联合使用治疗小细胞肺癌的说明。
用途
再一方面，本申请还提供本申请的药物组合、或本申请的试剂盒在制备用于治疗患者的小细胞肺癌的药物的用途。本申请还提供治疗患者的小细胞肺癌的方法，其包括向有需要的患者给予有效量的本申请的药物组合、或本申请的试剂盒。本申请还提供本申请的药物组合、或本申请的试剂盒用于治疗患者的小细胞肺癌的用途。所述药物组合、或试剂盒如前所述。
在本申请的一些实施方案中，上述用途或者治疗方法中，所述抗PD-L1抗体、安罗替尼或其药学上可接受的盐、和化疗药物各自呈药物组合物，可同时、顺序或间隔给药。
在本申请的一些实施方案中，上述用途或者治疗方法中，所述抗PD-L1抗体、安罗替尼或其药学上可接受的盐、和化疗药物各自以间隔给药的方式给药。在一些实施方案中所述抗PD-L1抗体、安罗替尼或其药学上可接受的盐、和化疗药物分别以相同或者不同的给药方案进行给药。在一些实施方案中，所述抗PD-L1抗体、安罗替尼或其药学上可接受的盐、和化疗药物分别以不同的给药方案进行给药。
在本申请的一些实施方案中，所述用途或治疗方法，所述抗PD-L1抗体可以每周(q1w)、每2周(q2w)、每3周(q3w)、或者每4周(q4w)施用一次。在一个具体的实施方案中，每3周给予抗PD-L1抗体一次。在一些实施方案中，所述抗PD-L1抗体每次以600～2400mg的剂量施用。
在本申请的一些实施方案中，所述安罗替尼或其药学上可接受的盐可以以每日一次6mg、8mg、10mg或者12mg的剂量，连续用药2周，停1周的给药方案给药。此时，每3周为一个给药周期。
在本申请的一些实施方案中，所述化疗药物可按照已知的给药方案给药。
在本申请的一些实施方案中，抗PD-L1抗体、安罗替尼或其药学上可接受的盐和化疗药物分别具有相同或者不同的给药周期。在一些具体的实施方案中，抗PD-L1抗体、安罗替尼或其药学上可接受的盐和化疗药物具有相同的给药周期，例如每1周、每2周、每3周或者每4周为一个给药周期。
在本申请的一些实施方案中，所述药物组合的给药方案，或所述用途或者治疗方法中，21天为一个给药周期，在每个给药周期的第一天给予PD-L1抗体，在每个周期的第1-14天每天给予安罗替尼或其药学上可接受的盐、和化疗药物，其中化疗药物可按照已知的给药方案给药。在一个具体的实施方案中，在每个周期的第一天给予PD-L1抗体一次，在每个周期的第1-14天每天一次给予安罗替尼或其药学上可接受的盐，和/或在每个周期的第1天给予卡铂，和/或在每个周期的第1、2、3天给予依托泊苷。
在本申请的一些实施方案中，所述用途或者治疗方法中，其中所述抗PD-L1抗体可以包括选自0.01至40mg/kg、0.1至30mg/kg、0.1至20mg/kg、0.1至15mg/kg、0.1至10mg/kg、1至15mg/kg、1至20mg/kg、1至3mg/kg、3至10mg/kg、3至15mg/kg、3至20mg/kg、3至30mg/kg、10至20mg/kg、或15至20mg/kg的剂量给予；或者以60mg至2400mg、90mg至约1800mg、120mg至1500mg、300mg至900mg、600mg至900mg、300mg至1200mg、600mg至1200mg、或900mg至1200mg的剂量施用于患者。
在所述用途或者治疗方法的一些实施方案中，21天为一个给药周期，在每个周期的第一天给予1200mg的PD-L1抗体，在每个周期的第1-14天每天给予6mg、8mg、10mg和/或12mg的安罗替尼。
在本申请的一些实施方案中，在每三周的一个治疗周期中，以(0.35-29):1、优选(3.5-29):1、更优选(3.5-14.5):1、最优选(7-14.5):1的重量比向受试者给予抗PD-L1抗体和安罗替尼，其中，将所述抗PD-L1抗体和安罗替尼分别以单剂量和多剂量进行给予。
在本申请的一些实施方案中，所述药物组合的给药方案、或所述用途或者治疗方法包括，在重复周期中，给予抗PD-L1抗体、安罗替尼或其药学上可接受的盐、和化疗药物进行第一治疗阶段治疗；然后，任选地，在重复周期中，给予抗PD-L1抗体、和安罗替尼或其药学上可接受的盐进行第二治疗阶段治疗。在一些实施方案中，所述第一治疗阶段和所述第二治疗阶段均是21天为一个给药周期。在一些实施方案中，在所述第一治疗阶段，在每个给药周期的第一天给予PD-L1抗体，在每个周期的第1-14天每天给予安罗替尼或其药学上可接受的盐、和化疗药物，其中化疗药物可按照已知的给药方案给药。在一些实施方案中，所述化疗药物选自铂类抗肿瘤药物、和/或拓扑异构酶抑制剂中的一种或几种。在一些实施方案中，所述化疗药物选自卡铂和依托泊苷。在一个具体的实施方案中，在每个周期的第一天给予PD-L1抗体一次，在每个周期的第1-14天每天一次给予安罗替尼或其药学上可接受的盐，和/或在每个周期的第1天给予卡铂，和/或在每个周期的第1、2、3天给予依托泊苷。在一些实施方案中，所述第一治疗阶段的治疗周期为1到10个治疗周期，优选2到8个治疗周期，最优选4个治疗周期。
在一些实施方案中，卡铂以AUC为4～7mg/ml/min的剂量给药，优选以AUC为5～7mg/ml/min的剂量给药，进一步优选以AUC为5mg/ml/min的剂量给药。
在一些实施方案中，依托泊苷以60～120mg/m 2的剂量给药，优选以60～100mg/m 2的剂量给药，进一步优选100mg/m 2的剂量给药。
在一些实施方案中，在所述第二治疗阶段，在每个给药周期的第一天给予PD-L1抗体，和在每个周期的第1-14天每天给予安罗替尼或其药学上可接受的盐。
小细胞肺癌
在一些实施方案中，所述的小细胞肺癌包括局限期和广泛期小细胞肺癌。根据本领域技术人员的常识，可以理解的是，术语“广泛期小细胞肺癌”包括但不限于初治的(即，初始治疗的)广泛期小细胞肺癌。
