WO2020151759A1 - 治疗肿瘤的联用药物组合物 - Google Patents

治疗肿瘤的联用药物组合物 Download PDF

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Publication number
WO2020151759A1
WO2020151759A1 PCT/CN2020/073957 CN2020073957W WO2020151759A1 WO 2020151759 A1 WO2020151759 A1 WO 2020151759A1 CN 2020073957 W CN2020073957 W CN 2020073957W WO 2020151759 A1 WO2020151759 A1 WO 2020151759A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
antibody
seq
anlotinib
amino acid
Prior art date
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PCT/CN2020/073957
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English (en)
French (fr)
Inventor
张喜全
王训强
杨朝强
樊宇晨
范孟雪
封帆
孙楠
刘瑶
张弛
江海
Original Assignee
正大天晴药业集团股份有限公司
正大天晴药业集团南京顺欣制药有限公司
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Application filed by 正大天晴药业集团股份有限公司, 正大天晴药业集团南京顺欣制药有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to CA3127388A priority Critical patent/CA3127388A1/en
Priority to CN202080010713.XA priority patent/CN113347996B/zh
Priority to JP2021543515A priority patent/JP2022526694A/ja
Priority to KR1020217026460A priority patent/KR20210120022A/ko
Priority to US17/425,006 priority patent/US20220089742A1/en
Priority to EP20745516.3A priority patent/EP3915583A4/en
Priority to AU2020212767A priority patent/AU2020212767A1/en
Publication of WO2020151759A1 publication Critical patent/WO2020151759A1/zh

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • 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

  • This application belongs to the field of biomedicine, and relates to a combined pharmaceutical composition for treating tumors.
  • 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 are also related to tumor cells. Proliferation, differentiation, migration and apoptosis are closely related. Many receptor tyrosine kinases are related to the formation of tumors, and can be divided into epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), and vascular endothelial cell growth factor receptor according to the structure of their extracellular region. Body (VEGFR), Fibroblast Growth Factor Receptor (FGFR), etc.
  • EGFR epidermal growth factor receptor
  • PDGFR platelet-derived growth factor receptor
  • 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 l (Programmed death, PD-1).
  • PD-L1 is highly expressed on the surface of a variety of tumor cells, and the degree of tumor malignancy and poor prognosis 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 to inhibit the activation and proliferation of T cells, promote effector T cells into a state of exhaustion or anergy, and induce T cell growth Apoptosis stimulates the differentiation of helper T cells 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 effector T cell activity in the tumor microenvironment , So that T cells can play the function of killing and inhibiting tumor cells. Because anti-PD-L1 antibody can directly act on tumor tissues, it has high specificity and safety.
  • WO2016022630 discloses a type of PD-L1 antibody, which has a high affinity for PD-L1, can significantly inhibit the interaction of PD-L1 and PD-1 on the cell surface, and significantly promote the secretion of IL-2 and INF- ⁇ by T cells .
  • cancer proliferative diseases
  • the present application provides a combination pharmaceutical composition, which includes an anti-PD-L1 antibody and anlotinib.
  • Anlotinib is in the free base form, or in the form of its pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt of anlotinib may be hydrochloride or dihydrochloride.
  • the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain CDR1 region having at least 80% homology with the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 4; and SEQ ID NO: 2 or A heavy chain CDR2 region with at least 80% homology to the amino acid sequence shown in SEQ ID NO: 5; a heavy chain with at least 80% homology to the amino acid sequence shown in SEQ ID NO: 3 or SEQ ID NO: 6 CDR3 region; light chain CDR1 region that has at least 80% homology with the amino acid sequence shown in SEQ ID NO: 7 or SEQ ID NO: 10; and the amino acid sequence shown in SEQ ID NO: 8 or SEQ ID NO: 11 A light chain CDR2 region having at least 80% homology; a light chain CDR3 region having at least 80% homology with the amino acid sequence shown in SEQ ID NO: 9 or SEQ ID NO: 12.
  • the 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; selected from SEQ ID NO: 3 or SEQ ID NO: 6 heavy chain CDR3 region; selected from SEQ ID NO: 7 or SEQ ID NO: 10 light chain CDR1 region; selected from SEQ ID NO: 8 or SEQ ID The light chain CDR2 region of NO: 11; the light chain CDR3 region of SEQ ID NO: 9 or SEQ ID NO: 12.
  • the anti-PD-L1 antibody comprises: a heavy chain CDR1 region having the amino acid sequence shown in SEQ ID NO: 1, and a heavy chain CDR2 region having the amino acid sequence shown in SEQ ID NO: 2, having The heavy chain CDR3 region having the amino acid sequence shown in SEQ ID NO: 3; and the light chain CDR1 region having the amino acid sequence shown in SEQ ID NO: 7, and the light chain CDR1 region having the amino acid sequence shown in SEQ ID NO: 8
  • the chain CDR2 region has the light chain CDR3 region with the amino acid sequence shown in SEQ ID NO: 9.
  • the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain variable region having at least 80% homology with the amino acid sequence shown in SEQ ID NO: 13 or SEQ ID NO: 14; and SEQ ID NO: 15 or SEQ ID NO: 16 has a light chain variable region with at least 80% homology.
  • the anti-PD-L1 antibody comprises: a variable heavy chain selected from a humanized antibody of hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4, and a variable heavy chain selected from hu13C5-hIgG1, hu13C5-hIgG4 , Hu5G11-hIgG1 or hu5G11-hIgG4 humanized variable light chain.
  • the above-mentioned combination pharmaceutical composition of the present application is packaged in the same kit, and the kit also includes the PD-L1 antibody and anlotinib combined for the treatment of biliary system tumors, liver cancer, triple-negative breast cancer and/or Illustration of lung cancer.
  • the application provides a combination pharmaceutical composition, which includes a pharmaceutical composition containing 600-2400 mg of anti-PD-L1 antibody and a single dose of 6 mg, 8 mg, 10 mg and/or 12 mg of anlotinib combination.
  • the pharmaceutical composition containing the anti-PD-L1 antibody is a single dose or multiple doses.
  • the present application provides a combination pharmaceutical composition, which includes a pharmaceutical composition containing 600-2400 mg of anti-PD-L1 antibody provided in multiple doses and a single dose of 6 mg, 8 mg, 10 mg and/or 12 mg.
  • the pharmaceutical composition of Rotinib is a pharmaceutical composition containing 600-2400 mg of anti-PD-L1 antibody provided in multiple doses and a single dose of 6 mg, 8 mg, 10 mg and/or 12 mg.
  • the pharmaceutical composition of Rotinib is provided in multiple doses and a single dose of 6 mg, 8 mg, 10 mg and/or 12 mg.
  • the present application provides a combination pharmaceutical composition, which is a formulation suitable for administration in a single treatment cycle (for example, a treatment cycle of 21 days), and includes a drug containing 600-2400 mg of anti-PD-L1 antibody The composition and the pharmaceutical composition containing 84-168 mg of anlotinib.
  • the present application provides a combined pharmaceutical composition, which 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 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); the anti-PD-L1 antibody can be packaged in single or Multiple equal parts (for example, 2 equal parts, 4 equal parts or more) are packaged.
  • the present application provides a combination pharmaceutical composition for the treatment of biliary system tumors, liver cancer, triple-negative breast cancer and/or lung cancer, which includes an anti-PD-L1 antibody and anlotinib.
  • the present application also provides a method for treating biliary system tumors, liver cancer, triple-negative breast cancer and/or lung cancer, which comprises administering to a subject an effective amount of the above-mentioned combination pharmaceutical composition of the present application.
  • the application also provides the use of the above-mentioned combined pharmaceutical composition in the preparation of a medicine for treating biliary system tumors, liver cancer, triple negative breast cancer and/or lung cancer.
  • the application also provides the use of anti-PD-L1 antibody and anlotinib in the preparation of drugs for the treatment of biliary system tumors, liver cancer, triple negative breast cancer and/or lung cancer.
  • the anti-PD-L1 antibody and anlotinib are each in the form of a pharmaceutical composition, which can be administered simultaneously, sequentially or at intervals. Furthermore, 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. Furthermore, the anlotinib is administered in a dose of 6 mg, 8 mg, 10 mg or 12 mg once a day for 2 weeks with a 1-week stop.
  • kits for the treatment of biliary system tumors, liver cancer, triple-negative breast cancer and/or lung cancer includes a pharmaceutical composition of anti-PD-L1 antibody and a pharmaceutical composition of anlotinib, And instructions for the combined use of anti-PD-L1 antibody and Anlotinib to treat biliary system tumors, liver cancer, triple negative breast cancer and/or lung cancer.
  • kit is a kit suitable for administration in a single treatment cycle (for example, a treatment cycle of 21 days), and includes a pharmaceutical composition containing 600-2400 mg of anti-PD-L1 antibody and 84-168 mg of An Luo The pharmaceutical composition of tinib.
  • this application provides a combined pharmaceutical composition for the treatment of biliary system tumors, which includes an anti-PD-L1 antibody and anlotinib.
  • the application also provides the use of the combined pharmaceutical composition in the preparation of a medicine for treating tumors of the biliary system.
  • the application also provides a method for treating tumors of the biliary system, which comprises administering to a subject an effective amount of the combination pharmaceutical composition of the application.
  • the application also provides the use of the combined pharmaceutical composition for treating tumors of the biliary system.
  • the combined pharmaceutical composition includes an anti-PD-L1 antibody and anlotinib.
  • the application also provides the use of anti-PD-L1 antibody and anlotinib in combination in the preparation of drugs for treating tumors of the biliary system.
  • the application also provides a method for treating tumors of the biliary system, which includes administering an effective amount of anti-PD-L1 antibody and anlotinib to the subject.
  • the application also provides the use of anti-PD-L1 antibody and anlotinib in combination to treat tumors of the biliary system.
  • the application also provides a combination of an anti-PD-L1 antibody and anlotinib for the treatment of tumors of the biliary system.
  • this application provides a combination pharmaceutical composition for the treatment of liver cancer, which includes an anti-PD-L1 antibody and anlotinib.
  • the application also provides the use of the combined pharmaceutical composition in the preparation of a medicine for treating liver cancer.
  • the application also provides a method for treating liver cancer, which comprises administering to a subject an effective amount of the combined pharmaceutical composition of the application.
  • the application also provides the use of the combined pharmaceutical composition for treating liver cancer.
  • the combined pharmaceutical composition includes an anti-PD-L1 antibody and anlotinib.
  • the application also provides the use of anti-PD-L1 antibody and anlotinib in combination in the preparation of drugs for the treatment of liver cancer.
  • the application also provides a method for treating liver cancer, including administering an effective amount of anti-PD-L1 antibody and anlotinib to the subject.
  • the application also provides the use of anti-PD-L1 antibody and anlotinib in combination to treat liver cancer.
  • This application also provides a combination of an anti-PD-L1 antibody and anlotinib for the treatment of liver cancer.
  • the present application provides a combination pharmaceutical composition for the treatment of triple-negative breast cancer, which includes an anti-PD-L1 antibody and anlotinib.
  • the application also provides the use of the combined pharmaceutical composition in the preparation of a medicine for treating triple negative breast cancer.
  • the application also provides a method for treating triple-negative breast cancer, which comprises administering an effective amount of the combined pharmaceutical composition of the application to a subject.
  • the application also provides the use of the combined pharmaceutical composition for treating triple-negative breast cancer.
  • the combined pharmaceutical composition includes an anti-PD-L1 antibody and anlotinib.
  • the application also provides the use of anti-PD-L1 antibody and anlotinib in combination to prepare a medicine for treating triple-negative breast cancer.
  • the application also provides a method for treating triple-negative breast cancer, including administering an effective amount of anti-PD-L1 antibody and anlotinib to the subject.
  • the application also provides the use of anti-PD-L1 antibody and anlotinib in combination to treat triple-negative breast cancer.
  • the application also provides a combination of an anti-PD-L1 antibody and anlotinib for the treatment of triple-negative breast cancer.
  • the present application provides a combination pharmaceutical composition for the treatment of lung cancer, which includes an anti-PD-L1 antibody and anlotinib.
  • the application also provides the use of the combined pharmaceutical composition in preparing a medicine for treating lung cancer.
  • the application also provides a method for treating lung cancer, which comprises administering to a subject an effective amount of the combined pharmaceutical composition of the application.
  • the application also provides the use of the combined pharmaceutical composition for treating lung cancer.
  • the combined pharmaceutical composition includes an anti-PD-L1 antibody and anlotinib.
  • this application also provides the use of anti-PD-L1 antibody and anlotinib in combination in the preparation of drugs for treating lung cancer.
  • the application also provides a method for treating lung cancer, including administering an effective amount of an anti-PD-L1 antibody and anlotinib to a subject.
  • the application also provides the use of anti-PD-L1 antibody and anlotinib in combination to treat lung cancer.
  • This application also provides a combination of an anti-PD-L1 antibody and anlotinib for the treatment of lung cancer.
  • This application provides a combination pharmaceutical composition, which includes an anti-PD-L1 antibody and anlotinib.
  • the combined pharmaceutical composition is used to treat tumor or cancer.
  • the tumor or cancer is selected from biliary system tumor, liver cancer, triple negative breast cancer or lung cancer.
  • the present application provides a combined pharmaceutical composition for the treatment of biliary system tumors, which includes an anti-PD-L1 antibody and anlotinib.
  • the combined pharmaceutical composition includes an anti-PD-L1 antibody pharmaceutical composition and anlotinib pharmaceutical composition.
  • the combination pharmaceutical composition is packaged in the same kit, and the kit further includes instructions for the combined use of PD-L1 antibody and anlotinib to treat tumors of the biliary system.
  • a combination pharmaceutical composition for the treatment of tumors of the biliary system which includes a pharmaceutical composition containing 600-2400 mg of anti-PD-L1 antibody and a single dose of 6 mg, 8 mg, 10 mg and/ Or a pharmaceutical composition of 12 mg Anlotinib.
  • the pharmaceutical composition containing the anti-PD-L1 antibody is a single dose or multiple doses.
  • a combination pharmaceutical composition for the treatment of tumors of the biliary system which comprises a pharmaceutical composition containing 600-2400 mg of anti-PD-L1 antibody in a multi-dose form and a single dose of 6 mg, A pharmaceutical composition of 8mg, 10mg and/or 12mg Anlotinib.
  • a combined pharmaceutical composition for the treatment of biliary system tumors which comprises a weight ratio of (0.35-29):1, preferably (3.5-29):1, more preferably (3.5- 14.5): 1.
  • the anti-PD-L1 antibody and Anlotinib can be packaged separately or 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).
  • a combination pharmaceutical composition for the treatment of tumors of the biliary system which includes an anti-PD-L1 antibody pharmaceutical composition and an anlotinib pharmaceutical composition, wherein the anti-PD-L1 antibody
  • the pharmaceutical composition of Anlotinib is prepared to be suitable for administering a single dose or multiple doses of 600-2400 mg of anti-PD-L1 antibody to the patient at the first administration.
  • the pharmaceutical composition of Anlotinib is prepared to be suitable for 14 consecutive days , Give patients a single dose of 6mg, 8mg, 10mg and/or 12mg Anlotinib every day.
  • a combination pharmaceutical composition for the treatment of tumors of the biliary system which comprises a pharmaceutical composition of an anti-PD-L1 antibody with an anti-PD-L1 antibody concentration of 10-60 mg/mL and a single dose It is a pharmaceutical composition of 6mg, 8mg, 10mg and/or 12mg Anlotinib.
  • a combination pharmaceutical composition for the treatment of tumors of the biliary system which includes an anti-PD-L1 antibody pharmaceutical composition with an anti-PD-L1 antibody concentration of 10 mg/mL and a single dose of 8 mg And/or a pharmaceutical composition of 10mg Anlotinib.
  • a combination pharmaceutical composition for the treatment of tumors of the biliary system which includes a pharmaceutical composition containing 1200 mg of anti-PD-L1 antibody provided in multiple doses and a single dose of 8 mg and/or A pharmaceutical composition of 10 mg Anlotinib.