在一些实施方案中，所述的小细胞肺癌为晚期和/或难治性和/或复发性和/或转移性小细胞肺癌。在一些实施方案中，所述的小细胞肺癌包括敏感复发和/或难治复发的小细胞肺癌。在一些实施方案中，小细胞肺癌为脑转移的小细胞肺癌。
在本申请的一些实施方案中，所述小细胞肺癌患者是接受过手术、化疗和/或放疗的小细胞肺癌患者。在一些方案中，所述化疗选自包括铂类抗肿瘤药物的化疗。在一些方案中，所述铂类抗肿瘤药物包括但不限于顺铂、卡铂。
在一些实施方案中，所述小细胞肺癌是在先未接受过系统治疗的小细胞肺癌。在一些实施方案中，所述小细胞肺癌是既往未接受过针对广泛期小细胞肺癌的系统治疗的小细胞肺癌。在一些实施方案中，所述小细胞肺癌是在先未接受过系统治疗的广泛期小细胞肺癌。
在一些实施方案中，所述小细胞肺癌患者是在先接受过针对局限期小细胞肺癌的放疗和/或化疗的患者。
所述的化疗药物包括但不限于铂类抗肿瘤药物、鬼臼类、烷化剂类、喜树碱类、紫杉类、抗代谢类、抗生素类抗肿瘤药物中的一种或多种；可以列举的实例包括但不限于铂类抗肿瘤药物(例如顺铂、卡铂、奈达铂、米铂、奥沙利铂)、依托泊苷、伊立替康、拓扑替康、紫杉醇、多西他赛、替莫唑胺、长春瑞滨、吉西他滨、环磷酰胺、阿霉素、长春新碱、苯达莫司汀、表阿霉素、甲氨蝶呤、氨柔比星中的一种或多种。
施用方式
下述内容并非限制本申请药物组合的施用方式。
本申请的药物组合物中的组分可以各自独立地、或者其中的部分或全部共同以适合的各种途径施用，包括但不限于口服或肠胃外(通过静脉内、肌内、局部或皮下途径)施用。在一些实施方案中，本申请的 药物组合的组分可以各自独立地、或者其中的部分或全部共同口服施用或注射施用，例如静脉注射或腹腔注射。
本申请的药物组合物中的组分可以各自独立地、或者其中的部分或全部共同是适合的剂型，包括但不限于片剂、含片、丸剂、胶囊剂(例如硬胶囊、软胶囊、肠溶胶囊、微囊剂)、酏剂、颗粒剂、糖浆剂、注射剂(肌肉内、静脉内、腹腔内)、颗粒剂、乳剂、悬浮液、溶液、分散剂和用于口服或非口服给药的缓释制剂的剂型。
本申请的药物组合中的组分可以各自独立地、或者其中的部分或全部共同含有药学上可接受的载体和/或赋形剂。
本申请的药物组合还可以包含另外的治疗剂。在一个实施方式中，所述另外的治疗剂可以是本领域已知的小细胞癌症治疗剂。
给药方案
对于本申请的药物组合、或本申请的试剂盒的给药方案，所述给药方案包括第一治疗阶段，任选地包括第二治疗阶段。
本申请所述的给药方案也适用于本申请所述的制备用于治疗患者的小细胞肺癌的药物的用途、治疗患者的小细胞肺癌的方法和用于治疗患者的小细胞肺癌的用途。
在本申请的一些实施方案中，所述第一治疗阶段包括1～10个治疗周期，优选包括2～8个治疗周期，最优选包括4个治疗周期。
在本申请的一些实施方案中，所述第二治疗阶段包括2～20个治疗周期。在一些实施方案中，所述第二治疗阶段持续直到失去临床获益或毒性不可耐受或疗效评价为PD或研究者认为不适合继续用药。
在本申请的一些实施方案中，所述治疗周期是14天～42天；在一些实施方案中，所述治疗周期为14天、21天、28天、35天或42天；在一些实施方案中，所述治疗周期是21天。在一些具体的实施方案中，第一治疗阶段与第二治疗阶段具有相同的治疗周期。在一些具体的实施方案中，第一治疗阶段与第二治疗阶段的治疗周期(例如单个治疗周期)均为21天。
在本申请的一些实施方案中，所述第一治疗阶段的给药方案包括：1)抗PD-L1抗体于每个治疗周期的第1-7天内的一天给药一次；和2)安罗替尼或其药学上可接受的盐于每个治疗周期的第1-28天连续给药；任选地，3)铂类抗肿瘤药物于每个治疗周期的第1-7天内的一天给药一次；和任选地，4)拓扑异构酶抑制剂于每个治疗周期的第1-7天连续给药。
在一些实施方案中，每21天为一个治疗周期，第一治疗阶段的给药方案包括：1)抗PD-L1抗体于每个治疗周期的第1天给药一次；和2)安罗替尼或其药学上可接受的盐于每个治疗周期的第1-14天连续给药；任选地，3)铂类抗肿瘤药物于每个治疗周期的第1天给药一次；任选地，4)拓扑异构酶抑制剂于每个周期的第1-3天连续给药。
在一些具体的实施方案中，所述第一治疗阶段的给药方案包括：1)抗PD-L1抗体于每个治疗周期的第1-7天内的一天给药一次；和2)安罗替尼或其药学上可接受的盐于每个治疗周期的第1-28天连续给药；和3)铂类抗肿瘤药物于每个治疗周期的第1-7天内的一天给药一次；和4)拓扑异构酶抑制剂于每个治疗周期的第1-7天连续给药。
在本申请的一些实施方案中，每21天为一个治疗周期，第一治疗阶段的给药方案包括：1)抗PD-L1抗体于每个治疗周期的第1天给药一次；和2)安罗替尼或其药学上可接受的盐于每个治疗周期的第1-14天连续给药；和3)铂类抗肿瘤药物于每个治疗周期的第1天给药一次；和4)拓扑异构酶抑制剂于每个周期的第1-3天连续给药。
在本申请的一些实施方案中，第一治疗阶段的给药方案包括：1)抗PD-L1抗体hu5G11-hIgG1于每个治疗周期的第1天给药一次；和2)安罗替尼二盐酸盐于每个治疗周期的第1-14天连续给药；和3)铂类抗肿瘤药物于每个治疗周期的第1天给药一次；和4)拓扑异构酶抑制剂于每个周期的第1-3天连续给药。
在本申请的一些实施方案中，第一治疗阶段的给药方案包括：1)抗PD-L1抗体hu5G11-hIgG1于每个治疗周期的第1天给药一次；和2)安罗替尼二盐酸盐于每个治疗周期的第1-14天连续给药；和3)卡铂 于每个治疗周期的第1天给药一次；和4)依托泊苷于每个周期的第1-3天连续给药。
在本申请的一些实施方案中，所述第二治疗阶段的给药方案包括：1)抗PD-L1抗体于每个治疗周期的第1-7天内的一天给药一次；任选地，2)安罗替尼或其药学上可接受的盐于每个治疗周期的第1-28天连续给药。
在本申请的一些实施方案中，所述第二治疗阶段的给药方案包括：1)抗PD-L1抗体于每个治疗周期的第1天给药一次；和2)安罗替尼或其药学上可接受的盐于每个治疗周期的第1-14天连续给药。
在本申请的一些实施方案中，所述第二治疗阶段的给药方案包括：1)抗PD-L1抗体hu5G11-hIgG1于每个治疗周期的第1天给药一次；2)安罗替尼二盐酸盐于每个治疗周期的第1-14天连续给药。
在本申请的一些实施方案中，所述抗PD-L1抗体于每个治疗周期的第1、2、3、4、5、6、或7天给药一次，优选于每个治疗周期的第1天给药一次。
在本申请的一些实施方案中，所述安罗替尼或其药学上可接受的盐于每个治疗周期的第1-7天、第7-14天、第1-14天、或第7-21天连续给药，优选于每个治疗周期的第1-14天连续给药。
在本申请的一些实施方案中，所述铂类抗肿瘤药物于每个治疗周期的第1、2、3、4、5、6、或7天给药一次，优选于每个治疗周期的第1天给药一次。
在本申请的一些实施方案中，所述拓扑异构酶抑制剂于每个治疗周期的第1-3天、第1-4天、第1-5天、第1-6天、第1-7天、第2-4天、第2-5天、第2-6天、第2-7天、第3-5天、第3-6天、第3-7天、第4-6天、第4-7天、或第5-7天连续给药，优选于每个治疗周期的第1-3天连续给药。
技术效果
本申请的药物组合可安全、有效地治疗小细胞肺癌。在一些实施方案中，本申请的药物组合可安全、有效地治疗广泛期小细胞肺癌。在一些实施方案中，本申请的药物组合在患者中可提供具有更高耐受性的治疗，与单独给予组合中任一药物或任两种药物相比，其抗肿瘤效果更好，和/或不良反应和/或并发症更少。在一些实施方案中，本申请的药物组合在小细胞肺癌的治疗中，表现出更优异的抗肿瘤协同效果。
小细胞肺癌患者中，尤其是广泛期小细胞肺癌患者，在接受本申请的药物组合治疗后，显著延长患者的中位PFS(无进展生存期)、和/或中位OS、和/或OS(总生存期)。在一些实施方案中，接受治疗后，患者的中位PFS达到5-10个月；在一些具体的实施方案中，患者的中位PFS甚至超过10个月。在一些实施方案中，接受治疗后，患者的中位OS达到13-20个月；在一些具体的实施方案中，患者的中位OS甚至超过20个月。
小细胞肺癌患者在接受本申请的药物组合治疗后，患者的客观缓解率(ORR)、疾病控制率(DCR)具有显著提高。
在本申请一个实施方案中，57岁患者，经临床诊断为右下肺广泛期小细胞肺癌，伴双肺门、纵隔、双锁骨上淋巴结、右肺中叶转移，在接受本申请所述的抗PD-L1抗体hu5G11-hIgG1注射液、盐酸安罗替尼胶囊、卡铂注射液和依托泊苷注射液的研究方案治疗2个周期(42天，每3周为一个治疗周期)后，靶病灶(右肺下叶肿块病灶、肺中叶肿块病灶和左肺门淋巴结)之和为21mm，缩小了65％，整体疗效评估为部分缓解(PR)。之后患者继续接受上述方案治疗2个周期，然后接受抗PD-L1抗体hu5G11-hIgG1注射液和盐酸安罗替尼胶囊进行维持治疗后，靶病灶进一步缩小或者消失，疗效评估持续为部分缓解(PR)。截止到数据统计日，无进展生存期(PFS)超过27个月，该患者仍在继续接受治疗。
在本申请另一个实施方案中，69岁患者，经临床诊断为左下肺小细胞肺癌，伴左下肺门、左下肺叶转移，在接受本申请所述的抗PD-L1抗体hu5G11-hIgG1注射液、盐酸安罗替尼胶囊、卡铂注射液和依托泊苷注射液的研究方案治疗2个周期(42天，每3周为一个治疗周期)后，靶病灶(包括：左下肺门肿块病灶、纵隔淋巴结、左下肺结节病灶)之和为21mm，缩小了79.4％，整体疗效评估为部分缓解(PR)。之后患者继续接受上述方案治疗2个周期，然后接受抗PD-L1抗体hu5G11-hIgG1注射液和盐酸安罗替尼胶囊进行维持治疗后，靶病灶进一步缩小或者消失，疗效评估持续为部分缓解(PR)，患者的无进展生存期(PFS)超过20个月。
在本申请又一个实施方案中，55岁患者，经临床诊断为左肺门小细胞肺癌，伴纵隔淋巴结、骨转移。 在接受本申请所述的抗PD-L1抗体hu5G11-hIgG1注射液、盐酸安罗替尼胶囊、卡铂注射液和依托泊苷注射液的研究方案治疗2个周期(42天，每3周为一个治疗周期)后，靶病灶(包括：左肺门肿物病灶、纵隔淋巴结)之和为41mm，缩小了39.7％，整体疗效评估为部分缓解(PR)。之后患者继续接受上述方案治疗2个周期，然后接受抗PD-L1抗体hu5G11-hIgG1注射液和盐酸安罗替尼胶囊进行维持治疗后，靶病灶进一步缩小或者消失，疗效评估持续为部分缓解(PR)。截止到数据统计日，无进展生存期(PFS)超过26个月，患者仍在继续接受治疗。
定义和说明
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本申请中出现商品名时，意在指代其对应的商品或其活性成分。
本文中，除非另有说明，其中涉及安罗替尼或其药学上可接受的盐的量，均是指其中活性成分安罗替尼游离碱的量。
除非另有说明，术语“剂量”是指不考虑患者的重量或体表面积(BSA)施用给患者的剂量。例如，60kg人和100kg人将接受相同剂量的抗体(例如，240mg抗PD-1抗体)。
如文本所用，术语“药物组合”是指同时或先后施用的两种或两种以上的活性成分(以各自的活性成分本身的形式施用，或者以其各自的药学上可接受的盐或酯等衍生物、前药或组合物的形式施用)的组合。所述活性物质可以各自作为单一制剂同时地、或各自作为单一制剂以任何顺序依次地施用于受试者。