  • the application also provides the use of the combined pharmaceutical composition in the preparation of a medicine for treating tumors of the biliary system.
  • the application also provides a method for treating tumors of the biliary system, which comprises administering to a subject an effective amount of the combination pharmaceutical composition of the application.
  • the application also provides the use of the combined pharmaceutical composition for treating tumors of the biliary system.
  • the combination pharmaceutical composition includes an anti-PD-L1 humanized monoclonal antibody and anlotinib.
  • the application also provides the use of the composition of anti-PD-L1 antibody and Anlotinib in the preparation of drugs for treating tumors of the biliary system.
  • the application also provides a method for treating tumors of the biliary system, which includes administering to the subject an effective amount of a combination of anti-PD-L1 antibody and anlotinib.
  • the application also provides the use of the combination of anti-PD-L1 antibody and anlotinib to treat tumors of the biliary system.
  • the present application provides a kit for the treatment of tumors of the biliary system, the kit comprising an anti-PD-L1 antibody pharmaceutical composition and anlotinib pharmaceutical composition, and an anti-PD-L1 antibody and anlotinib Instructions for the combined use of tinib in the treatment of biliary system tumors.
  • the present application also provides anti-PD-L1 antibodies for the treatment of tumors of the biliary system.
  • the application also provides a method for treating tumors of the biliary system, which comprises administering to a subject an effective amount of the anti-PD-L1 antibody of the application.
  • the application also provides the use of anti-PD-L1 antibodies for the treatment of biliary system tumors.
  • the application also provides the use of anti-PD-L1 antibodies in the preparation of drugs for treating tumors of the biliary system.
  • the present application provides a combined pharmaceutical composition for the treatment of liver cancer, which includes an anti-PD-L1 antibody and anlotinib.
  • the combined pharmaceutical composition includes an anti-PD-L1 antibody pharmaceutical composition and anlotinib pharmaceutical composition.
  • the combination pharmaceutical composition is packaged in the same kit, and the kit also includes instructions for the combined use of anti-PD-L1 antibody and anlotinib to treat liver cancer.
  • a combination pharmaceutical composition for the treatment of liver cancer which includes a pharmaceutical composition containing 600-2400 mg of anti-PD-L1 antibody and a single dose of 6 mg, 8 mg, 10 mg and/or 12 mg
  • the pharmaceutical composition of Anlotinib is single dose or multiple doses.
  • a combination pharmaceutical composition for the treatment of liver cancer which includes a pharmaceutical composition containing 600-2400 mg of anti-PD-L1 antibody in multiple doses and a single dose of 6 mg, 8 mg, A pharmaceutical composition of 10mg and/or 12mg Anlotinib.
  • a combination pharmaceutical composition for the treatment of liver cancer which comprises a weight ratio of (0.35-29):1, preferably (3.5-29):1, more preferably (3.5-14.5) :1.
  • the anti-PD-L1 antibody and Anlotinib can be packaged separately or 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).
  • a combined pharmaceutical composition for the treatment of liver cancer which includes an anti-PD-L1 antibody pharmaceutical composition and an anlotinib pharmaceutical composition, wherein the anti-PD-L1 antibody is prepared
  • the pharmaceutical composition of Anlotinib is prepared to be suitable for administering 6 mg to the patient every day for 14 consecutive days , 8mg, 10mg and/or 12mg anlotinib single dose.
  • a combination pharmaceutical composition for the treatment of liver cancer which includes an anti-PD-L1 antibody pharmaceutical composition with an anti-PD-L1 antibody concentration of 10-60 mg/mL and a single dose of 6 mg , 8mg, 10mg and/or 12mg anlotinib pharmaceutical composition.
  • a combination pharmaceutical composition for the treatment of liver cancer which includes an anti-PD-L1 antibody pharmaceutical composition with an anti-PD-L1 antibody concentration of 10 mg/mL and a single dose of 8 mg and/ Or a pharmaceutical composition of 10 mg Anlotinib.
  • a combination pharmaceutical composition for the treatment of liver cancer which includes a pharmaceutical composition containing 1200 mg of anti-PD-L1 antibody provided in multiple doses and a single dose of 8 mg and/or 10 mg of safety.
  • the pharmaceutical composition of Rotinib is provided, which includes a pharmaceutical composition containing 1200 mg of anti-PD-L1 antibody provided in multiple doses and a single dose of 8 mg and/or 10 mg of safety.
  • the pharmaceutical composition of Rotinib is provided, which includes a pharmaceutical composition containing 1200 mg of anti-PD-L1 antibody provided in multiple doses and a single dose of 8 mg and/or 10 mg of safety.
  • the application also provides the use of the combined pharmaceutical composition in the preparation of a medicine for treating liver cancer.
  • the application also provides a method for treating liver cancer, which comprises administering to a subject an effective amount of the combined pharmaceutical composition of the application.
  • the application also provides the use of the combined pharmaceutical composition for treating liver cancer.
  • the combination pharmaceutical composition includes an anti-PD-L1 humanized monoclonal antibody and anlotinib.
  • this application also provides the use of the composition of anti-PD-L1 antibody and Anlotinib in the preparation of drugs for the treatment of liver cancer.
  • the application also provides a method for treating liver cancer, which includes administering to a subject an effective amount of a composition of an anti-PD-L1 antibody and anlotinib.
  • the application also provides the use of the combination of anti-PD-L1 antibody and anlotinib to treat liver cancer.
  • the present application provides a kit for the treatment of liver cancer, the kit comprising an anti-PD-L1 antibody drug composition and anlotinib pharmaceutical composition, and an anti-PD-L1 antibody and anlotinib Instructions for combined use to treat liver cancer.
  • the present application also provides anti-PD-L1 antibodies for the treatment of liver cancer.
  • the application also provides a method for treating liver cancer, which comprises administering to a subject an effective amount of the anti-PD-L1 antibody of the application.
  • the application also provides the use of anti-PD-L1 antibodies for the treatment of liver cancer.
  • the application also provides the use of the anti-PD-L1 antibody in the preparation of drugs for treating liver cancer.
  • the present application provides a combined pharmaceutical composition for the treatment of triple-negative breast cancer, which includes an anti-PD-L1 antibody and anlotinib.
  • the combined pharmaceutical composition includes an anti-PD-L1 antibody pharmaceutical composition and anlotinib pharmaceutical composition.
  • the combination pharmaceutical composition is packaged in the same kit, and the kit also includes instructions for the combined use of PD-L1 antibody and anlotinib to treat triple-negative breast cancer.
  • a combination pharmaceutical composition for the treatment of triple-negative breast cancer which includes a pharmaceutical composition containing 600-2400 mg of anti-PD-L1 antibody and a single dose of 6 mg, 8 mg, 10 mg, and / Or a pharmaceutical composition of 12 mg anlotinib.
  • the anti-PD-L1 antibody pharmaceutical composition is single dose or multiple doses.
  • a combination pharmaceutical composition for the treatment of triple-negative breast cancer which includes a pharmaceutical composition containing 600-2400 mg of anti-PD-L1 antibody in a multi-dose form and a single dose of 6 mg , 8mg, 10mg and/or 12mg anlotinib pharmaceutical composition.
  • a combination pharmaceutical composition for the treatment of triple-negative breast cancer which comprises a weight ratio of (0.35-29):1, preferably (3.5-29):1, more preferably (3.5 -14.5): 1.
  • the anti-PD-L1 antibody and Anlotinib can be packaged separately or 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).
  • a combination pharmaceutical composition for the treatment of triple-negative breast cancer which includes a pharmaceutical composition of anti-PD-L1 antibody and a pharmaceutical composition of anlotinib, wherein anti-PD-L1
  • the antibody is prepared to be suitable for administering a single dose or multiple doses of 600-2400 mg of anti-PD-L1 antibody to the patient at the first administration
  • the pharmaceutical composition of anlotinib is prepared to be suitable for 14 consecutive days, every day Patients were given a single dose of 6mg, 8mg, 10mg and/or 12mg Anlotinib.
  • a combination pharmaceutical composition for the treatment of triple-negative breast cancer which comprises an anti-PD-L1 antibody pharmaceutical composition with an anti-PD-L1 antibody concentration of 10-60 mg/mL and a single The dosage is a pharmaceutical composition of 6mg, 8mg, 10mg and/or 12mg Anlotinib.
  • a combination pharmaceutical composition for the treatment of triple-negative breast cancer which comprises an anti-PD-L1 antibody concentration of 10 mg/mL of an anti-PD-L1 antibody pharmaceutical composition and a single dose of A pharmaceutical composition of 8mg and/or 10mg Anlotinib.
  • a combination pharmaceutical composition for the treatment of triple-negative breast cancer which includes a pharmaceutical composition containing 1200 mg of anti-PD-L1 antibody provided in multiple doses and a single dose of 8 mg and/ Or a pharmaceutical composition of 10 mg Anlotinib.
  • the application also provides the use of the combined pharmaceutical composition in the preparation of a medicine for treating triple-negative breast cancer.
  • the application also provides a method for treating triple-negative breast cancer, which comprises administering an effective amount of the combined pharmaceutical composition of the application to a subject.
  • the application also provides the use of the combined pharmaceutical composition for treating triple-negative breast cancer.
  • the combination pharmaceutical composition includes an anti-PD-L1 humanized monoclonal antibody and anlotinib.
  • this application also provides the use of the composition of anti-PD-L1 antibody and Anlotinib in the preparation of a medicine for treating triple-negative breast cancer.
  • the application also provides a method for treating triple-negative breast cancer, which includes administering to a subject an effective amount of an anti-PD-L1 antibody and anlotinib combination.
  • the application also provides the use of the combination of anti-PD-L1 antibody and anlotinib to treat triple-negative breast cancer.
  • the present application provides a kit for the treatment of triple-negative breast cancer.
  • the kit includes a pharmaceutical composition of anti-PD-L1 antibody and a pharmaceutical composition of anlotinib, and an anti-PD-L1 antibody and an anti-PD-L1 antibody. Instructions for the combined use of Rotinib in the treatment of triple-negative breast cancer.
  • the present application also provides an anti-PD-L1 antibody for the treatment of triple-negative breast cancer.
  • the application also provides a method for treating triple-negative breast cancer, which comprises administering to a subject an effective amount of the anti-PD-L1 antibody of the application.
  • the application also provides the use of anti-PD-L1 antibodies for the treatment of triple-negative breast cancer.
  • the application also provides the use of the anti-PD-L1 antibody in the preparation of a medicine for treating triple-negative breast cancer.
  • the present application provides a combined pharmaceutical composition for treating lung cancer, which includes an anti-PD-L1 antibody and anlotinib.
  • the combined pharmaceutical composition includes an anti-PD-L1 antibody pharmaceutical composition and anlotinib pharmaceutical composition.
  • the combination pharmaceutical composition is packaged in the same kit, and the kit also includes instructions for the combined use of PD-L1 antibody and anlotinib to treat lung cancer.
  • a combination pharmaceutical composition for the treatment of lung cancer which includes a pharmaceutical composition containing 600-2400 mg of anti-PD-L1 antibody and a single dose of 6 mg, 8 mg, 10 mg and/or 12 mg
  • the pharmaceutical composition of Anlotinib is a single dose or multiple doses.
  • a combination pharmaceutical composition for the treatment of lung cancer which includes a pharmaceutical composition containing 600-2400 mg of anti-PD-L1 antibody provided in multiple doses and a single dose of 6 mg, 8 mg, A pharmaceutical composition of 10mg and/or 12mg Anlotinib.
  • a combination pharmaceutical composition for the treatment of lung cancer which includes an anti-PD-L1 antibody pharmaceutical composition and an anlotinib pharmaceutical composition, wherein the anti-PD-L1 antibody is prepared
  • the pharmaceutical composition of Anlotinib is prepared to be suitable for administering 6 mg to the patient every day for 14 consecutive days , 8mg, 10mg and/or 12mg anlotinib single dose.
  • a combination pharmaceutical composition for the treatment of lung cancer which comprises an anti-PD-L1 antibody pharmaceutical composition with an anti-PD-L1 antibody concentration of 10-60 mg/mL and a single dose of 6 mg , 8mg, 10mg and/or 12mg anlotinib pharmaceutical composition.
  • a combination pharmaceutical composition for the treatment of lung cancer which comprises a weight ratio of (0.35-29):1, preferably (3.5-29):1, more preferably (3.5-14.5) :1.
  • the anti-PD-L1 antibody and Anlotinib can be packaged separately or 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).
  • a combination pharmaceutical composition for the treatment of lung cancer which includes an anti-PD-L1 antibody pharmaceutical composition with an anti-PD-L1 antibody concentration of 10 mg/mL and a single dose of 8 mg and/ Or a pharmaceutical composition of 10 mg Anlotinib.
  • a combination pharmaceutical composition for the treatment of lung cancer which includes a pharmaceutical composition containing 1200 mg of anti-PD-L1 antibody provided in multiple doses and a single dose of 8 mg and/or 10 mg of safety.
  • the pharmaceutical composition of Rotinib is provided, which includes a pharmaceutical composition containing 1200 mg of anti-PD-L1 antibody provided in multiple doses and a single dose of 8 mg and/or 10 mg of safety.
  • the pharmaceutical composition of Rotinib is provided, which includes a pharmaceutical composition containing 1200 mg of anti-PD-L1 antibody provided in multiple doses and a single dose of 8 mg and/or 10 mg of safety.
  • the application also provides the use of the combined pharmaceutical composition in preparing a medicine for treating lung cancer.
  • the application also provides a method for treating lung cancer, which comprises administering to a subject an effective amount of the combined pharmaceutical composition of the application.
  • the application also provides the use of the combined pharmaceutical composition for treating lung cancer.
  • the combined pharmaceutical composition includes an anti-PD-L1 humanized monoclonal antibody and anlotinib.
  • this application also provides the use of the composition of anti-PD-L1 antibody and Anlotinib in the preparation of drugs for treating lung cancer.
  • the application also provides a method for treating lung cancer, which includes administering to a subject an effective amount of a composition of anti-PD-L1 antibody and anlotinib.
  • the application also provides the use of the combination of anti-PD-L1 antibody and anlotinib to treat lung cancer.
  • the present application provides a kit for the treatment of lung cancer, the kit comprising an anti-PD-L1 antibody pharmaceutical composition and anlotinib pharmaceutical composition, and an anti-PD-L1 antibody and anlotinib Instructions for combined use to treat lung cancer.
  • the application also provides anti-PD-L1 antibodies for the treatment of lung cancer.
  • the application also provides a method for treating lung cancer, which comprises administering to a subject an effective amount of the anti-PD-L1 antibody of the application.
  • the application also provides the use of anti-PD-L1 antibodies for the treatment of lung cancer.
  • the application also provides the use of the anti-PD-L1 antibody in the preparation of drugs for treating lung cancer.
  • the anti-PD-L1 antibody and anlotinib are each in the form of a pharmaceutical composition, which can be administered simultaneously, sequentially or at intervals.
  • the anti-PD-L1 antibody and anlotinib are each administered in an interval administration manner.
  • the antibody and anlotinib are administered in the same or different dosage regimens, respectively.
  • different dosing schedules are used for administration.
  • the anti-PD-L1 antibody in the use or treatment method, may be weekly (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks ( q4w) Apply once.
  • the anti-PD-L1 antibody is administered every 3 weeks.
  • the anti-PD-L1 antibody is administered at a dose of 600-2400 mg each time.
  • the anlotinib can be administered in a dose of 6 mg, 8 mg, 10 mg or 12 mg once a day for 2 weeks with a 1-week stop.
  • the anti-PD-L1 antibody and Anlotinib have the same or different treatment cycles, respectively. In some specific embodiments, the anti-PD-L1 antibody and anlotinib have the same treatment cycle, for example, every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks is a treatment cycle.
  • 21 days is a treatment cycle
  • the PD-L1 antibody is administered on the first day of each cycle
  • the PD-L1 antibody is administered daily on the 1-14th day of each cycle Anlotinib.