如本文所用，术语“抗体”是指具有至少一个抗原结合结构域的结合蛋白。本申请的抗体和其片段可以是整个抗体或其任何片段。因此，本申请的抗体和片段包括单克隆抗体或其片段和抗体变体或其片段，以及免疫缀合物。抗体片段的实例包括Fab片段、Fab'片段、F(ab)'片段、Fv片段、分离的CDR区、单链Fv分子(scFv)、Fd片段和本领域已知的其他抗体片段。抗体和其片段还可以包括重组多肽、融合蛋白和双特异性抗体。本文公开的抗PD-L1抗体和其片段可以是IgG1、IgG2、IgG3或IgG4同种型。术语“同种型”是指由重链恒定区基因编码的抗体种类。在一个实施方案中，本文公开的抗PD-L1抗体和其片段是IgG1或IgG4同种型。本申请的PD-L1抗体和其片段可以衍生自任何物种，其包括但不限于小鼠、大鼠、兔、灵长类动物、美洲驼和人。PD-L1抗体和其片段可以是嵌合抗体、人源化抗体或完整的人抗体。在一个实施方案中，抗PD-L1抗体是由源自小鼠的杂交瘤细胞系产生的抗体。因此，在一个实施方案中，抗PD-L1抗体是鼠类抗体。在另一个实施方案中，抗PD-L1抗体是嵌合抗体。在另一个实施方案中，嵌合抗体是小鼠-人嵌合抗体。在另一个实施方案中，抗体是人源化抗体。在另一个实施方案中，抗体衍生自鼠类抗体并且是人源化的。
“人源化抗体”是下述抗体：所述抗体含有衍生自非人抗体的互补决定区(CDR)；和衍生自人抗体的框架区以及恒定区。例如，本文提供的抗PD-L1抗体可以包含衍生自一种或多种鼠类抗体的CDR以及人框架区和恒定区。因此，在一个实施方案中，本文提供的人源化抗体与所述抗体的CDR所衍生自的鼠类抗体结合PD-L1上的相同表位。本文提供了示例性人源化抗体。包含本文提供的重链CDR和轻链CDR的另外的抗PD-L1抗体或其变体可以使用任何人框架序列产生，并且也包括在本申请中。在一个实施方案中，适用于在本申请中使用的框架序列包括在结构上与本文提供的框架序列类似的那些框架序列。可以在框架区中进行另外修饰以改进本文提供的抗体的特性。此类另外的框架修饰可以包括化学修饰；点突变以降低免疫原性或去除T细胞表位；或使突变回复为原始种系序列中的残基。在一些实施方案中，此类修饰包括对应于本文示例的突变的那些修饰，包括对种系序列的回复突变。例如，在一个实施方案中，本文提供的人源化抗体的VH和/或VL的人框架区中的一个或多个氨基酸被回复突变为亲本鼠类抗体中对应的氨基酸。例如，对于人源化5G11和人源化13C5的VH和VL，上述模板人抗体的框架氨基酸的几个位点被回复突变为小鼠5G11和13C5抗体中对应的氨基酸序列。在一个实施方案中，轻链可变区的位置53和/或60和/或67处的氨基酸被回复突变为在小鼠5G11或13C5轻链可变区中的所述位置处发现的对应的氨基酸。在另一个实施方案中，重链可变区的位置24和/或28和/或30和/或49和/或73和/或83和/或94处的氨基酸被回复突变为在小鼠5G11或13C5重链可变区中的所述位置处发现的对应的氨基酸。在一个实施方案中，人源化5G11抗体包含轻链可变区，其中在位置60处的氨基酸从Ser(S)突变为Asp(D)，并且在位置67处 的氨基酸从Ser(S)突变为Tyr(Y)；以及重链可变区，其中在位置24处的氨基酸从Phe(F)突变为Val(V)，在位置49处的氨基酸从Ala(A)突变为Gly(G)，在位置73处的氨基酸从Thr(T)突变为Asn(N)，并且在位置83处的氨基酸从Thr(T)突变为Asn(N)。在一个实施方案中，人源化13C5抗体包含轻链可变区，其中在位置53处的氨基酸从Tyr(Y)突变为Lys(K)；以及重链可变区，其中在位置28处的氨基酸从Thr(T)突变为Ile(I)，在位置30处的氨基酸从Ser(S)突变为Arg(R)，在位置49处的氨基酸从Ser(S)突变为Ala(A)，并且在位置94处的氨基酸从Tyr(Y)突变为Asp(D)。另外的或另选的回复突变可以在本文提供的人源化抗体的框架区中进行以改进抗体的特性。本申请还包括下述人源化抗体，所述人源化抗体结合PD-L1并且包含对应于本文所述的相对于任何合适的框架序列的示例性修饰的框架修饰，以及以其他方式改进抗体特性的其他框架修饰。
本申请提供了结合PD-L1的分离的抗体或其片段，其中所述抗体由可以杂交瘤产生，所述杂交瘤选自由本文称为13C5、5G11的杂交瘤组成的组。因此，本申请还包括杂交瘤13C5、5G11，以及产生本文公开的抗体的任何杂交瘤。本申请还提供了编码本文提供的抗体和其片段的分离的多核苷酸。本申请还包括包含分离的多核苷酸的表达载体，和包含所述表达载体的宿主细胞。
“分离的抗体”表示这样的抗体：其基本上不含有具有不同抗原特异性的其它抗体(例如，分离的特异性地结合PD-1的抗体基本上不含有特异性地结合除PD-1以外的抗原的抗体)。但是，分离的特异性地结合PD-1的抗体可以具有与其它抗原(诸如来自不同物种的PD-1分子)的交叉反应性。此外，分离的抗体可以基本上不含有其它细胞材料和/或化学物质。
术语“单克隆抗体”(“mAb”)表示单一分子组成的抗体分子(即，这样的抗体分子：其基本序列是基本上相同的，并且其表现出对特定表位的单一结合特异性和亲和力)的非天然存在的制备物。mAb是分离的抗体的一个例子。通过本领域技术人员已知的杂交瘤技术、重组技术、转基因技术或其它技术，可以生产mAb。
本文公开的抗体和其抗原结合片段对PD-L1是特异性的。在一个实施方案中，抗体或和其片段对PD-L1是特异性的。在一个实施方案中，本文提供的抗体和片段结合人或灵长类动物PD-L1，但不结合来自任何其他哺乳动物的PD-L1。在另一个实施方案中，抗体或和其片段不结合小鼠PD-L1。术语“人PD-L1”、“hPD-L1”和“huPD-L1”等在本文中可互换使用，并且是指人PD-L1和人PD-L1的变体或同种型。“特异于”意指抗体和其片段以比任何其他靶标更大的亲和力结合PD-L1。
术语“治疗”一般是指获得需要的药理和/或生理效应。该效应根据部分或完全稳定或治愈疾病和/或由于疾病产生的副作用，可以是治疗性的。本文使用的“治疗”涵盖了对患者疾病的任何治疗，包括：(a)抑制疾病的症状，即阻止其发展；或(b)缓解疾病的症状，即，导致疾病或症状退化。