  • the PD-L1 antibody is administered once on the first day of each cycle
  • anlotinib is administered once a day on days 1-14 of each cycle.
  • the anti-PD-L1 antibody may comprise selected from 0.01 to 40 mg/kg, 0.1 to 30 mg/kg, 0.1 to 20 mg/kg, 0.1 to 15 mg /kg, 0.1 to 10 mg/kg, 1 to 15 mg/kg, 1 to 20 mg/kg, 1 to 3 mg/kg, 3 to 10 mg/kg, 3 to 15 mg/kg, 3 to 20 mg/kg, 3 to 30 mg/kg , 10 to 20 mg/kg, or 15 to 20 mg/kg to the subject; 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 a dose of 900mg to 1200mg administered to the subject.
  • 21 days are a treatment cycle, and 1200 mg of PD-L1 antibody is administered on the first day of each cycle, and 6 mg, 8mg, 10mg and/or 12mg of Anlotinib.
  • a single dose of the anti-PD-L1 antibody pharmaceutical composition includes 300 mg or 600 mg of anti-PD-L1 antibody.
  • the total dose of the anti-PD-L1 antibody pharmaceutical composition is 600-2400 mg. In some schemes, the total dose of the anti-PD-L1 antibody pharmaceutical composition includes a range selected from 600 mg, 900 mg, 1200 mg, 1500 mg, 1800 mg, 2100 mg, 2400 mg, or any of the foregoing values. In some schemes, the total dose of the anti-PD-L1 antibody pharmaceutical composition is preferably 600-2100 mg, or 900 mg-1500 mg.
  • the pharmaceutical composition of the anti-PD-L1 antibody includes one or more of a buffer, an isotonicity regulator, a stabilizer, and/or a surfactant.
  • the pharmaceutical composition of the anti-PD-L1 antibody comprises 1-150 mg/mL anti-PD-L1 antibody (e.g. monoclonal antibody), 3-50 mM buffer, 2-150 mg/mL isotonic regulator/stabilizer, and 0.01-0.8 mg/mL surfactant, and the pH is about 4.5-6.8.
  • the pharmaceutical composition of the anti-PD-L1 antibody is calculated in w/v, and the concentration of the anti-PD-L1 monoclonal antibody is about 5-150 mg/mL; preferably about 10-60 mg/mL; More preferably, it is about 10-30 mg/mL.
  • the anti-PD-L1 monoclonal antibody has a mass volume concentration of about 10 mg/mL, about 20 mg/mL, about 30 mg/mL, about 40 mg/mL, about 50 mg/mL, about 60 mg/mL, about 70 mg/mL, About 80mg/mL, about 90mg/mL, about 100mg/mL, about 110mg/mL or about 120mg/mL, preferably about 10mg/mL, about 20mg/mL, about 30mg/mL, about 40mg/mL, about 50mg/mL mL or about 60 mg/mL, more preferably about 10 mg/mL, about 20 mg/mL, or about 30 mg/mL.
  • the anti-PD-L1 monoclonal antibody has a mass volume concentration of about 10 mg/mL. In other embodiments, the mass volume concentration of anti-PD-L1 monoclonal antibody is about 30 mg/mL. In other embodiments, the mass volume concentration of anti-PD-L1 monoclonal antibody is about 60 mg/mL.
  • the buffer is a histidine salt buffer.
  • the concentration of the histidine salt buffer is about 5-30 mM, preferably about 10-25 mM, more preferably about 10-20 mM, and most preferably about 10-15 mM.
  • the histidine salt buffer has a concentration of about 5mM, about 10mM, about 15mM, about 20mM, about 25mM, or about 30mM.
  • the histidine salt buffer concentration is about 10 mM.
  • the histidine salt buffer has a concentration of about 15 mM.
  • the histidine salt buffer concentration is about 20 mM.
  • the histidine salt buffer contains histidine and hydrochloric acid.
  • the isotonicity regulator/stabilizer is about 20-150 mg/mL sucrose, preferably about 40-100 mg/mL sucrose, more preferably about 60 -80mg/mL of sucrose.
  • the concentration of the sucrose is about 40 mg/mL, 50 mg/mL, 60 mg/mL, 70 mg/mL, 80 mg/mL, 90 mg/mL, or 100 mg/mL.
  • the concentration of the sucrose is about 60 mg/mL.
  • the concentration of the sucrose is about 70 mg/mL.
  • the concentration of sucrose is about 80 mg/mL.
  • the concentration of the sucrose is about 90 mg/mL.
  • the surfactant is selected from polysorbate 80, polysorbate 20, poloxamer 188; preferably polysorbate 80 or polysorbate 20; more preferably polysorbate 80 .
  • the concentration of the surfactant is about 0.05-0.6 mg/mL, preferably about 0.1-0.4 mg/mL, and more preferably about 0.2-0.3 mg/mL.
  • the surfactant in terms of w/v, is about 0.01-0.8 mg/mL of polysorbate 80 or polysorbate 20. In some specific solutions, the surfactant is about 0.05-0.6 mg/mL polysorbate 80, preferably about 0.1-0.4 mg/mL polysorbate 80, more preferably about 0.2-0.3 mg/mL Polysorbate 80 of about 0.2 mg/mL is most preferred.
  • the content of polysorbate 80 in the pharmaceutical composition is about 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; preferably Preferably, the content of polysorbate 80 in the pharmaceutical composition is about 0.2 mg/mL, 0.3 mg/mL, 0.4 mg/mL or 0.5 mg/mL; more preferably, the content of polysorbate 80 in the pharmaceutical composition It is about 0.2 mg/mL, 0.3 mg/mL or 0.4 mg/mL; optimally, the content of polysorbate 80 in the pharmaceutical composition is about 0.2 mg/mL.
  • the content of polysorbate 80 in the pharmaceutical composition is about 0.1 mg/mL. In other embodiments, the content of polysorbate 80 in the pharmaceutical composition is about 0.2 mg/mL. In some embodiments, the content of polysorbate 80 in the pharmaceutical composition is about 0.3 mg/mL. In some other embodiments, the content of polysorbate 80 in the pharmaceutical composition is about 0.4 mg/mL. In some embodiments, the content of polysorbate 80 in the pharmaceutical composition is about 0.5 mg/mL.
  • the pH value of the aqueous solution of the pharmaceutical composition is selected from 4.0-6.8; preferably 4.5-6.5; more preferably 5.5-6.0; most preferably 5.5.
  • the pH of the aqueous solution of the pharmaceutical composition is about 4.5, about 4.8, about 5.0, about 5.2, about 5.4, about 5.5, about 5.6, about 5.8, or about 6.0, preferably about 5.0, about 5.2, about 5.4, about 5.5 or about 5.6, more preferably about 5.5.
  • the pH of the aqueous pharmaceutical composition is about 5.0.
  • the pH value of the aqueous pharmaceutical composition is about 5.2.
  • the pH of the aqueous pharmaceutical composition is about 5.4. In some embodiments, the pH of the aqueous pharmaceutical composition is about 5.5. In some embodiments, the pH of the aqueous pharmaceutical composition is about 5.6. In some embodiments, the pH of the aqueous pharmaceutical composition is about 5.8. In some embodiments, the pH of the aqueous pharmaceutical composition is about 6.0.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody with a mass volume concentration of about 20 mg/mL, (b) sucrose with a mass volume concentration of about 70 mg/mL, ( c) Polysorbate 80 with a mass volume concentration of about 0.1 mg/mL, (d) histidine with a molar concentration of about 20 mM, (e) optional hydrochloric acid in an appropriate amount, and adjust the pH of the composition to about 5.0.
  • the pharmaceutical composition comprises: (a) anti-PD-L1 monoclonal antibody with a mass volume concentration of about 20 mg/mL, (b) sucrose with a mass volume concentration of about 70 mg/mL, ( c) Polysorbate 80 with a mass volume concentration of about 0.1 mg/mL, (d) histidine with a molar concentration of about 20 mM, (e) optional hydrochloric acid in an appropriate amount, and adjust the pH of the composition to about 5.0.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody with a mass volume concentration of about 10 mg/mL, (b) sucrose with a mass volume concentration of about 80 mg/mL, (c) Polysorbate 80 with a mass volume concentration of about 0.2 mg/mL, (d) histidine with a molar concentration of about 10 mM, (e) optional hydrochloric acid, and adjust the pH of the composition to about 5.5.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody with a mass volume concentration of about 50 mg/mL, (b) sucrose with a mass volume concentration of about 80 mg/mL, (c) Polysorbate 80 with a mass volume concentration of about 0.3 mg/ml, (d) histidine with a molar concentration of about 10 mM, (e) optional hydrochloric acid, and adjust the pH of the composition to about 5.5.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody with a mass volume concentration of about 100 mg/mL, (b) sucrose with a mass volume concentration of about 80 mg/mL, (c) Polysorbate 80 with a mass volume concentration of about 0.5 mg/mL, (d) Histidine with a molar concentration of about 10 mM, and (e) optionally an appropriate amount of hydrochloric acid to adjust the pH of the composition to about 5.5.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody with a mass volume concentration of about 30 mg/mL, (b) sucrose with a mass volume concentration of about 80 mg/mL, (c) Polysorbate 80 with a mass volume concentration of about 0.2 mg/mL, (d) histidine with a molar concentration of about 10 mM, (e) optional hydrochloric acid, and adjust the pH of the composition to about 5.5.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody with a mass volume concentration of about 60 mg/mL, (b) sucrose with a mass volume concentration of about 80 mg/mL, (c) Polysorbate 80 with a mass volume concentration of about 0.2 mg/mL, (d) histidine with a molar concentration of about 10 mM, (e) optional hydrochloric acid, and adjust the pH of the composition to about 5.5.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody with a mass volume concentration of about 10 mg/mL, (b) sucrose with a mass volume concentration of about 70 mg/mL, (c) Polysorbate 80 with a mass volume concentration of about 0.4 mg/mL, (d) histidine with a molar concentration of about 20 mM, (e) optionally acetic acid, adjust the pH of the composition to about 6.5.
  • the pharmaceutical composition comprises: (a) anti-PD-L1 monoclonal antibody with a mass volume concentration of about 10 mg/mL, (b) sucrose with a mass volume concentration of about 80 mg/mL (C) Polysorbate 80 with a mass volume concentration of about 0.2 mg/mL, (d) histidine with a molar concentration of about 20 mM, (e) optional hydrochloric acid, and adjust the pH of the composition to about 5.5.
  • the pharmaceutical composition is a water-soluble injection
  • the water-soluble injection includes but is not limited to a water-soluble preparation that has not been lyophilized or a water-soluble preparation reconstituted by a lyophilized powder.
  • the pharmaceutical composition is a lyophilized formulation.
  • the freeze-dried preparation refers to a preparation prepared by an aqueous solution undergoing a freeze-drying process, in which the substance is first frozen, and then the amount of solvent is reduced by sublimation (primary drying process), and then the amount of solvent is reduced by desorption (secondary drying) Process) until the amount of solvent is a value that no longer supports biological activity or chemical reaction.
  • the freeze-dried preparation of the present application can also be dried by other methods known in the art, such as spray drying and bubble drying.
  • the single dose of the pharmaceutical composition of anlotinib includes 6 mg, 8 mg, 10 mg, or 12 mg of anlotinib.
  • the total dose of the anlotinib pharmaceutical composition administered in each cycle includes 84-168 mg according to a treatment cycle of 2 weeks of administration and 1 week off. In some of the schemes, the total dose of the anlotinib pharmaceutical composition includes a range selected from 84 mg, 112 mg, 140 mg, 168 mg or any of the foregoing values. In some schemes, the total dose of the anlotinib pharmaceutical composition preferably includes 112 mg to 168 mg.
  • the anti-PD-L1 antibody is an antibody in WO2016022630 or CN107001463A.
  • the anti-PD-L1 antibody comprises the following amino acid sequence: at least 80% (e.g., 81%, 82%, or 81%) of the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 4 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% (for example, 81%, 82%, 83%, 84%, 85%) with the amino acid sequence shown in SEQ ID NO: 2 or SEQ ID NO: 5 , 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology Heavy chain CDR2 region; at least 80% (for example, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%)
  • the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain CDR1 region selected from SEQ ID NO: 1 or SEQ ID NO: 4; selected from SEQ ID NO: 2 or SEQ ID NO: 5 heavy chain CDR2 region; selected from SEQ ID NO: 3 or SEQ ID NO: 6 heavy chain CDR3 region; selected from SEQ ID NO: 7 or SEQ ID NO: 10 light chain CDR1 region; selected from SEQ ID NO: 3 or SEQ ID NO: 6
  • the isolated anti-PD-L1 antibody described herein comprises: a heavy chain CDR1 region having an amino acid sequence shown in SEQ ID NO: 1 and having a heavy chain CDR1 region shown in SEQ ID NO: 2
  • the light chain CDR2 region of the amino acid sequence shown in :8 has the light chain CDR3 region of the amino acid sequence shown in SEQ ID NO:9.
  • the various CDR regions described herein and the various variants described above can specifically recognize and bind 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% (e.g., 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% (for example, 81%, 82%, 83%, 84%, 85%) with the amino acid sequence shown in SEQ ID NO: 15 or SEQ ID NO: 16 %, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology The variable region of the light chain.
  • the anti-PD-L1 antibody comprises the following amino acid sequence: the heavy chain variable region shown in SEQ ID NO: 13; the light chain variable region shown in SEQ ID NO: 15 .
  • the anti-PD-L1 antibody comprises the following amino acid sequence: the heavy chain variable region shown in SEQ ID NO: 14; the light chain variable region shown in SEQ ID NO: 16 .
  • the anti-PD-L1 antibody comprises the following amino acid sequence: 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.
  • the anti-PD-L1 antibody comprises the following amino acid sequence: the heavy chain amino acid sequence shown in SEQ ID NO: 19; and the light chain amino acid sequence shown in SEQ ID NO: 20.
  • the anti-PD-L1 antibody comprises the following amino acid sequence: the heavy chain amino acid sequence shown in SEQ ID NO: 21; and the light chain amino acid sequence shown in SEQ ID NO: 18.
  • the anti-PD-L1 humanized monoclonal antibody provided in the present application comprises a monoclonal antibody selected from SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO :5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, One of SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 19, SEQ ID NO. 20, SEQ ID NO. 21 Or multiple conservative substitution variants.
  • the anti-PD-L1 humanized monoclonal antibody containing the conservative substitution variant retains the ability to specifically recognize and bind to PD-L1.
  • the anti-PD-L1 antibody may be an IgG1 or IgG4 antibody.
  • the anti-PD-L1 antibody is an IgG1 antibody. In some embodiments, the anti-PD-L1 antibody is a glycosylated IgG1 antibody.
  • the anti-PD-L1 antibody comprises a heavy chain complementarity determining region (CDR) selected from a 13C5 or 5G11 antibody, and a light chain complementarity determining region selected from a 13C5 or 5G11 antibody.
  • CDR heavy chain complementarity determining region
  • the anti-PD-L1 antibody described in the present application comprises a variable heavy chain selected from the group consisting of ch5G11-hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, ch13C5-hIgG4 chimeric antibody, and a variable heavy chain selected from ch5G11- Variable light chain of hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, ch13C5-hIgG4 chimeric antibody.
  • the anti-PD-L1 antibody described in the present application comprises a variable heavy chain selected from the group consisting of hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4 humanized antibody, and is selected from hu13C5 -The variable light chain of 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 NO: 5) ), HCDR3 sequence is GYDSGFAY (SEQ ID NO: 6), LCDR1 sequence is ASQSVSTSSSSFMH (SEQ ID NO: 10), LCDR2 sequence is YASNLES (SEQ ID NO: 11), LCDR3 sequence is QHSWEIPYT (SEQ ID NO: 12); The HCDR1 sequence of 5G11, ch5G11-hIgG1, ch5G11-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG
  • the anti-PD-L1 antibody in the drug combination may be selected from one or more.
  • the term "plurality" may be more than one, for example, two, three, four, five or more.