术语“有效量”意指(i)治疗特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的活性物质(例如本申请的抗体或化合物)的量可根据一些因素而变化，诸如个体的疾病状态、年龄、性别和重量，以及治疗剂或治疗剂组合在个体中引发所需应答的能力。有效量也可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“施用”或“给予”可互换使用，表示使用本领域技术人员已知的多种方法和递送系统中的任一种，向主体物理引入包含治疗剂的组合物。免疫检验点抑制剂(例如，抗PD-1抗体或抗PD-L1抗体)的施用途径包括静脉内、肌肉内、皮下、腹膜内、脊柱或其它胃肠外施用途径，例如通过注射或输注。本文中使用的短语“胃肠外施用”是指通常通过注射进行的除了肠内和局部施用以外的施用模式，且包括但不限于，静脉内、肌肉内、动脉内、鞘内、淋巴管内、病灶内、囊内、眶内、心内、真皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内、硬膜外和胸骨内注射和输注、以及体内电穿孔。在某些实施方案中，所述免疫检验点抑制剂(例如，抗-PD-1抗体或抗-PD-L1抗体)通过非胃肠外途径施用，在某些实施方案中，口服施用。其它非胃肠外途径包括局部、表皮或粘膜施用途径，例如，鼻内地、阴道地、直肠地、舌下地或局部地。还可以执行施用，例如，一次、多次，和/或在一个或多个延长的时间段中。
术语“药学上可接受的”是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或 并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”包括碱根离子与自由酸形成的盐或酸根离子与自由碱形成的盐，例如包括盐酸盐、氢溴酸盐、硝酸盐、硫酸盐、磷酸盐、甲酸盐、乙酸盐、三氟乙酸盐、富马酸盐、草酸盐、马来酸盐、柠檬酸盐、琥珀酸盐、甲磺酸盐、苯磺酸盐或对甲基苯磺酸盐，优选盐酸盐、氢溴酸盐、硫酸盐、甲酸盐、乙酸盐、三氟乙酸盐、富马酸盐、马来酸盐、甲磺酸盐、对甲基苯磺酸盐、钠盐、钾盐、铵盐、氨基酸盐等。本申请中，当形成药学上可接受的盐时，所述自由酸与碱根离子的摩尔量之比为约1:0.5～1:5，优选1:0.5、1:1、1:2、1:3、1:4、1:5、1:6、1:7或1:8。本申请中，当形成药学上可接受的盐时，所述自由碱与酸根离子的摩尔量之比为约1:0.5～1:5，优选1:0.5、1:1、1:2、1:3、1:4、1:5、1:6、1:7或1:8。
在本文中，术语“受试者”或“患者”可互换使用。在一些实施方案中，术语“受试者”或“患者”是哺乳动物。在部分实施方案中，所述受试者或患者是小鼠。在部分实施方案中，所述受试者或患者是人。
术语“约”应理解为包括在平均值的三个标准偏差内或特定领域中的标准公差范围内。在某些实施方式中，约应理解为不超过0.5的变异。“约”修饰其后所有列举的值。例如，“约1、2、3”表示“约1”、“约2”、“约3”。
如本文所用，“联用”或“联合使用”意指两种或更多种活性物质可以各自作为单一制剂同时地、或各自作为单一制剂以任何顺序依次地施用于患者。
术语“单剂量”是指含有一定量药品的最小包装单元，例如一盒药有七粒胶囊，则每个胶囊为单剂量；或者每瓶注射液为单剂量。
术语“多剂量”由多个单剂量组成。
术语“固定组合”指活性组分(例如抗PD-L1抗体和安罗替尼)以固定总剂量或剂量比例，或以单一实体、药物组合物或制剂的形式同时给予患者。
术语“非固定组合”指两种以上活性组分作为独立的实体(例如药物组合物、制剂)同时、并行或依序且无具体时间限制地给予患者，其中所述给予患者的活性成分达到治疗有效量水平。非固定组合可列举的例子是鸡尾酒疗法，例如给予3种或以上之活性组分。在非固定组合中，所述各个活性组分可以作为完全独立的药物组合物进行包装、销售或给药。所述“非固定组合”也包括“固定组合”之间、或“固定组合”与任一或多种活性组分的独立实体的联合使用。
术语“药物组合物”是指一种或多种本申请的活性成分或其药物组合与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对患者给予本申请的化合物或其药物组合。
在本文中，除非另有说明，否则术语“包含、包括和含有(comprise、comprises和comprising)”或等同物为开放式表述，意味着除所列出的要素、组分和步骤外，还可涵盖其它未指明的要素、组分和步骤。
除非上下文另有明确指示，单数术语涵盖复数的指示对象，反之亦然。类似地，除非上下文另有明确指示，词语“或”意在包括“和”，反之亦然。
为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它出版物在此明确地并入本文。这些出版物仅因为它们的公开早于本申请的申请日而提供。所有关于这些文件的日期的声明或这些文件的内容的表述是基于申请者可得的信息，并且不构成任何关于这些文件的日期或这些文件的内容的正确性的承认。而且，在任何国家，在本中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。
具体实施方式
为清楚起见，进一步用实施例来阐述本申请，但是实施例并非限制本申请的范围。本申请所使用的所有试剂是市售的，无需进一步纯化即可使用。实施例中抗PD-L1抗体按WO2016022630中所述方法制得，经亲和层析后，按常规的抗体纯化方法得到含有该抗体的洗脱液。
实施例1临床试验
符合条件的受试者随机进入试验组1、试验组2或者对照组。治疗分为诱导治疗阶段和维持阶段。每2个周期评估一次疗效。疾病控制(CR+PR+SD)且不良反应可以耐受的患者，可持续用药，至失去临床 获益、毒性不可耐受、疗效评价为PD、研究者认为不适合继续用药时研究结束。
1.1主要入选标准