  • the anti-PD-L1 antibody is selected from the group consisting of 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 the heavy chain variable region as shown in SEQ ID NO: 14 and the 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
  • the heavy chain amino acid sequence and the light chain amino acid sequence shown in SEQ ID NO: 20, or selected from the heavy chain amino acid sequence shown in SEQ ID NO: 21 and the light chain amino acid sequence shown in SEQ ID NO: 18, or It is selected from the combination of any of the above.
  • the anlotinib includes its non-salt form (for example, free base) and also its pharmaceutically acceptable salt, and the non-salt form or salt is included in the protection scope of the application.
  • the pharmaceutically acceptable salt of anlotinib may be hydrochloride or dihydrochloride.
  • the dosage of anlotinib or its salt in this application, unless otherwise specified, is based on the molecular weight of anlotinib free base.
  • the biliary system tumor is selected from biliary system adenocarcinoma.
  • the biliary system tumors include gallbladder cancer (Gallbladder Cancer, GBC), intrahepatic cholangiocarcinoma (IHCC), and extrahepatic cholangiocarcinoma (EHCC).
  • GBC gallbladder Cancer
  • IHCC intrahepatic cholangiocarcinoma
  • EHCC extrahepatic cholangiocarcinoma
  • the extrahepatic cholangiocarcinoma includes hilar cholangiocarcinomas (also known as Klatskin tumor) and distal cholangiocarcinomas.
  • the biliary system tumors include adenocarcinoma type gallbladder carcinoma, adenocarcinoma type intrahepatic cholangiocarcinoma, or adenocarcinoma type extrahepatic cholangiocarcinoma.
  • the biliary system tumors include unresectable, advanced or metastatic biliary system tumors.
  • the biliary system tumor includes unresectable, advanced or metastatic adenocarcinoma type gallbladder carcinoma, adenocarcinoma type intrahepatic cholangiocarcinoma, or adenocarcinoma type extrahepatic cholangiocarcinoma.
  • the patient with a tumor of the biliary system has previously received chemotherapy but the treatment has failed.
  • the patient with a tumor of the biliary system has failed previous first-line chemotherapy.
  • the liver cancer is Hepatocellular Carcinoma (HCC).
  • HCC Hepatocellular Carcinoma
  • the liver cancer is selected from primary hepatocellular carcinoma.
  • the liver cancer is selected from advanced and/or metastatic hepatocellular carcinoma.
  • the liver cancer is inoperable hepatocellular carcinoma.
  • the liver cancer is hepatocellular carcinoma that has failed prior local treatment or hepatocellular carcinoma that is not suitable for local treatment.
  • the local treatment includes, but is not limited to, ablation (including but not limited to radiofrequency ablation, cryotherapy). Ablation, percutaneous ethanol injection therapy and microwave ablation), radiotherapy and/or hepatic artery chemotherapy.
  • the liver cancer is liver cancer that has failed treatment with sorafenib and/or lenvatinib.
  • the subject of the triple-negative breast cancer has received surgery, chemotherapy and/or radiation therapy. In some specific schemes, the subject with triple-negative breast cancer has previously received first-line chemotherapy. In some specific schemes, the subject with triple-negative breast cancer has received anthracycline and/or taxane drug treatment. In some specific schemes, the subject with triple-negative breast cancer has received at least first-line system therapy and has used anthracycline and/or taxane drugs.
  • the lung cancer is selected from non-small cell lung cancer.
  • the lung cancer includes lung squamous cell carcinoma or lung adenocarcinoma.
  • the lung cancer is advanced lung cancer.
  • the lung cancer is EGFR or ALK wild-type non-small cell lung cancer.
  • the lung cancer is selected from advanced squamous cell carcinoma type non-small cell lung cancer, advanced adenocarcinoma type non-small cell lung cancer.
  • the lung cancer is selected from EGFR or ALK wild type squamous cell non-small cell lung cancer, EGFR or ALK wild type adenocarcinoma non-small cell lung cancer.
  • the lung cancer is BRaf or EGFR mutated non-small cell lung cancer, such as BRAF p.V600E, EGFR del and/or EGFR-T790M non-small cell lung cancer.
  • the lung cancer patient has previously received chemotherapy; in some embodiments, the lung cancer is an advanced (IIIB and/or IV) lung cancer that has failed first-line standard chemotherapy or cannot tolerate chemotherapy.
  • the lung cancer is an advanced (IIIB and/or IV) lung cancer that has failed first-line standard chemotherapy or cannot tolerate chemotherapy.
  • the chemotherapy includes, but is not limited to, including but not limited to platinum drugs, fluoropyrimidine derivatives, camptothecins, taxanes, vinblastines, anthracyclines, antibiotics, podophyllum, anti- One or more of tumor drugs and antimetabolites.
  • platinum drugs such as oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin
  • Fluoropyrimidine derivatives e.g.
  • gemcitabine capecitabine, amcitabine, fluorouracil, difurfurouracil, deoxyfluridine, tegafur, carmofur, trifluorouridine), taxanes (e.g. Paclitaxel, albumin-bound paclitaxel and docetaxel), camptothecins (e.g.
  • camptothecin hydroxycamptothecin, 9-aminocamptothecin, 7-ethylcamptothecin, irinotecan, topotecan
  • vinblastines vinorelbine, vinblastine, vincristine, vindesine, vinflunine
  • anthracyclines epirubicin, adriamycin, daunorubicin, pirarubicin
  • Star Amrubicin, Idarubicin, Mitoxantrone, Alrubicin, Valrubicin, Zorubicin, Pishancin
  • Pemetrexed Carmustine, Melphalan
  • Etoposide etoposide
  • tenibin mitomycin, ifosfamide, cyclophosphamide, azacitidine, methotrexate, bendamustine, liposome Dactinomycin, Actinomycin D (Dactinomycin), Bleomycin, Pingyangmycin, Temozo
  • the components in the pharmaceutical composition of the present application can be administered independently, or part or all of them can be administered by various suitable routes, including but not limited to oral or parenteral (by intravenous, intramuscular, topical or subcutaneous way).
  • the components of the pharmaceutical combination of the present application can be administered orally or by injection, such as intravenous injection or intraperitoneal injection, independently, or part or all of them can be co-administered.
  • the components of the pharmaceutical composition of the present application may be independently, or some or all of them may be a suitable dosage form, including but not limited to tablets, troches, pills, capsules (such as hard capsules, soft capsules, Enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and for oral or non-oral administration
  • a sustained-release drug including but not limited to tablets, troches, pills, capsules (such as hard capsules, soft capsules, Enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and for oral or non-oral administration
  • a sustained-release drug including but not limited to tablets, troches, pills,
  • the components in the pharmaceutical combination of the present application may each independently, or part or all of them together contain a pharmaceutically acceptable carrier and/or excipient.
  • the pharmaceutical combination of the present application may also contain additional therapeutic agents.
  • the additional therapeutic agent may be a cancer therapeutic agent known in the art.
  • the treated patients have a longer survival period (such as median survival, progression-free survival, or overall survival);
  • the term “combined pharmaceutical composition” refers to two or more active ingredients administered simultaneously or sequentially (administered in the form of the respective active ingredients themselves, or in their respective pharmaceutically acceptable salts). Or esters and other derivatives, prodrugs or compositions).
  • the terms “combined pharmaceutical composition”, “pharmaceutical composition” and “pharmaceutical combination” are used interchangeably.
  • the term "antibody” refers to a binding protein having at least one antigen binding domain.
  • the antibodies and fragments of the present application may be whole antibodies or any fragments thereof. Therefore, the antibodies and fragments of the present application include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof, and immunoconjugates. Examples of antibody fragments include Fab fragments, Fab' fragments, F(ab')2 fragments, Fv fragments, isolated CDR regions, single chain Fv molecules (scFv), Fd fragments, and other antibody fragments known in the art. Antibodies and fragments thereof can also include recombinant polypeptides, fusion proteins, and bispecific antibodies.
  • the anti-PD-L1 antibodies and fragments thereof disclosed herein may be of IgG1, IgG2, IgG3, or IgG4 isotype.
  • the term "isotype" refers to the antibody species 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 can be derived from any species, including but not limited to mice, rats, rabbits, primates, llamas and humans.
  • the PD-L1 antibody and its fragments can be chimeric antibodies, humanized antibodies or whole human antibodies.
  • the anti-PD-L1 antibody is an antibody produced by a hybridoma cell line derived from a mouse. Therefore, in one embodiment, the anti-PD-L1 antibody is a murine antibody. In another embodiment, the anti-PD-L1 antibody is a chimeric antibody. In another embodiment, the chimeric antibody is a mouse-human chimeric antibody. In another embodiment, the antibody is a humanized antibody. In another embodiment, the antibody is derived from a murine antibody and is humanized.
  • Humanized antibodies are antibodies that contain complementarity determining regions (CDRs) derived from non-human antibodies; and framework regions and constant regions derived from human antibodies.
  • 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. Therefore, in one embodiment, the humanized antibody provided herein binds to the same epitope on PD-L1 as the murine antibody from which the CDR of the antibody is derived.
  • Exemplary humanized antibodies are provided herein. Additional anti-PD-L1 antibodies or variants thereof comprising the heavy chain CDRs and light chain CDRs provided herein can be produced using any human framework sequence and are also included in this application.
  • framework sequences suitable for use in this 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 the mutations exemplified herein, including back mutations to the germline sequence. For example, in one embodiment, one or more amino acids in the human framework region of the VH and/or VL of the humanized antibody provided herein are backmutated to the corresponding amino acid in the parent murine antibody.
  • the amino acid at positions 53 and/or 60 and/or 67 of the light chain variable region is backmutated to the corresponding one found at that position in the mouse 5G11 or 13C5 light chain variable region Amino acids.
  • 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 5G11 Or the corresponding amino acid found at that position in the variable region of the 13C5 heavy chain.
  • 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, where 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, wherein the amino acid at position 53 is mutated from Tyr (Y) to Lys (K); and a heavy chain variable region, wherein the amino acid at position 28
  • the amino acid is mutated from Thr(T) to Ile(I)
  • the amino acid at position 30 is mutated from Ser(S) to Arg(R)
  • the amino acid at position 49 is mutated from Ser(S) to Ala(A)
  • the amino acid at position 94 was mutated from Tyr (Y) to Asp (D).
  • Additional or alternative back mutations can be made in the framework regions of the humanized antibodies provided herein to improve the properties of the antibodies.
  • the application also includes the following humanized antibodies that bind to PD-L1 and contain framework modifications corresponding to the exemplary modifications described herein relative to any suitable framework sequence, as well as other ways to improve the antibody Other frame modifications of characteristics.
  • the present application provides isolated antibodies or fragments thereof that bind PD-L1, wherein the antibodies can be produced by hybridomas selected from the group consisting of hybridomas referred to herein as 13C5, 5G11. Therefore, this application also includes hybridomas 13C5, 5G11, and any hybridoma that produces the antibodies disclosed herein.
  • the application also provides isolated polynucleotides encoding the antibodies and fragments thereof provided herein.
  • the application also includes an expression vector containing the isolated polynucleotide, and a host cell containing the expression vector.
  • isolated antibody means an antibody that does not substantially contain other antibodies with different antigen specificities (for example, an isolated antibody that specifically binds PD-1 does not substantially contain specific binding other than PD-1 Of the antigen). However, an isolated antibody that specifically binds PD-1 may have cross-reactivity with other antigens, such as PD-1 molecules from different species. In addition, the isolated antibody may be substantially free of other cellular materials and/or chemical substances.
  • mAb refers to an antibody molecule composed of a single molecule (ie, an antibody molecule whose basic sequence is substantially the same, and which exhibits a single binding specificity and affinity for a specific epitope ) Non-naturally occurring preparations.
  • mAb is an example of an isolated antibody.
  • the mAb can be produced by hybridoma technology, recombinant technology, transgenic technology or other technologies known to those skilled in the art.
  • the antibodies and antigen-binding fragments thereof disclosed herein are specific to PD-L1. In one embodiment, the antibody or fragments thereof are specific to PD-L1. In one embodiment, the antibodies and fragments provided herein bind to human or primate PD-L1, but not to PD-L1 from any other mammal. In another embodiment, the antibody or fragments thereof do not bind to 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 human PD-L1 variants or isoforms. "Specificity" means that the antibody and its fragments bind PD-L1 with greater affinity than any other target.
  • treatment generally refers to obtaining a desired pharmacological and/or physiological effect.
  • the effect can be therapeutic based on partial or complete stabilization or cure of the disease and/or side effects due to the disease.
  • Treatment covers any treatment of a patient's disease, including: (a) inhibiting the symptoms of the disease, that is, preventing its development; or (b) alleviating the symptoms of the disease, that is, causing the disease or symptoms to degenerate.
  • the term "effective amount” means (i) treating a particular disease, condition or disorder, (ii) reducing, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying the symptoms herein
  • the dosage of the compound of the present application for the onset of one or more symptoms of the specified disease, condition or disorder.
  • the amount of the active substance (such as the antibody or compound of the present application) that constitutes a "therapeutically effective amount” can vary depending on factors such as the individual’s disease state, age, sex, and weight, and the therapeutic agent or combination of therapeutic agents triggers in the individual The ability to respond.
  • the effective amount can also be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.
  • administering refers to the physical introduction of a composition containing a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those skilled in the art.
  • the route of administration of immune checkpoint inhibitors includes intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral administration routes, such as by injection or infusion .
  • parenteral administration refers to modes of administration other than enteral and local administration that are usually performed by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, and intralymphatic , Intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspine, epidural and intrasternal injections and infusions , And electroporation in vivo.
  • the immune checkpoint inhibitor e.g., anti-PD-1 antibody or anti-PD-L1 antibody
  • a non-parenteral route e.g., anti-PD-1 antibody or anti-PD-L1 antibody
  • Other non-parenteral routes include topical, epidermal or mucosal routes of administration, for example, intranasal, vaginal, rectal, sublingual, or topical. Administration can also be performed, for example, once, multiple times, and/or over one or more extended periods of time.
  • dose refers to the dose administered to a patient regardless of the patient's weight or body surface area (BSA). For example, a 60 kg person and a 100 kg person will receive the same dose of antibody (e.g., 240 mg of anti-PD-1 antibody).
  • BSA body surface area
  • weight-based dose refers to the dose calculated based on the weight of the patient and administered to the patient. For example, when a patient with a weight of 60 kg needs 3 mg/kg of anti-PD-1 antibody, one can withdraw an appropriate amount of anti-PD-1 antibody (ie, 180 mg) from a fixed-dose preparation of anti-PD-1 antibody at one time.
  • Anlotinib can be administered by a variety of routes, including but not limited to oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, and transdermal Inhalation, vaginal, intraocular, topical, subcutaneous, intra-fat, intra-articular, intraperitoneal, and intrathecal. In some specific embodiments, it is administered orally.
  • the amount of Anlotinib administered can be determined based on the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health of the patient. For example, the daily dose of anlotinib may be 2 mg to 20 mg.
  • the daily dose of anlotinib or a pharmaceutically acceptable salt thereof may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16 mg.
  • Anlotinib can be administered one or more times a day. In some embodiments, Anlotinib is administered as an oral solid formulation once a day.
  • the dosage regimen of Anlotinib can be comprehensively determined according to the activity, toxicity and patient tolerance of the drug.
  • Anlotinib is administered in an interval dosing manner.
  • the interval administration includes an administration period and a drug withdrawal period, during which anlotinib can be administered once or multiple times a day.
  • the ratio of the administration period and the drug withdrawal period in days is 2:0.5-5, preferably 2:0.5-3, more preferably 2:0.5-2, more preferably 2:0.5-1.
  • the administration is continued for 2 weeks and the drug is stopped for 2 weeks.
  • the administration is continued for 2 weeks and the drug is stopped for 1 week.
  • the administration for 5 consecutive days is discontinued for 2 days.
  • Anlotinib can be administered orally at a dose of 6 mg, 8 mg, 10 mg, or 12 mg once a day for 2 weeks with a 1-week stop.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues, but not Many toxicity, irritation, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • salts formed by alkali ions and free acids or salts formed by acid ions and free bases including, for example, hydrochloride, hydrobromide, nitrate, sulfate, phosphate, Formate, acetate, trifluoroacetate, fumarate, oxalate, maleate, citrate, succinate, methanesulfonate, benzenesulfonate, or p-toluene Sulfonate, preferably hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, methanesulfonate, p-toluene Sulfonate, sodium salt, potassium salt, ammonium salt, amino acid salt, etc.
  • the molar ratio of the 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 terms “subject” or “patient” are used interchangeably.
  • the term “subject” or “patient” is a mammal.
  • the subject or patient is a mouse.
  • the subject or patient is a human.
  • combined use or “combined use” means that two or more active substances can each be administered to a subject simultaneously as a single formulation, or each as a single formulation sequentially in any order.
  • single dose refers to the smallest packaging unit containing a certain amount of medicine.
  • a box of medicines has seven capsules, and each capsule is a single dose; or each bottle of injection is a single dose.
  • single dose and unit dose have the same meaning and can be used interchangeably.
  • multi-dose consists of multiple single doses.
  • pharmaceutical composition refers to a mixture of one or more of the active ingredients of the application or their pharmaceutical combination and pharmaceutically acceptable excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound of the present application or its pharmaceutical combination to a subject.
  • IHCC intrahepatic cholangiocarcinoma
  • EHCC extrahepatic cholangiocarcinoma
  • GPC gallbladder cancer
  • the patient has at least one measurable lesion (RECIST 1.1).
  • Chemotherapy failure refers to disease progression during treatment or after the last treatment; or intolerable toxic side effects during treatment.
  • Anti-PD-L1 antibody injection hu5G11-hIgG1 1200mg anti-PD-L1 antibody injection (100mg/10mL) diluted with normal saline to 250mL, infusion time 60 ⁇ 5min, after the infusion is completed, flush the tube with normal saline as required by the hospital , administeristration once every 21 days, that is, 21 days is a treatment cycle.
  • Anlotinib Hydrochloride Capsules (the active ingredient is Anlotinib dihydrochloride): Anti-PD-L1 antibody injection starts to infuse within ⁇ 5 minutes. Take Anlotinib Hydrochloride Capsules 10 mg on an empty stomach, and stop for 1 week after oral administration for 2 weeks , That is, 21 days is a treatment cycle.
  • PFS progression-free survival
  • DCR disease control rate
  • OS overall survival
  • SD stable disease
  • PR partial remission
  • C01002 patient left hepatectomy + hilar enlarged lymph node resection. She received radiotherapy, transfer after 2 cycles of DC-CIK cell therapy, 3 times of cyberknife therapy, and 4 cycles of GP regimen (gemcitabine + cisplatin), and then the disease progressed.
  • C01006 patient Immunohistochemistry: CA19.9(2+), CK18(3+), CK19(2+), CK7(2+), Ki-67(+20-30%).
  • the albumin paclitaxel + Tigio capsules are treated for 6 cycles, which is effective for PD, and after interventional treatment, it is effective for PD (disease progression).
  • C01007 patients Immunohistochemistry: CA19.9(2+), CD34(2+), CK18(2+), CK19(2+), CK7(2+), Ki-67(+, 10%).
  • Gemcitabine + capecitabine combination therapy bone marrow suppression. After oxaliplatin + Tiggio capsule q3w, the disease progressed. Then albumin paclitaxel combined with apatinib treatment.
  • C01009 patient Immunohistochemistry: PCX (+), CK (+), CK19 (partial +), AFP (+), CD56 (+), Ki-67 (+10%).
  • gemcitabine 1.4g d1,8+cisplatin 40mg d2 and 3, the patient was intolerant.
  • C01017 patients immunohistochemistry: CK18(3+), CK19(3+), CK7(3+), CA19.9(1+), AFP(1+), Ki-67(+30%).
  • the GC regimen (Gemcitabine 1.6g d1/1.4g d8+Tesio 60mg bid po/3w) was intolerant after 4 cycles.
  • the patient has at least one measurable lesion (RECIST 1.1).
  • Anti-PD-L1 antibody injection hu5G11-hIgG1 1200mg anti-PD-L1 antibody injection (100mg/10mL) diluted with normal saline to 250mL, infusion time 60 ⁇ 5min, after the infusion is completed, flush the tube with normal saline as required by the hospital , Dosing once every 21 days.
  • Anlotinib Hydrochloride Capsules (the active ingredient is Anlotinib dihydrochloride): Anti-PD-L1 antibody injection starts to infuse within ⁇ 5 minutes. Take Anlotinib Hydrochloride Capsules 10 mg on an empty stomach, and stop for 1 week after oral administration for 2 weeks , That is, 21 days is a treatment cycle.
  • PFS progression-free survival
  • DCR disease control rate
  • OS overall survival
  • SD stable disease
  • PR partial remission
  • C01013 patients were treated with 1200mg anti-PD-L1 antibody injection hu5G11-hIgG1 and 12mg Anlotinib hydrochloride capsules.
  • Patient C01019 used 1200mg anti-PD-L1 antibody injection hu5G11-hIgG1 and 10mg Anlotinib Hydrochloride Capsules, and then Anlotinib Hydrochloride Capsules was reduced to 8mg.
  • C01003 patient Immunohistochemistry: Arg-1(1+), CD34(3+), CK18(2+), GPC3(1+), Hepatocyte(3+), Ki-67(+80%), CD31( 3+); intolerance after sorafenib medication.
  • Patient C01005 Disease progression after Sorafenib administration.
  • Triple-negative breast cancer is defined as estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor (Her -2) All negative.
  • ER, PR negative is defined as: ER ⁇ 1% positive, PR ⁇ 1% positive.
  • Her-2 negative is defined as: Her-2(-) or (1+) by immunohistochemical detection, of which Her-2(2+) must be tested by FISH and the result is negative, such as Her-2(-) or ( 1+) can choose FISH test, but the result must be negative.
  • the patient has at least one measurable lesion (RECIST 1.1).
  • Anti-PD-L1 antibody injection hu5G11-hIgG1 1200mg anti-PD-L1 antibody injection (100mg/10mL) diluted with normal saline to 250mL, infusion time 60 ⁇ 5min, after the infusion is completed, flush the tube with normal saline as required by the hospital , Dosing once every 21 days.
  • Anlotinib Hydrochloride Capsules (the active ingredient is Anlotinib dihydrochloride): Anti-PD-L1 antibody injection starts to infuse within ⁇ 5 minutes. Take Anlotinib Hydrochloride Capsules 10 mg on an empty stomach, and stop for 1 week after oral administration for 2 weeks , That is, 21 days is a treatment cycle.
  • PFS progression-free survival
  • DCR disease control rate
  • SD stable disease
  • OS overall survival
  • Patient medication specifications C01001 and C01003 patients were combined with 1200mg anti-PD-L1 antibody injection hu5G11-hIgG1 and 10mg Anlotinib hydrochloride capsules.
  • C01001 patient left breast invasive breast cancer, lymph node metastasis, received radical surgery, chemotherapy (AT regimen (doxorubicin + docetaxel, 3 cycles), AC regimen (adriamycin + cyclophosphamide, 3 cycles) ), GP regimen (gemcitabine + carboplatin, 4 cycles)) and radiotherapy (100Gy, 50Gy).
  • AT regimen doxorubicin + docetaxel, 3 cycles
  • AC regimen adriamycin + cyclophosphamide, 3 cycles
  • GP regimen domcitabine + carboplatin, 4 cycles
  • radiotherapy 100Gy, 50Gy
  • C03003 patient right breast invasive breast cancer, lymph node metastasis, received radical surgery, chemotherapy (pirubicin + cyclophosphamide + docetaxel, 8 cycles) and radiotherapy.
  • C01004 Right breast invasive breast cancer, lung metastasis, bone metastasis is possible, received radical surgery, chemotherapy (AC-T regimen (pirubicin + cyclophosphamide + paclitaxel, 8 cycles), capecitabine (6 Cycle), TC program (docetaxel + carboplatin, 8 cycles), docetaxel (2 cycles)) and radiotherapy (50Gy).
  • AC-T regimen pirubicin + cyclophosphamide + paclitaxel, 8 cycles
  • capecitabine (6 Cycle)
  • TC program docetaxel + carboplatin, 8 cycles
  • docetaxel 2 cycles
  • radiotherapy 50Gy
  • C01005 Right breast invasive breast cancer, lung metastasis, liver metastasis, received radical surgery, chemotherapy (AC-T regimen (pirubicin + cyclophosphamide + paclitaxel, 8 cycles), TX + nimotuzumab ( Docetaxel + Cappe, 6 cycles), GP regimen (Gemcitabine + Cisplatin, 4 cycles), (Gemcitabine + Carboplatin, 1 cycle) and IMP4297 capsules (PARP inhibitor)) and radiotherapy.
  • AC-T regimen pirubicin + cyclophosphamide + paclitaxel, 8 cycles
  • TX + nimotuzumab Docetaxel + Cappe, 6 cycles
  • GP regimen Gamcitabine + Cisplatin, 4 cycles
  • C01006 Right breast invasive breast cancer, successively received radical mastectomy, chemotherapy (TEC regimen (paclitaxel + epirubicin + cyclophosphamide), GP regimen (gemcitabine + cisplatin, 6 cycles), TX regimen (doceta) Race + capecitabine, 1 cycle)) and radiotherapy.
  • TEC regimen paclitaxel + epirubicin + cyclophosphamide
  • GP regimen g., GP regimen
  • TX regimen doceta) Race + capecitabine, 1 cycle
  • C01007 Left breast invasive breast cancer, lymph node metastasis, successively received radical surgery, chemotherapy (TC regimen (paclitaxel + carboplatin, 6 cycles), (paclitaxel + capecitabine, 3 cycles)) and radiotherapy (223.4Gy) .
  • chemotherapy TC regimen (paclitaxel + carboplatin, 6 cycles), (paclitaxel + capecitabine, 3 cycles)
  • radiotherapy 223.4Gy
  • C01008 Left breast invasive breast cancer, received radical mastectomy, chemotherapy (EC-T regimen (epirubicin + cyclophosphamide + paclitaxel, 8 cycles)) and radiotherapy.
  • E-T regimen epirubicin + cyclophosphamide + paclitaxel, 8 cycles
  • C01009 Left breast invasive ductal carcinoma, lymph node metastasis, successively received radical surgery, chemotherapy (TAC regimen (pirubicin + cyclophosphamide + paclitaxel, 6 cycles), paclitaxel (9 cycles), carboplatin (1 cycle) ).
  • TAC regimen pirubicin + cyclophosphamide + paclitaxel, 6 cycles
  • paclitaxel 9 cycles
  • carboplatin (1 cycle)
  • Advanced (stage IIIB/IV) patients who have received at least first-line standard chemotherapy failure or cannot tolerate chemotherapy, according to the RECIST 1.1 for the evaluation of the efficacy of solid tumors, have at least one measurable lesion.
  • Tumors express PD-L1 positive (tumor ratio score TPS ⁇ 1%).
  • Tissue sample requirements formalin-fixed, paraffin-embedded archived tumor samples for PD-L1 analysis.
  • the tissue samples must be received and evaluated by the central service provider before being randomized into the group. Fine needle aspiration samples are not accepted. Accept thick needles or excision biopsy tissue samples, or resected tissue.
  • Hb hemoglobin
  • ANC absolute neutrophil count
  • PHT platelet
  • ALT Alanine aminotransferase
  • AST aspartate aminotransferase
  • TBIL serum total bilirubin
  • Tr Serum creatinine
  • Coagulation function activated partial thromboplastin time (APTT), international normalized ratio (INR), prothrombin time (PT) ⁇ 1.5 ⁇ ULN.
  • autoimmune disease there is any active autoimmune disease or a history of autoimmune disease (such as the following, but not limited to: autoimmune hepatitis, interstitial pneumonia, enteritis, vasculitis, nephritis; subjects need bronchodilators for medical treatment Interventional asthma cannot be included); however, the following patients are allowed to be included: vitiligo, psoriasis, alopecia without systemic treatment, well-controlled type I diabetes, and hypothyroidism with normal thyroid function after replacement therapy.
  • Imaging shows that the tumor invades large blood vessels or is unclearly separated from the blood vessels.
  • liver cirrhosis decompensated liver disease, active hepatitis* or chronic hepatitis require antiviral treatment;
  • hepatitis B reference HBsAg positive, and HBV DNA test value exceeds the upper limit of normal
  • hepatitis C reference HCV antibody positive, and HCV virus titer test value exceeds the upper limit of normal
  • Diabetes is poorly controlled (fasting blood glucose ⁇ CTCAE level 2);
  • Urine routine test showed urine protein ⁇ ++, and confirmed 24-hour urine protein quantification>1.0g.
  • Anti-PD-L1 antibody injection hu5G11-hIgG1 1200mg anti-PD-L1 antibody injection (100mg/10mL) diluted with normal saline to 250mL, infusion time 60 ⁇ 5min, after the infusion is completed, flush the tube with normal saline as required by the hospital , Dosing once every 21 days.
  • Anlotinib Hydrochloride Capsules (the active ingredient is Anlotinib dihydrochloride): Anti-PD-L1 antibody injection starts to infuse within ⁇ 5 minutes. Take Anlotinib Hydrochloride Capsules 10 mg on an empty stomach, and stop for 1 week after oral administration for 2 weeks , That is, 21 days is a treatment cycle.
  • PFS Progression-free survival
  • Patient 01 Middle to poorly differentiated adenocarcinoma of the left upper lung, lymph node and both lung metastases.
  • Genotype BRAF p.V600E.
  • Patient 08 Left lung adenocarcinoma.
  • Genotype EGFR del/EGFR-T790M.
  • 011 patient lung adenocarcinoma, stage IVA with recurrence and metastasis.
  • Genotype EGFR.
  • each administration cycle is 21 days, and C2, C4, C6, C8, and C10 respectively represent administration 2 cycles, 4 cycles, 6 cycles, 8 cycles and 10 cycles.
  • the target lesion size (baseline) refers to the longest diameter of the target lesion during imaging examination before administration.