1)招募经病理学证实的广泛期小细胞肺癌患者(按照美国退伍军人肺癌协会Veterans Administration Lung Study Group,VALG分期)进入临床研究；
2)所述患者既往未接受过针对广泛期小细胞肺癌的系统治疗；
3)既往曾针对局限期SCLC接受放化疗的患者，必须接受过根治性治疗，并从化疗、放疗、或放化疗结束至诊断为广泛期SCLC之间至少有6个月的无治疗间歇期；
4)存在RECIST 1.1标准定义的可测量病灶；
5)年满18-75周岁；ECOG体力状况：0～1分；预计生存期超过3个月。
1.2试验药
抗PD-L1抗体注射剂hu5G11-hIgG1或抗PD-L1抗体空白注射液：1200mg或0mg抗PD-L1抗体注射液用生理盐水稀释至250mL，输注时间60±10min，输注完成后按医院常规要求进行生理盐水冲管，每21天为一治疗周期给药一次，每个周期的第1天给药。规格：100mg/10mL、300mg/10mL。
盐酸安罗替尼胶囊(活性成分为安罗替尼二盐酸盐)或盐酸安罗替尼空白胶囊：空腹服用盐酸安罗替尼胶囊(12mg)或空白胶囊(0mg)每日一次，每次一粒，连续口服2周停1周，即21天为一治疗周期，每个周期的第1-14天给药。规格：12mg、10mg、8mg。
卡铂注射液：用5％葡萄糖注射液溶解本品，浓度为10mg/ml，再将此浓度的溶液加入至5％葡萄糖注射液250-500mL中静脉滴注，每21天为一治疗周期，每个周期的第1天给药。
剂量(mg)＝5(AUC)(mg/mL/min)×[用药前7天内的肌酐清除率(mL/min)+25]。
根据肌酐Scr值计算肌酐清除率Ccr(单位：mL/min)，计算公式为：Ccr＝(140-年龄)×体重(kg)/[72×Scr(mg/dl)]或Ccr＝[(140-年龄)×体重(kg)]/[0.818×Scr(umol/L)]，肌酐清除率计算过程中应注意肌酐的单位，女性患者按计算结果×0.85。
依托泊苷注射液：计算公式算出给药剂量后，用氯化钠注射液稀释本品，浓度每毫升不超过0.25mg，每21天为一治疗周期，每个周期第1、2、3天连续给药。剂量：100mg/m 2。
1.3给药方案
治疗分为诱导治疗阶段(即第一治疗阶段)和维持阶段(即第二治疗阶段)。
第一治疗阶段为4个治疗周期：
试验组1：每21天为一治疗周期。
抗PD-L1抗体注射液，1200mg/次，21天给药一次，静脉滴注；
盐酸安罗替尼胶囊，12mg/次，连续用2周停1周，口服；
注射用卡铂，第1天给药，AUC 5mg/mL/min，静脉滴注(最大使用剂量为800mg)；
依托泊苷注射液，第1、2、3天连续给药，100mg/m 2，静脉滴注。
试验组2：每21天为一治疗周期。
抗PD-L1抗体空白注射液，0mg/次，21天给药一次，静脉滴注；
盐酸安罗替尼胶囊，12mg/次，连续用2周停1周，口服；
注射用卡铂，第1天给药，AUC 5mg/mL/min，静脉滴注(最大使用剂量为800mg)；
依托泊苷注射液，第1、2、3天连续给药，100mg/m 2，静脉滴注。
对照组：每21天为一治疗周期。
抗PD-L1抗体空白注射液，0mg/次，21天给药一次，静脉滴注；
盐酸安罗替尼空白胶囊，0mg/次，连续用2周停1周，口服；
注射用卡铂，第1天给药，AUC 5mg/mL/min，静脉滴注(最大使用剂量为800mg)；
依托泊苷注射液，第1、2、3天连续给药，100mg/m 2，静脉滴注。
第二治疗阶段(持续直到失去临床获益、毒性不可耐受、疗效评价为PD、研究者认为不适合继续用药)：
试验组1：每21天为一治疗周期。
抗PD-L1抗体注射液，1200mg/次，21天给药一次，静脉滴注；
盐酸安罗替尼胶囊，12mg/次，连续用2周停1周，口服；
试验组2：每21天为一治疗周期。
抗PD-L1抗体空白注射液，0mg/次，21天给药一次，静脉滴注；
盐酸安罗替尼胶囊，12mg/次，连续用2周停1周，口服；
对照组：每21天为一治疗周期。
抗PD-L1抗体空白注射液，0mg/次，21天给药一次，静脉滴注；
盐酸安罗替尼空白胶囊，0mg/次，连续用2周停1周，口服。
1.3评价标准
1)安全性评价：采用NCI－CTC AE 5.0标准评价药物的不良反应。
2)疗效评价：根据RECIST 1.1/iRECIST判定疾病状态。以RECIST 1.1评价标准为主。
1.4终点指标
主要终点：无进展生存期(PFS)、总生存期(OS)；
次要终点：客观缓解率(ORR)＝(完全缓解(CR)+部分缓解(PR))、疾病控制率(DCR＝CR+PR+疾病稳定(SD))、无进展生存期(PFS)、总生存期(OS)、缓解持续时间(DOR)等。不良事件(AE)和严重不良事件(SAE)的发生率和严重程度，以及异常实验室检查指标。
1.5试验结果
截至数据统计日，本试验入组超过500名受试者，根据目前整体的研究数据来看，与传统一线标准化疗方案(即，对照组)相比，接受试验组1和试验组2中方案，受试者均有希望能达到显著的临床获益。此外，目前整体疗效数据的提升，提示着接受试验组1中方案治疗的受试者中位PFS显著提高；中位OS有望超过14个月。表明抗PD-L1抗体联合安罗替尼或其药学上可接受的盐和化疗药物可以作为小细胞肺癌、尤其是广泛期小细胞肺癌的更加有效的一线治疗方案。
本领域技术人员将认识到，本申请的范围并不限于上文描述的各种具体实施方式和实施例，而是能够在不脱离本申请的精神的情况下，进行各种修改、替换、或重新组合，这都落入了本申请的保护范围内。

Claims (48)

  1. 含抗PD-L1抗体、安罗替尼或其药学上可接受的盐、和化疗药物的药物组合在制备用于治疗小细胞肺癌的药物中的用途。
  2. 根据权利要求1所述的用途，其中，所述药物组合包括第一药物组合，以及任选地，第二药物组合，所述第一药物组合包括抗PD-L1抗体、安罗替尼或其药学上可接受的盐、和化疗药物。