Abstract

属于生物医药领域，涉及用于治疗胆道系统肿瘤、肝癌、三阴乳腺癌或肺癌的联用药物组合物，其包括抗PD-L1抗体和安罗替尼，具有良好的抗胆道系统肿瘤、肝癌、三阴乳腺癌或肺癌的活性。

Description

治疗肿瘤的联用药物组合物 技术领域
本申请属于生物医药领域，涉及治疗肿瘤的联用药物组合物。
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。
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。
发明概述
一方面，本申请提供联用药物组合物，其包括抗PD-L1抗体和安罗替尼。
进一步地，安罗替尼处于自由碱形式、或处于其药学上可接受的盐的形式。例如，所述安罗替尼的药学上可接受的盐可以是盐酸盐或二盐酸盐。
进一步地，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，本申请的上述联用药物组合物包装于同一试剂盒中，所述试剂盒还包括PD-L1抗体和安罗替尼联合使用治疗胆道系统肿瘤、肝癌、三阴乳腺癌和/或肺癌的说明。
进一步地，本申请提供了一种联用药物组合物，其包括含600～2400mg的抗PD-L1抗体的药物组合物和单剂量为6mg、8mg、10mg和/或12mg安罗替尼的药物组合物。其中含抗PD-L1抗体的药物组合物为单剂量或者多剂量。
进一步地，本申请提供了一种联用药物组合物，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剂量为6mg、8mg、10mg和/或12mg安罗替尼的药物组合物。
进一步地，本申请提供了一种联用药物组合物，其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。
进一步地，本申请提供了一种联用药物组合物，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；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。
另外，本申请提供用于治疗胆道系统肿瘤、肝癌、三阴乳腺癌和/或肺癌的联用药物组合物，其包括抗PD-L1抗体和安罗替尼。另外，本申请还提供治疗胆道系统肿瘤、肝癌、三阴乳腺癌和/或肺癌的方法，其包括向受试者给予有效量的本申请的上述联用药物组合物。另外，本申请还提供了上述联用药物组合物在制备用于治疗胆道系统肿瘤、肝癌、三阴乳腺癌和/或肺癌的药物的用途。或者，本申请还提供抗PD-L1抗体和安罗替尼在制备用于治疗胆道系统肿瘤、肝癌、三阴乳腺癌和/或肺癌的药物的用途。
进一步地，所述抗PD-L1抗体和安罗替尼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。
另外，本申请提供用于治疗胆道系统肿瘤、肝癌、三阴乳腺癌和/或肺癌的试剂盒，所述试剂盒包括抗PD-L1抗体的药物组合物和安罗替尼的药物组合物，以及抗PD-L1抗体和安罗替尼联合使用治疗胆道系统肿瘤、肝癌、三阴乳腺癌和/或肺癌的说明。
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。
第一方面，本申请提供用于治疗胆道系统肿瘤的联用药物组合物，其包括抗PD-L1抗体和安罗替尼。
另一方面，本申请还提供联用药物组合物在制备用于治疗胆道系统肿瘤的药物的用途。本申请还提供治疗胆道系统肿瘤的方法，其包括向受试者给予有效量的本申请的联用药物组合物。本申请还提供联用药物组合物用于治疗胆道系统肿瘤的用途。所述联用药物组合物包括抗PD-L1抗体和安罗替尼。
另一方面，本申请还提供抗PD-L1抗体和安罗替尼联用在制备治疗胆道系统肿瘤的药物的用途。本申请还提供治疗胆道系统肿瘤的方法，包括向受试者给予有效量的抗PD-L1抗体和安罗替尼。本申请还提供抗PD-L1抗体和安罗替尼联用治疗胆道系统肿瘤的用途。本申请还提供用于治疗胆道系统肿瘤的抗PD-L1抗体和安罗替尼联用。
第二方面，本申请提供用于治疗肝癌的联用药物组合物，其包括抗PD-L1抗体和安罗替尼。
另一方面，本申请还提供联用药物组合物在制备用于治疗肝癌的药物的用途。本申请还提供治疗肝癌的方法，其包括向受试者给予有效量的本申请的联用药物组合物。本申请还提供联用药物组合物用于治疗肝癌的用途。所述联用药物组合物包括抗PD-L1抗体和安罗替尼。
另一方面，本申请还提供抗PD-L1抗体和安罗替尼联用在制备治疗肝癌的药物的用途。本申请还提供治疗肝癌的方法，包括向受试者给予有效量的抗PD-L1抗体和安罗替尼。本申请还提供抗PD-L1抗体和安罗替尼联用治疗肝癌的用途。本申请还提供用于治疗肝癌的抗PD-L1抗体和安罗替尼联用。
第三方面，本申请提供用于治疗三阴乳腺癌的联用药物组合物，其包括抗PD-L1抗体和安罗替尼。
另一方面，本申请还提供联用药物组合物在制备用于治疗三阴乳腺癌的药物的用途。本申请还提供治疗三阴乳腺癌的方法，其包括向受试者给予有效量的本申请的联用药物组合物。本申请还提供联用药物组合物用于治疗三阴乳腺癌的用途。所述联用药物组合物包括抗PD-L1抗体和安罗替尼。
另一方面，本申请还提供抗PD-L1抗体和安罗替尼联用在制备治疗三阴乳腺癌的药物的用途。本申请还提供治疗三阴乳腺癌的方法，包括向受试者给予有效量的抗PD-L1抗体和安罗替尼。本申请还提供抗PD-L1抗体和安罗替尼联用治疗三阴乳腺癌的用途。本申请还提供用于治疗三阴乳腺癌的抗PD-L1抗体和安罗替尼联用。
第四方面，本申请提供用于治疗肺癌的联用药物组合物，其包括抗PD-L1抗体和安罗替尼。
另一方面，本申请还提供联用药物组合物在制备用于治疗肺癌的药物的用途。本申请还提供治疗肺癌的方法，其包括向受试者给予有效量的本申请的联用药物组合物。本申请还提供联用药物组合物用于治疗肺癌的用途。所述联用药物组合物包括抗PD-L1抗体和安罗替尼。
另一方面，本申请还提供抗PD-L1抗体和安罗替尼联用在制备治疗肺癌的药物的用途。本申请还提供 治疗肺癌的方法，包括向受试者给予有效量的抗PD-L1抗体和安罗替尼。本申请还提供抗PD-L1抗体和安罗替尼联用治疗肺癌的用途。本申请还提供用于治疗肺癌的抗PD-L1抗体和安罗替尼联用。
发明详述
本申请提供联用药物组合物，其包括抗PD-L1抗体和安罗替尼。在本申请的一些实施方案中，所述联用药物组合物用于治疗肿瘤或癌症。在本申请的一些实施方案中，所述肿瘤或癌症选自胆道系统肿瘤、肝癌、三阴乳腺癌或肺癌。
治疗胆道系统肿瘤的联用药物组合物
一方面，本申请提供一种用于治疗胆道系统肿瘤的联用药物组合物，其包括抗PD-L1抗体和安罗替尼。
在本申请的一些实施方案中，所述联用药物组合物包括抗PD-L1抗体的药物组合物和安罗替尼的药物组合物。
在本申请的一些实施方案中，所述联用药物组合物包装于同一试剂盒中，所述试剂盒还包括PD-L1抗体和安罗替尼联合使用治疗胆道系统肿瘤的说明。
在一些实施方案中，提供了一种用于治疗胆道系统肿瘤的联用药物组合物，其包括含600～2400mg的抗PD-L1抗体的药物组合物和单剂量为6mg、8mg、10mg和/或12mg安罗替尼的药物组合物。其中含抗PD-L1抗体的药物组合物为单剂量或者多剂量。
在一些实施方案中，提供了一种用于治疗胆道系统肿瘤的联用药物组合物，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剂量为6mg、8mg、10mg和/或12mg安罗替尼的药物组合物。
在一些实施方案中，提供了一种用于治疗胆道系统肿瘤的联用药物组合物，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。
在一些实施方案中，提供了一种用于治疗胆道系统肿瘤的联用药物组合物，其包括抗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抗体的单剂量或多剂量，所述安罗替尼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安罗替尼的单剂量。
在一些实施方案中，提供了一种用于治疗胆道系统肿瘤的联用药物组合物，其包括抗PD-L1抗体浓度为10-60mg/mL的抗PD-L1抗体的药物组合物和单剂量为6mg、8mg、10mg和/或12mg安罗替尼的药物组合物。
在一些实施方案中，提供了一种用于治疗胆道系统肿瘤的联用药物组合物，其包括抗PD-L1抗体浓度为10mg/mL的抗PD-L1抗体的药物组合物和单剂量为8mg和/或10mg安罗替尼的药物组合物。
在一些实施方案中，提供了一种用于治疗胆道系统肿瘤的联用药物组合物，其包括含1200mg的抗PD-L1抗体以多剂量形式提供的药物组合物和单剂量为8mg和/或10mg安罗替尼的药物组合物。
另一方面，本申请还提供联用药物组合物在制备用于治疗胆道系统肿瘤的药物的用途。本申请还提供治疗胆道系统肿瘤的方法，其包括向受试者给予有效量的本申请的联用药物组合物。本申请还提供联用药物组合物用于治疗胆道系统肿瘤的用途。在一些实施方案中，所述联用药物组合物包括抗PD-L1人源化单克隆抗体和安罗替尼。
另一方面，本申请还提供抗PD-L1抗体和安罗替尼的组合物在制备治疗胆道系统肿瘤的药物的用途。本申请还提供治疗胆道系统肿瘤的方法，包括向受试者给予有效量的抗PD-L1抗体和安罗替尼的组合物。本申请还提供抗PD-L1抗体和安罗替尼的组合物治疗胆道系统肿瘤的用途。
又一方面，本申请提供用于治疗胆道系统肿瘤的试剂盒，所述试剂盒包括抗PD-L1抗体的药物组合物和安罗替尼的药物组合物，以及抗PD-L1抗体和安罗替尼联合使用治疗胆道系统肿瘤的说明。
又一方面，本申请还提供用于治疗胆道系统肿瘤的抗PD-L1抗体。本申请还提供治疗胆道系统肿瘤的方法，其包括向受试者给予有效量的本申请的抗PD-L1抗体。本申请还提供抗PD-L1抗体用于治疗胆道系统肿瘤的用途。本申请还提供抗PD-L1抗体在制备用于治疗胆道系统肿瘤的药物中的用途。
治疗肝癌的联用药物组合物
一方面，本申请提供一种用于治疗肝癌的联用药物组合物，其包括抗PD-L1抗体和安罗替尼。
在本申请的一些实施方案中，所述联用药物组合物包括抗PD-L1抗体的药物组合物和安罗替尼的药物组合物。
在本申请的一些实施方案中，所述联用药物组合物包装于同一试剂盒中，所述试剂盒还包括抗PD-L1抗体和安罗替尼联合使用治疗肝癌的说明。
在一些实施方案中，提供了一种用于治疗肝癌的联用药物组合物，其包括含600～2400mg的抗PD-L1抗体的药物组合物和单剂量为6mg、8mg、10mg和/或12mg安罗替尼的药物组合物。其中抗PD-L1抗体的药物组合物为单剂量或者多剂量。
在一些实施方案中，提供了一种用于治疗肝癌的联用药物组合物，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剂量为6mg、8mg、10mg和/或12mg安罗替尼的药物组合物。
在一些实施方案中，提供了一种用于治疗肝癌的联用药物组合物，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。
在一些实施方案中，提供了一种用于治疗肝癌的联用药物组合物，其包括抗PD-L1抗体的药物组合物和安罗替尼的药物组合物，其中抗PD-L1抗体被制备为适合第一次给药时向患者给予600～2400mg的抗PD-L1抗体的单剂量或多剂量，所述安罗替尼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安罗替尼的单剂量。
在一些实施方案中，提供了一种用于治疗肝癌的联用药物组合物，其包括抗PD-L1抗体浓度为10-60mg/mL的抗PD-L1抗体的药物组合物和单剂量为6mg、8mg、10mg和/或12mg安罗替尼的药物组合物。
在一些实施方案中，提供了一种用于治疗肝癌的联用药物组合物，其包括抗PD-L1抗体浓度为10mg/mL的抗PD-L1抗体的药物组合物和单剂量为8mg和/或10mg安罗替尼的药物组合物。
在一些实施方案中，提供了一种用于治疗肝癌的联用药物组合物，其包括含1200mg的抗PD-L1抗体以多剂量形式提供的药物组合物和单剂量为8mg和/或10mg安罗替尼的药物组合物。
另一方面，本申请还提供联用药物组合物在制备用于治疗肝癌的药物的用途。本申请还提供治疗肝癌的方法，其包括向受试者给予有效量的本申请的联用药物组合物。本申请还提供联用药物组合物用于治疗肝癌的用途。在一些实施方案中，所述联用药物组合物包括抗PD-L1人源化单克隆抗体和安罗替尼。
另一方面，本申请还提供抗PD-L1抗体和安罗替尼的组合物在制备治疗肝癌的药物的用途。本申请还提供治疗肝癌的方法，包括向受试者给予有效量的抗PD-L1抗体和安罗替尼的组合物。本申请还提供抗PD-L1抗体和安罗替尼的组合物治疗肝癌的用途。
又一方面，本申请提供用于治疗肝癌的试剂盒，所述试剂盒包括抗PD-L1抗体药物的组合物和安罗替尼的药物组合物，以及抗PD-L1抗体和安罗替尼联合使用治疗肝癌的说明。
又一方面，本申请还提供用于治疗肝癌的抗PD-L1抗体。本申请还提供治疗肝癌的方法，其包括向受试者给予有效量的本申请的抗PD-L1抗体。本申请还提供抗PD-L1抗体用于治疗肝癌的用途。本申请还提供抗PD-L1抗体在制备用于治疗肝癌的药物中的用途。
治疗三阴乳腺癌的联用药物组合物
一方面，本申请提供一种用于治疗三阴乳腺癌的联用药物组合物，其包括抗PD-L1抗体和安罗替尼。
在本申请的一些实施方案中，所述联用药物组合物包括抗PD-L1抗体的药物组合物和安罗替尼的药物组合物。
在本申请的一些实施方案中，所述联用药物组合物包装于同一试剂盒中，所述试剂盒还包括PD-L1抗体和安罗替尼联合使用治疗三阴乳腺癌的说明。
在一些实施方案中，提供了一种用于治疗三阴乳腺癌的联用药物组合物，其包括含600～2400mg的抗PD-L1抗体的药物组合物和单剂量为6mg、8mg、10mg和/或12mg安罗替尼的药物组合物。其中抗PD-L1抗体的药物组合物为单剂量或者多剂量。
在一些实施方案中，提供了一种用于治疗三阴乳腺癌的联用药物组合物，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剂量为6mg、8mg、10mg和/或12mg安罗替尼的药物组合物。
在一些实施方案中，提供了一种用于治疗三阴乳腺癌的联用药物组合物，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。
在一些实施方案中，提供了一种用于治疗三阴乳腺癌的联用药物组合物，其包括抗PD-L1抗体的药物 组合物和安罗替尼的药物组合物，其中抗PD-L1抗体被制备为适合第一次给药时向患者给予600～2400mg的抗PD-L1抗体的单剂量或多剂量，所述安罗替尼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安罗替尼的单剂量。
在一些实施方案中，提供了一种用于治疗三阴乳腺癌的联用药物组合物，其包括抗PD-L1抗体浓度为10-60mg/mL的抗PD-L1抗体的药物组合物和单剂量为6mg、8mg、10mg和/或12mg安罗替尼的药物组合物。
在一些实施方案中，提供了用于一种治疗三阴乳腺癌的联用药物组合物，其包括抗PD-L1抗体浓度为10mg/mL的抗PD-L1抗体的药物组合物和单剂量为8mg和/或10mg安罗替尼的药物组合物。
在一些实施方案中，提供了一种用于治疗三阴乳腺癌的联用药物组合物，其包括含1200mg的抗PD-L1抗体以多剂量形式提供的药物组合物和单剂量为8mg和/或10mg安罗替尼的药物组合物。
另一方面，本申请还提供联用药物组合物在制备用于治疗三阴乳腺癌的药物的用途。本申请还提供治疗三阴乳腺癌的方法，其包括向受试者给予有效量的本申请的联用药物组合物。本申请还提供联用药物组合物用于治疗三阴乳腺癌的用途。在一些实施方案中，所述联用药物组合物包括抗PD-L1人源化单克隆抗体和安罗替尼。
另一方面，本申请还提供抗PD-L1抗体和安罗替尼的组合物在制备治疗三阴乳腺癌的药物的用途。本申请还提供治疗三阴乳腺癌的方法，包括向受试者给予有效量的抗PD-L1抗体和安罗替尼的组合物。本申请还提供抗PD-L1抗体和安罗替尼的组合物治疗三阴乳腺癌的用途。
又一方面，本申请提供用于治疗三阴乳腺癌的试剂盒，所述试剂盒包括抗PD-L1抗体的药物组合物和安罗替尼的药物组合物，以及抗PD-L1抗体和安罗替尼联合使用治疗三阴乳腺癌的说明。
又一方面，本申请还提供用于治疗三阴乳腺癌的抗PD-L1抗体。本申请还提供治疗三阴乳腺癌的方法，其包括向受试者给予有效量的本申请的抗PD-L1抗体。本申请还提供抗PD-L1抗体用于治疗三阴乳腺癌的用途。本申请还提供抗PD-L1抗体在制备用于治疗三阴乳腺癌的药物中的用途。
治疗肺癌的联用药物组合物
一方面，本申请提供一种用于治疗肺癌的联用药物组合物，其包括抗PD-L1抗体和安罗替尼。
在本申请的一些实施方案中，所述联用药物组合物包括抗PD-L1抗体的药物组合物和安罗替尼的药物组合物。
在本申请的一些实施方案中，所述联用药物组合物包装于同一试剂盒中，所述试剂盒还包括PD-L1抗体和安罗替尼联合使用治疗肺癌的说明。
在一些实施方案中，提供了一种用于治疗肺癌的联用药物组合物，其包括含600～2400mg的抗PD-L1抗体的药物组合物和单剂量为6mg、8mg、10mg和/或12mg安罗替尼的药物组合物。其中含抗PD-L1抗体的药物组合物为单剂量或者多剂量。
在一些实施方案中，提供了一种用于治疗肺癌的联用药物组合物，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剂量为6mg、8mg、10mg和/或12mg安罗替尼的药物组合物。