  3. 根据权利要求2所述的用途，其中，所述第二药物组合包括抗PD-L1抗体、和安罗替尼或其药学上可接受的盐。
  4. 根据权利要求2或3所述的用途，其中，所述第一药物组合为在第一治疗阶段向有需要的患者给予，以及任选地，所述第二药物组合为在第二治疗阶段向有需要的患者给予。
  5. 根据权利要求4所述的用途，其中，所述第一治疗阶段的治疗周期为1到10个治疗周期，优选2到8个治疗周期，最优选4个治疗周期。
  6. 根据权利要求1-5任一所述的用途，其中，所述化疗药物选自铂类抗肿瘤药物和拓扑异构酶抑制剂中的一种或多种。
  7. 根据权利要求6所述的用途，其中，所述铂类抗肿瘤药物选自顺铂、卡铂、奈达铂、双环铂、吡铂、奥沙利铂、米铂或洛铂中的一种或者多种。
  8. 根据权利要求6或7所述的用途，其中，所述拓扑异构酶抑制剂选自喜树碱、托泊替康、阿霉素、柔红霉素、表柔比星、伊达比星、米托蒽醌、伊立替康、拓扑替康、依托泊苷、或替尼泊苷中的一种或者多种。
  9. 根据权利要求1-8任一所述的用途，其中，所述化疗药物选自铂类抗肿瘤药物和依托泊苷，优选地选自卡铂和依托泊苷。
  10. 根据权利要求1-9任一所述的用途，其中，抗PD-L1抗体被制备成药物组合物，所述药物组合物中抗PD-L1抗体的浓度为10～60mg/mL，或者10、20、30、40、50或者60mg/mL。
  11. 根据权利要求1-10任一所述的用途，其中，所述药物组合为适用于在单个治疗周期(例如21天的一个治疗周期)内施用的制剂，包括：含600-2400mg抗PD-L1抗体的药物组合物和含84-168mg安罗替尼或其药学上可接受的盐的药物组合物。
  12. 根据权利要求9-11任一所述的用途，其中所述适用于在单个治疗周期内施用的制剂还包括：含90mg～1800mg的依托泊苷的药物组合物，和/或含50～800mg的卡铂的药物组合物。
  13. 根据权利要求1-12任一所述的用途，其中，抗PD-L1抗体或其药物组合物的日剂量为600、800、1000、1200、1400、1600、1800、2000、2200或2400mg，安罗替尼或其药学上可接受的盐的日剂量为6mg-12mg，或者6mg、8mg、10mg或者12mg。
  14. 根据权利要求9-13任一所述的用途，其中，依托泊苷以60～100mg/m 2的剂量给药，优选以100mg/m 2的剂量给药。
  15. 根据权利要求9-14任一所述的用途，其中，卡铂以AUC为5～7mg/ml/min的剂量给药，优选以AUC为5mg/ml/min的剂量给药。
  16. 根据权利要求1-15任一所述的用途，其中，所述抗PD-L1抗体、安罗替尼或其药学上可接受的盐和化疗药物各自呈药物组合物的形式，可同时、先后或者依次序给药。
  17. 根据权利要求1-16任一所述的用途，其中，每1周、每2周、每3周、或者每4周为一个治疗周期。
  18. 根据权利要求1-17任一所述的用途，其中，每3周为一个治疗周期，抗PD-L1抗体在每个周期的第1天给药，安罗替尼或其药学上可接受的盐在每个周期的第1-14天给药。
  19. 根据权利要求9-18任一所述的用途，其中，每3周为一个治疗周期，依托泊苷在每个周期的第1-3天给药，卡铂在每个周期的第1天给药。
  20. 根据权利要求1-19任一所述的用途，其中，所述小细胞肺癌包括局限期和广泛期小细胞肺癌；
    或者，所述小细胞肺癌为在先未接受过系统治疗的小细胞肺癌，优选地所述小细胞肺癌为在先未接受过系 统治疗的广泛期小细胞肺癌；
    或者，所述小细胞肺癌为晚期和/或难治性和/或复发性和/或转移性的小细胞肺癌。
  21. 治疗小细胞肺癌的方法，包括：向有需要的患者给予治疗有效量的抗PD-L1抗体、安罗替尼或其药学上可接受的盐、和化疗药物。
  22. 根据权利要求21所述的方法，其包括在第一治疗阶段向有需要的患者给予第一药物组合；以及任选地，在第二治疗阶段向有需要的患者给予第二药物组合，所述第一药物组合包括抗PD-L1抗体、安罗替尼或其药学上可接受的盐、和化疗药物。
  23. 根据权利要求22所述的方法，其中，所述第二药物组合包括抗PD-L1抗体、和安罗替尼或其药学上可接受的盐。
  24. 根据权利要求22或23所述的方法，其中，所述第一治疗阶段的治疗周期为1到10个治疗周期，优选2到8个治疗周期，最优选4个治疗周期。
  25. 根据权利要求21-24任一所述的方法，其中，所述化疗药物选自铂类抗肿瘤药物和拓扑异构酶抑制剂中的一种或多种。
  26. 根据权利要求21-25任一所述的方法，其中，所述化疗药物选自铂类抗肿瘤药物和依托泊苷，优选地选自卡铂和依托泊苷。
  27. 根据权利要求21-26任一所述的方法，其中，抗PD-L1抗体、安罗替尼或其药学上可接受的盐和化疗药物各自呈药物组合物的形式，可同时、先后或依次给药。
  28. 根据权利要求21-27任一所述的方法，其中，抗PD-L1抗体或其药物组合物的日剂量为600～2400mg或者600、800、1000、1200、1400、1600、1800、2000、2200或2400mg。
  29. 根据权利要求21-30任一所述的方法，其中，安罗替尼或其药学上可接受的盐或其药物组合物的日剂量为6mg-12mg，或者6mg、8mg、10mg或者12mg。
  30. 根据权利要求26-29任一所述的方法，其中，依托泊苷以60～100mg/m 2的剂量给药，优选以100mg/m 2的剂量给药。
  31. 根据权利要求26-30任一所述的方法，其中，卡铂以AUC为5～7mg/ml/min的剂量给药，优选以AUC为5mg/ml/min的剂量给药。
  32. 根据权利要求21-31任一所述的方法，其中，每1周、每2周、每3周、或者每4周为一个治疗周期。
  33. 根据权利要求21-32任一所述的方法，其中，每3周为一个治疗周期，抗PD-L1抗体在每个周期的第1天给药，安罗替尼或其药学上可接受的盐在每个周期的第1-14天给药。
  34. 根据权利要求26-33任一所述的方法，其中，每3周为一个治疗周期，依托泊苷在每个周期的第1-3天给药，卡铂在每个周期的第1天给药。
  35. 根据权利要求21-34任一所述的方法，其中，所述小细胞肺癌包括局限期和广泛期小细胞肺癌；
    或者，所述小细胞肺癌为在先未接受过系统治疗的小细胞肺癌，优选地所述小细胞肺癌为在先未接受过系统治疗的广泛期小细胞肺癌；
    或者，所述小细胞肺癌为晚期和/或难治性和/或复发性和/或转移性的小细胞肺癌。
  36. 治疗小细胞肺癌的药物组合，其包括：抗PD-L1抗体、安罗替尼或其药学上可接受的盐和化疗药物。
  37. 根据权利要求36所述的药物组合，其中，所述药物组合包括第一药物组合，以及任选地，第二药物组合，所述第一药物组合包括抗PD-L1抗体、安罗替尼或其药学上可接受的盐、和化疗药物。
  38. 根据权利要求37所述的药物组合，其中，所述第二药物组合包括抗PD-L1抗体、和安罗替尼或其药学上可接受的盐。
  39. 根据权利要求36-38任一所述的药物组合，其中，所述化疗药物选自铂类抗肿瘤药物、和/或拓扑异构酶抑制剂中的一种或多种，优选所述化疗药物选自铂类抗肿瘤药物和依托泊苷，进一步优选地选自卡铂和依托泊苷。
  40. 根据权利要求36-39任一所述的药物组合，所述抗PD-L1抗体、安罗替尼或其药学上可接受的盐和化疗药物各自呈药物组合物的形式。
  41. 根据权利要求36-40任一所述的药物组合，其包括：含600～2400mg的抗PD-L1抗体以多剂量形式提供的药物组合物和单位剂量为6mg、8mg、10mg和/或12mg的安罗替尼或其药学上可接受的盐的药物组合物。
  42. 根据权利要求39-41任一所述的药物组合，其还包括：含90mg～1800mg的依托泊苷的药物组合物，和/或含50～800mg的卡铂的药物组合物。
  43. 根据权利要求36-42任一所述的药物组合，其包装于同一试剂盒中，所述试剂盒还包括治疗小细胞肺癌的说明。
  44. 根据权利要求1-20任一所述的用途、或权利要求21-35任一所述的方法、或权利要求36-43任一所述的药物组合，其中，所述抗PD-L1抗体包含如下氨基酸序列：与SEQ ID NO:1或SEQ ID NO:4所示的氨基酸序列有至少80％同源性的重链CDR1区；与SEQ ID NO:2或SEQ ID NO:5所示的氨基酸序列有至少80％同源性的重链CDR2区；与SEQ ID NO:3或SEQ ID NO:6所示的氨基酸序列有至少80％同源性的重链CDR3区；与SEQ ID NO:7或SEQ ID NO:10所示的氨基酸序列有至少80％同源性的轻链CDR1区；与SEQ ID NO:8或SEQ ID NO:11所示的氨基酸序列有至少80％同源性的轻链CDR2区；与SEQ ID NO:9或SEQ ID NO:12所示的氨基酸序列有至少80％同源性的轻链CDR3区。
  45. 根据权利要求1-20任一所述的用途、或权利要求21-35任一所述的方法、或权利要求36-43所述的药物组合，其中，所述抗PD-L1抗体包含如下氨基酸序列：选自SEQ ID NO:1或SEQ ID NO:4的重链CDR1区；选自SEQ ID NO:2或SEQ ID NO:5的重链CDR2区；选自SEQ ID NO:3或SEQ ID NO:6的重链CDR3区；选自SEQ ID NO:7或SEQ ID NO:10的轻链CDR1区；选自SEQ ID NO:8或SEQ ID NO:11的轻链CDR2区；选自SEQ ID NO:9或SEQ ID NO:12的轻链CDR3区。
  46. 根据权利要求1-20任一所述的用途、或权利要求21-35任一所述的方法、或权利要求36-43任一所述的药物组合，其中，所述抗PD-L1抗体包含：具有以SEQ ID NO:1示出的氨基酸序列的重链CDR1区，具有以SEQ ID NO:2示出的氨基酸序列的重链CDR2区，具有以SEQ ID NO:3示出的氨基酸序列的重链CDR3区；以及具有以SEQ ID NO:7示出的氨基酸序列的轻链CDR1区，具有以SEQ ID NO:8示出的氨基酸序列的轻链CDR2区，具有以SEQ ID NO:9示出的氨基酸序列的轻链CDR3区。
  47. 根据权利要求1-20任一所述的用途、或权利要求21-35任一所述的方法、或权利要求36-43任一所述的药物组合，其中，所述抗PD-L1抗体包含如下氨基酸序列：与SEQ ID NO:13或SEQ ID NO:14所示的氨基酸序列有至少80％同源性的重链可变区；与SEQ ID NO:15或SEQ ID NO:16所示的氨基酸序列有至少80％同源性的轻链可变区。
  48. 根据权利要求1-20任一所述的用途、或权利要求21-35任一所述的方法、或权利要求36-43任一所述的药物组合，其中，所述抗PD-L1抗体包含：选自hu13C5-hIgG1、hu13C5-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4人源化抗体的可变重链，和选自hu13C5-hIgG1、hu13C5-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4人源化抗体的可变轻链。
PCT/CN2022/110539 2021-08-05 2022-08-05 治疗小细胞肺癌的药物组合 Ceased WO2023011631A1 (zh)

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