在一些实施方案中，提供了一种用于治疗肺癌的联用药物组合物，其包括抗PD-L1抗体的药物组合物和安罗替尼的药物组合物，其中抗PD-L1抗体被制备为适合第一次给药时向患者给予600～2400mg的抗PD-L1抗体的单剂量或多剂量，所述安罗替尼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安罗替尼的单剂量。
在一些实施方案中，提供了一种用于治疗肺癌的联用药物组合物，其包括抗PD-L1抗体浓度为10-60mg/mL的抗PD-L1抗体的药物组合物和单剂量为6mg、8mg、10mg和/或12mg安罗替尼的药物组合物。
在一些实施方案中，提供了一种用于治疗肺癌的联用药物组合物，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。
在一些实施方案中，提供了一种用于治疗肺癌的联用药物组合物，其包括抗PD-L1抗体浓度为10mg/mL的抗PD-L1抗体的药物组合物和单剂量为8mg和/或10mg安罗替尼的药物组合物。
在一些实施方案中，提供了一种用于治疗肺癌的联用药物组合物，其包括含1200mg的抗PD-L1抗体以多剂量形式提供的药物组合物和单剂量为8mg和/或10mg安罗替尼的药物组合物。
另一方面，本申请还提供联用药物组合物在制备用于治疗肺癌的药物的用途。本申请还提供治疗肺癌的方法，其包括向受试者给予有效量的本申请的联用药物组合物。本申请还提供联用药物组合物用于治疗 肺癌的用途。所述联用药物组合物包括抗PD-L1人源化单克隆抗体和安罗替尼。
另一方面，本申请还提供抗PD-L1抗体和安罗替尼的组合物在制备治疗肺癌的药物的用途。本申请还提供治疗肺癌的方法，包括向受试者给予有效量的抗PD-L1抗体和安罗替尼的组合物。本申请还提供抗PD-L1抗体和安罗替尼的组合物治疗肺癌的用途。
又一方面，本申请提供用于治疗肺癌的试剂盒，所述试剂盒包括抗PD-L1抗体的药物组合物和安罗替尼的药物组合物，以及抗PD-L1抗体和安罗替尼联合使用治疗肺癌的说明。
又一方面，本申请还提供用于治疗肺癌的抗PD-L1抗体。本申请还提供治疗肺癌的方法，其包括向受试者给予有效量的本申请的抗PD-L1抗体。本申请还提供抗PD-L1抗体用于治疗肺癌的用途。本申请还提供抗PD-L1抗体在制备用于治疗肺癌的药物中的用途。
联用药物组合物的给药/治疗方案
在本申请的一些实施方案中，上述用途或者治疗方法中，所述抗PD-L1抗体和安罗替尼各自呈药物组合物的形式，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抗体和安罗替尼各自以间隔给药的方式给药。在一些实施方案中，所述抗体和安罗替尼分别以相同或者不同的给药方案进行给药。在一些实施方案中，分别以不同的给药方案进行给药。
在本申请的一些实施方案中，所述用途或治疗方法中，所述抗PD-L1抗体可以每周(q1w)、每2周(q2w)、每3周(q3w)、或者每4周(q4w)施用一次。在一个具体的实施方案中，每3周给予抗PD-L1抗体一次。在一些实施方案中，所述抗PD-L1抗体每次以600～2400mg的剂量施用。
所述安罗替尼可以每日一次6mg、8mg、10mg或者12mg的剂量，连续用药2周，停1周的给药方案给药。
在一些实施方案中，抗PD-L1抗体和安罗替尼分别具有相同或者不同的治疗周期。在一些具体的实施方案中，抗PD-L1抗体和安罗替尼具有相同的治疗周期，例如每1周、每2周、每3周或者每4周为一个治疗周期。
在本申请的一些实施方案中，所述用途或者治疗方法中，21天为一个治疗周期，在每个周期的第一天给予PD-L1抗体，在每个周期的第1-14天每天给予安罗替尼。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。
在本申请的一些实施方案中，所述用途或者治疗方法中，其中所述抗PD-L1抗体可以包括选自0.01至40mg/kg，0.1至30mg/kg，0.1至20mg/kg，0.1至15mg/kg，0.1至10mg/kg，1至15mg/kg，1至20mg/kg，1至3mg/kg，3至10mg/kg，3至15mg/kg，3至20mg/kg，3至30mg/kg，10至20mg/kg，或15至20mg/kg的剂量给予受试者；或者以60mg至2400mg，90mg至约1800mg，120mg至1500mg，300mg至900mg，600mg至900mg，300mg至1200mg，600mg至1200mg，或900mg至1200mg的剂量施用于受试者。
在所述用途或者治疗方法的一些实施方案中，21天为一个治疗周期，在每个周期的第一天给予1200mg的PD-L1抗体，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。
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抗体的药物组合物的单剂量包括300mg或600mg的抗PD-L1抗体。
在本申请的一些实施方案中，所述抗PD-L1抗体的药物组合物的总剂量为600～2400mg。在部分方案中，所述抗PD-L1抗体的药物组合物的总剂量包括选自600mg、900mg、1200mg、1500mg、1800mg、2100mg、2400mg、或上述任意值形成的范围。在部分方案中，所述抗PD-L1抗体的药物组合物的总剂量优选600～2100mg、或900mg～1500mg。
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几种。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为约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单抗浓度约为 5-150mg/mL；优选为约10-60mg/mL；更优选为约10-30mg/mL。在一些具体方案中，抗PD-L1单抗质量体积浓度约10mg/mL、约20mg/mL、约30mg/mL、约40mg/mL、约50mg/mL、约60mg/mL、约70mg/mL、约80mg/mL、约90mg/mL、约100mg/mL、约110mg/mL或约120mg/mL，优选为约10mg/mL、约20mg/mL、约30mg/mL、约40mg/mL、约50mg/mL或约60mg/mL，更优选为约10mg/mL、约20mg/mL或约30mg/mL。在一些实施方案中，抗PD-L1单抗质量体积浓度为约10mg/mL。在另一些实施方案中，抗PD-L1单抗质量体积浓度为约30mg/mL。在另一些实施方案中，抗PD-L1单抗质量体积浓度为约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约为5-30mM，优选约为10-25mM，更优选约为10-20mM，最优选约为10-15mM。在一些具体方案中，所述组氨酸盐缓冲液浓度约为5mM、约10mM、约15mM、约20mM、约25mM或约30mM。在一些实施方案中，所述组氨酸盐缓冲液浓度约为10mM。在另一些实施方案中，所述组氨酸盐缓冲液浓度约为15mM。在另一些实施方案中，所述组氨酸盐缓冲液浓度约为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/稳定剂为约20-150mg/mL的蔗糖，优选约为40-100mg/mL的蔗糖，更优选约为60-80mg/mL的蔗糖。在一些具体方案中，所述蔗糖的浓度约为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，所述蔗糖的浓度约60mg/mL。在一些具体实施方案中，所述蔗糖的浓度约为70mg/mL。在一些具体实施方案中，所述蔗糖的浓度约为80mg/mL。在一些具体实施方案中，所述蔗糖的浓度为约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；优选聚山梨酯80或聚山梨酯20；更优选为聚山梨酯80。在一些方案中，以w/v计算，所述表面活性剂的浓度约为0.05-0.6mg/mL，优选约为0.1-0.4mg/mL，更优选约为0.2-0.3mg/mL。
在本申请的一些实施方案中，以w/v计算，所述表面活性剂为约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，所述表面活性剂为约0.05-0.6mg/mL的聚山梨酯80，优选约为0.1-0.4mg/mL的聚山梨酯80，更优选约为0.2-0.3mg/mL的聚山梨酯80，最优选约为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含量约为0.1mg/mL、0.2mg/mL、0.3mg/mL、0.4mg/mL、0.5mg/mL或0.6mg/mL；优选地，所述药物组合物中聚山梨酯80含量约为0.2mg/mL、0.3mg/mL、0.4mg/mL或0.5mg/mL；更优地，所述药物组合物中聚山梨酯80含量约为0.2mg/mL、0.3mg/mL或0.4mg/mL；最优地，所述药物组合物中聚山梨酯80含量约为0.2mg/mL。在一些实施方案中，所述药物组合物中聚山梨酯80含量约为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含量约为0.2mg/mL。在一些实施方案中，所述药物组合物中聚山梨酯80含量约为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含量约为0.4mg/mL。在一些实施方案中，所述药物组合物中聚山梨酯80含量约为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；优选为4.5-6.5；更优选为5.5-6.0；最优选5.5。在一些实施方案中，药物组合物水溶液的pH值为约4.5、约4.8、约5.0、约5.2、约5.4、约5.5、约5.6、约5.8或约6.0，优选为约5.0、约5.2、约5.4、约5.5或约5.6，更优选为约5.5。在一些实施方案中，药物组合物水溶液的pH值为约5.0。在一些实施方案中，药物组合物水溶液的pH值为约5.2。在一些实施方案中，药物组合物水溶液的pH值为约5.4。在一些实施方案中，药物组合物水溶液的pH值为约5.5。在一些实施方案中，药物组合物水溶液的pH值为约5.6。在一些实施方案中，药物组合物水溶液的pH值为约5.8。在一些实施方案中，药物组合物水溶液的pH值为约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)质量体积浓度为约20mg/mL的抗PD-L1抗体，(b)质量体积浓度为约70mg/mL的蔗糖，(c)质量体积浓度为约0.1mg/mL的聚山梨酯80，(d)摩尔浓度为约20mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为约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)质量体积浓度为约20mg/mL的抗PD-L1单抗，(b)质量体积浓度为约70mg/mL的蔗糖，(c)质量体积浓度为约0.1mg/mL的聚山梨酯80，(d)摩尔浓度为约20mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为约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)质量体积浓度为约10mg/mL的抗PD-L1抗体，(b)质量体积浓度为约80mg/mL的蔗糖，(c)质量体积浓度为约0.2mg/mL的聚山梨酯80，(d)摩尔浓度为约10mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为约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)质量体积浓度为约50mg/mL的抗PD-L1抗体，(b)质量体积浓度为约80mg/mL的蔗糖，(c)质量体积浓度为约0.3mg/ml的聚山梨酯80，(d)摩尔浓度为约10mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为约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)质量体积浓度为约100mg/mL的抗PD-L1抗体，(b)质量体积浓度为约80mg/mL的蔗糖，(c)质量体积浓度为约0.5mg/mL的聚山梨酯80， (d)摩尔浓度为约10mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为约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)质量体积浓度为约30mg/mL的抗PD-L1抗体，(b)质量体积浓度为约80mg/mL的蔗糖，(c)质量体积浓度为约0.2mg/mL的聚山梨酯80，(d)摩尔浓度为约10mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为约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)质量体积浓度为约60mg/mL的抗PD-L1抗体，(b)质量体积浓度为约80mg/mL的蔗糖，(c)质量体积浓度为约0.2mg/mL的聚山梨酯80，(d)摩尔浓度为约10mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为约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)质量体积浓度为约10mg/mL的抗PD-L1抗体，(b)质量体积浓度为约70mg/mL的蔗糖，(c)质量体积浓度为约0.4mg/mL的聚山梨酯80，(d)摩尔浓度为约20mM的组氨酸，(e)任选醋酸适量，调节组合物的pH值为约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)质量体积浓度为约10mg/mL的抗PD-L1单抗，(b)质量体积浓度为约80mg/mL的蔗糖，(c)质量体积浓度为约0.2mg/mL的聚山梨酯80，(d)摩尔浓度为约20mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为约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，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)。
安罗替尼的药物组合物
在本申请的一些实施方案中，所述安罗替尼的药物组合物的单剂量包括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，所述安罗替尼药物组合物的总剂量优选包括112mg～168mg。
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。
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 PCTCN2020073957-appb-000001
如本申请所用，所述安罗替尼包括其非盐形式(例如自由碱)，也包括其药学上可接受的盐，所述非盐形式或盐都纳入本申请的保护范围内。例如，所述安罗替尼的药学上可接受的盐可以是盐酸盐或二盐酸盐。本申请中涉及的安罗替尼或其盐的剂量，除非另有说明，均基于安罗替尼游离碱的分子量。
胆道系统肿瘤
在本申请的一些实施方案中，所述胆道系统肿瘤选自胆道系统腺癌。在本申请的一些实施方案中，所述胆道系统肿瘤包括胆囊癌(Gallbladder Cancer,GBC)、肝内胆管细胞癌(Intrahepatic Cholangiocarcinoma,IHCC)、肝外胆管细胞癌(Extrahepatic Cholangiocarcinoma,EHCC)。在本申请的一些实施方案中，所述的肝外胆管细胞癌包括肝门胆管癌(hilar cholangiocarcinomas，也称为Klatskin肿瘤)和远端胆管癌(distal cholangiocarcinomas)。在本申请的一些实施方案中，胆道系统肿瘤包括腺癌型胆囊癌、腺癌型肝内胆管细胞癌、或腺癌型肝外胆管细胞癌。
在本申请的一些实施方案中，所述胆道系统肿瘤包括不能手术切除、晚期或转移性胆道系统肿瘤。在本申请的一些实施方案中，所述胆道系统肿瘤包括不能手术切除、晚期或转移性腺癌型胆囊癌、腺癌型肝内胆管细胞癌、或腺癌型肝外胆管细胞癌。在本申请的一些实施方案中，所述胆道系统肿瘤的患者在先接受过化疗但治疗失败。在本申请的一些实施方案中，所述胆道系统肿瘤的患者既往一线化疗失败。
肝癌
在本申请的一些实施方案中，所述肝癌为肝细胞癌(Hepatocellular Carcinoma,HCC)。在本申请的一些实施方案中，所述肝癌选自原发性肝细胞癌。在本申请的一些实施方案中，所述肝癌选自晚期和/或转移性肝细胞癌。在一些实施方案中，所述肝癌为不可手术的肝细胞癌。在一些实施方案中，所述肝癌为在先经局部治疗失败的肝细胞癌或者不适合接受局部治疗的肝细胞癌，所述的局部治疗包括但不限于消融(包括但不限于射频消融、冷冻消融、经皮乙醇注射治疗和微波消融)、放射治疗和/或肝动脉化疗。在一些实施方案中，所述肝癌为索拉非尼和/或乐伐替尼治疗失败的肝癌。
三阴乳腺癌
在本申请的一些实施方案中，所述三阴乳腺癌的受试者已接受过手术、化疗和/或放射治疗。在一些具体方案中，所述三阴乳腺癌的受试者为在先接受过一线化疗。在一些具体方案中，所述三阴乳腺癌的受试者已接受过蒽环类和/或紫杉类药物治疗。在一些具体方案中，所述三阴乳腺癌的受试者至少接受过一线系统治疗且已使用过蒽环类和/或紫杉类药物。
肺癌
在本申请的一些实施方案中，所述肺癌选自非小细胞肺癌。在一些实施方案中，所述肺癌包括肺鳞癌或肺腺癌。在一些实施方案中，所述肺癌是晚期肺癌。在一些实施方案中，所述肺癌是EGFR或ALK野生型的非小细胞肺癌。在一些实施方案中，所述肺癌选自晚期鳞癌型非小细胞肺癌、晚期腺癌型非小细胞肺癌。在一些实施方案中，所述肺癌选自EGFR或ALK野生型的鳞癌型非小细胞肺癌、EGFR或ALK野生型的腺癌型非小细胞肺癌。在一些实施方案中，所述的肺癌为BRaf或EGFR突变的非小细胞肺癌，例如BRAF p.V600E、EGFR del和/或EGFR-T790M的非小细胞肺癌。
在一些实施方案中，所述肺癌患者在先接受过化疗；在一些实施方案中，所述肺癌是接受过一线标准化疗失败或无法耐受化疗的晚期(IIIB和/或IV期)肺癌。
本申请中，所述的化疗包括但不限于包括但不限于铂类药物、氟嘧啶衍生物、喜树碱类、紫杉类、长春碱类、蒽环类、抗生素类、鬼臼类、抗肿瘤类药物、抗代谢类药物中的一种或多种，可以列举的实例包括但不限于铂类药物(例如奥沙利铂、顺铂、卡铂、奈达铂、双环铂(dicycloplatin))、氟嘧啶衍生物(例如吉西他滨、卡培他滨、安西他滨、氟尿嘧啶、双呋氟尿嘧啶、去氧氟尿苷、替加氟、卡莫氟、三氟尿苷)、紫杉烷类(例如紫杉醇、白蛋白结合的紫杉醇以及多烯紫杉醇)、喜树碱类(例如喜树碱、羟基喜树碱、9-氨基喜树碱、7-乙基喜树碱、伊立替康、拓扑替康)、长春碱类(长春瑞滨、长春碱、长春新碱、长春地 辛、长春富宁(vinflunine))、蒽环类(表柔比星、阿霉素、柔红霉素、吡柔比星、氨柔比星、伊达柔比星、米托蒽醌、阿柔比星、戊柔比星、佐柔比星、匹杉琼)、培美曲塞、卡氮芥、美法仑、依托泊苷(足叶乙苷)、替尼铂苷、丝裂霉素、异环磷酰胺、环磷酰胺、阿扎胞苷、甲氨蝶呤、苯达莫司汀、脂质体阿霉素、放线菌素D(更生霉素)、博来霉素、平阳霉素、替莫唑胺、氨烯咪胺、培洛霉素、艾日布林、普那布林(plinabulin)、Sapacitabine、曲奥舒凡(treosulfan)、153Sm-EDTMP、替吉奥和encequidar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)。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癌症治疗剂。
技术效果
通常，使用上述的本申请的联用药物组合物将有助于：
(1)与单独给予该组合中的任一药物相比，在减少肿瘤的生长或甚至消除肿瘤方面产生更好的疗效；
(2)与该组合中的任一药物单独给药相比，提供更少量的给药；
(3)提供在患者中具有良好耐受的治疗，与单一给予的任一药物相比，其不良反应和/或并发症更少；
(4)提供在所治疗患者之中的更好的疾病控制率；
(5)提供在所治疗的患者具有更长的生存期(例如中位生存期、无进展生存期或总生存期)；
(6)提供相比于标准的化疗而言，所治疗患者具有更长的生存期(例如中位生存期、无进展生存期或总生存期)；
(7)提供更长时间的疾病缓解持续时间(DOR)；和/或
(8)与单独给予该组合中的任一药物相比，具有良好的治疗胆道系统肿瘤、肝癌、三阴乳腺癌和/或肺癌的活性，表现出更优异的抗肿瘤协同效果。
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。
如文本所用，术语“联用药物组合物”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。在本文中，术语“联用药物组合物”、“药物组合物”和“药物组合”可互换使用。
如本文所用，术语“抗体”是指具有至少一个抗原结合结构域的结合蛋白。本申请的抗体和其片段可以是整个抗体或其任何片段。因此，本申请的抗体和片段包括单克隆抗体或其片段和抗体变体或其片段，以及免疫缀合物。抗体片段的实例包括Fab片段、Fab'片段、F(ab')2片段、Fv片段、分离的CDR区、单链Fv分子(scFv)、Fd片段和本领域已知的其它抗体片段。抗体和其片段还可以包括重组多肽、融合蛋白和双特异性抗体。本文公开的抗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，以及以其它方式改进抗体特性的其它框架修饰。
本申请提供了结合PD-L1的分离的抗体或其片段，其中所述抗体可以由杂交瘤产生，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它哺乳动物的PD-L1。在另一个实施方案中，抗体或和其片段不结合小鼠PD-L1。术语“人PD-L1”、“hPD-L1”和“huPD-L1”等在本文中可互换使用，并且是指人PD-L1和人PD-L1的变体或同种型。“特异性”意指抗体和其片段以比任何其他靶标更大的亲和力结合PD-L1。
术语“治疗”一般是指获得需要的药理和/或生理效应。该效应根据部分或完全稳定或治愈疾病和/或由于疾病产生的副作用，可以是治疗性的。本文使用的“治疗”涵盖了对患者疾病的任何治疗，包括：(a)抑制疾病的症状，即阻止其发展；或(b)缓解疾病的症状，即，导致疾病或症状退化。
术语“有效量”意指(i)治疗特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的活性物质(例如本申请的抗体或化合物)的量可根据一些因素而变化，诸如个体的疾病状态、年龄、性别和重量，以及治疗剂或治疗剂组合在个体中引发所需应答的能力。有效量也可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“施用”表示，使用本领域技术人员已知的多种方法和递送系统中的任一种，向主体物理引入包含治疗剂的组合物。免疫检查点抑制剂(例如，抗PD-1抗体或抗PD-L1抗体)的施用途径包括静脉内、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，所述免疫检查点抑制剂(例如，抗PD-1抗体或抗PD-L1抗体)通过非胃肠外途径施用，在某些实施方案中，口服施用。其它非胃肠外途径包括局部、表皮或粘膜施用途径，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“剂量”的应用是指，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)。
本文提及的术语“基于重量的剂量”是指基于患者的重量计算出的、施用给患者的剂量。例如，当具有60kg体重的患者需要3mg/kg的抗PD-1抗体时，人们可以从抗PD-1抗体的固定剂量制剂中一次性抽取适当量的抗PD-1抗体(即，180mg)。
安罗替尼可通过多种途径给药，该途径包括但不限于口服、肠胃外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、经吸入、阴道、眼内、经局部给药、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。安罗替尼可以每日施用一次或多次。在一些实施方案中，安罗替尼以口服固体制剂每天给药一次。
安罗替尼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。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。例如给药期和停药期的以天数计的比值为2:0.5～5，优选2:0.5～3，较优选2:0.5～2，更优选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。
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。
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受试者。
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。在本文中，术语“单剂量”和“单位剂量”具有相同的含义，并可互换使用。
术语“多剂量”由多个单剂量组成。
术语“药物组合物”是指一种或多种本申请的活性成分或其药物组合与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对受试者给予本申请的化合物或其药物组合。
在本文中，除非另有说明，否则术语“包含、包括和含有(comprise、comprises和comprising)”或等同物为开放式表述，意味着除所列出的要素、组分和步骤外，还可涵盖其它未指明的要素、组分和步骤。
为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它已确定的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胆道系统肿瘤的临床试验
1.1入选标准
1)年满18周岁；ECOG体力状况：0～1分；预计生存期超过3个月。
2)经组织学或病理学确诊的不能手术切除或转移性胆道癌患者，包括肝内胆管细胞癌(IHCC)、肝外胆管细胞癌(EHCC)和胆囊癌(GBC)。
3)患者至少具有一个可测量病灶(RECIST 1.1)。
4)既往一线化疗失败的患者。化疗失败是指：治疗过程中或末次治疗后出现疾病进展；或治疗过程中因为毒副作用不可耐受。
5)实验室检查需满足：血常规检查：血红蛋白(Hb)≥80g/L(14天内未输血)；绝对中性粒细胞计数(ANC)≥1.5×10 9/L；血小板(PLT)≥75×10 9/L；生化检查：谷丙转氨酶(ALT)及谷草转氨酶(AST)≤2.5×ULN(肿瘤肝脏转移者，≤5×ULN)；血清总胆红素(TBIL)≤2×ULN(Gilbert综合症患者，≤3×ULN)；血清肌酐(Cr)≤1.5×ULN，且肌酐清除率＞50μmol/L；凝血功能：活化部分凝血活酶时间(APTT)、国际标准化比值(INR)、凝血酶原时间(PT)≤1.5×ULN；多普勒超声评估：左室射血分数(LVEF)≥50％。
6)女性应同意在研究期间和研究结束后6个月内必须采用避孕措施(如宫内节育器[IUD]、避孕药或避孕套)；在研究入组前的7天内血清或尿妊娠试验阴性，且必须为非哺乳期患者；男性应同意在研究期间和研究期结束后6个月内必须采用避孕措施的患者。
7)患者自愿加入本研究，签署知情同意书，依从性好。
1.2试验药
抗PD-L1抗体注射剂hu5G11-hIgG1：1200mg抗PD-L1抗体注射液(100mg/10mL)用生理盐水稀释至250mL，输注时间60±5min，输注完成后按医院常规要求进行生理盐水冲管，每21天给药一次，即21天为一个治疗周期。
盐酸安罗替尼胶囊(活性成分为安罗替尼二盐酸盐)：抗PD-L1抗体注射液开始输注±5min内空腹服用盐酸安罗替尼胶囊10mg，连续口服2周停1周，即21天为一治疗周期。
规格：12mg、10mg、8mg。
1.3评价标准
根据RECIST 1.1/irRECIST判定疾病状态。以RECIST 1.1评价标准为主。
1.4终点指标
客观缓解率(ORR)＝(完全缓解(CR)+部分缓解(PR))；
抗肿瘤疗效指标：无进展生存期(PFS)、疾病控制率(DCR＝CR+PR+疾病稳定(SD))、总生存期(OS)、疾病稳定(SD)、PR(部分缓解)等。
1.5结果
Figure PCTCN2020073957-appb-000002
Figure PCTCN2020073957-appb-000003
患者用药规格：C01002、C01007和C01017患者联用1200mg抗PD-L1抗体注射剂hu5G11-hIgG1和10mg盐酸安罗替尼胶囊。C01009和C01021患者联用1200mg抗PD-L1抗体注射剂hu5G11-hIgG1和12mg盐酸安罗替尼胶囊。患者C01006患者联用1200mg抗PD-L1抗体注射剂hu5G11-hIgG1和12mg盐酸安罗替尼胶囊，后盐酸安罗替尼胶囊降为10mg(在本申请的实施例中，盐酸安罗替尼胶囊的量以其中包含的安罗替尼的重量计)。
患者诊断及在先治疗情况：
C01002患者：左半肝切除+肝门部肿大淋巴结切除术。先后接受过放疗，DC-CIK细胞治疗2周期后转移，射波刀治疗3次，和GP方案(吉西他滨+顺铂)4周期，之后疾病进展。C01006患者：免疫组化：CA19.9(2+)，CK18(3+)，CK19(2+)，CK7(2+)，Ki-67(+20-30％)。白蛋白紫杉醇+替吉奥胶囊治疗共6周期，疗效PD，之后介入治疗，疗效PD(疾病进展)。
C01007患者：免疫组化：CA19.9(2+)，CD34(2+)，CK18(2+)，CK19(2+)，CK7(2+)，Ki-67(+,10％)。吉西他滨+卡培他滨联合治疗，骨髓抑制。之后奥沙利铂+替吉奥胶囊q3w，疾病进展。之后白蛋白紫杉醇联合阿帕替尼治疗。
C01009患者：免疫组化：PCX(+)，CK(+)，CK19(部分+)，AFP(+)，CD56(+)，Ki-67(+10％)。吉西他滨1.4g d1,8+顺铂40mg d2、3方案治疗后，患者不耐受。
C01017患者：免疫组化：CK18(3+)，CK19(3+)，CK7(3+)，CA19.9(1+)，AFP(1+)，Ki-67(+30％)。GC方案(吉西他滨1.6g d1/1.4g d8+替西奥60mg bid po/3w)4周期后不耐受。
C01021患者：替吉奥+奥沙利铂联用，6周期。
实施例2肝癌的临床试验
2.1入选标准
1)年满18周岁；ECOG体力状况：0～1分；预计生存期超过3个月。
2)经病理组织学或者细胞学检查确诊的晚期肝细胞癌患者(巴塞罗那肝癌临床分期C期，或不适合接受或局部治疗失败的B期患者)。
3)患者至少具有一个可测量病灶(RECIST 1.1)。
4)肝癌患者未经过免疫治疗。
5)实验室检查需满足：血常规检查：血红蛋白(Hb)≥80g/L(14天内未输血)；绝对中性粒细胞计 数(ANC)≥1.5×10 9/L；血小板(PLT)≥75×10 9/L；生化检查：谷丙转氨酶(ALT)及谷草转氨酶(AST)≤2.5×ULN(肿瘤肝脏转移者，≤5×ULN)；血清总胆红素(TBIL)≤2×ULN(Gilbert综合症患者，≤3×ULN)；血清肌酐(Cr)≤1.5×ULN，且肌酐清除率＞50μmol/L；凝血功能：活化部分凝血活酶时间(APTT)、国际标准化比值(INR)、凝血酶原时间(PT)≤1.5×ULN；多普勒超声评估：左室射血分数(LVEF)≥50％。
6)女性应同意在研究期间和研究结束后6个月内必须采用避孕措施(如宫内节育器[IUD]、避孕药或避孕套)；在研究入组前的7天内血清或尿妊娠试验阴性，且必须为非哺乳期患者；男性应同意在研究期间和研究期结束后6个月内必须采用避孕措施的患者。
7)患者自愿加入本研究，签署知情同意书，依从性好。
2.2试验药
抗PD-L1抗体注射剂hu5G11-hIgG1：1200mg抗PD-L1抗体注射液(100mg/10mL)用生理盐水稀释至250mL，输注时间60±5min，输注完成后按医院常规要求进行生理盐水冲管，每21天给药一次。
盐酸安罗替尼胶囊(活性成分为安罗替尼二盐酸盐)：抗PD-L1抗体注射液开始输注±5min内空腹服用盐酸安罗替尼胶囊10mg，连续口服2周停1周，即21天为一治疗周期。
规格：12mg、10mg、8mg。
2.3评价标准
根据RECIST 1.1/irRECIST判定疾病状态。以RECIST 1.1评价标准为主。
2.4终点指标
客观缓解率(ORR)＝(完全缓解(CR)+部分缓解(PR))；
抗肿瘤疗效指标：无进展生存期(PFS)、疾病控制率(DCR＝CR+PR+疾病稳定(SD))、总生存期(OS)、疾病稳定(SD)、部分缓解(PR)等。
2.5结果
Figure PCTCN2020073957-appb-000004
Figure PCTCN2020073957-appb-000005
患者用药规格：C01003、C01005、C01015、C01020患者联用1200mg抗PD-L1抗体注射剂hu5G11-hIgG1和10mg盐酸安罗替尼胶囊。C01013患者联用1200mg抗PD-L1抗体注射剂hu5G11-hIgG1和12mg盐酸安罗替尼胶囊。患者C01019联用1200mg抗PD-L1抗体注射剂hu5G11-hIgG1和10mg盐酸安罗替尼胶囊，后盐酸安罗替尼胶囊降为8mg。
患者诊断及在先治疗情况：
C01003患者：免疫组化：Arg-1(1+)，CD34(3+)，CK18(2+)，GPC3(1+)，Hepatocyte(3+)，Ki-67(+80％)，CD31(3+)；索拉非尼用药后不耐受。
C01005患者：索拉非尼用药后疾病进展。
C01013患者：手术，后口服乐伐替尼胶囊，疾病进展。
C01020患者：口服乐伐替尼后不耐受。
C01019和C01015患者：在先未接受过标准治疗。
实施例3三阴乳腺癌的临床试验
实施例1临床试验
3.1入选标准
1)18-75周岁；ECOG体力状况：0～1分；预计生存期超过3个月。
2)采用组织学或细胞学方法确诊的复发或转移性三阴乳腺癌，三阴乳腺癌定义为雌激素受体(ER)、孕激素受体(PR)、人类表皮生长因子受体(Her-2)均阴性。ER、PR阴性定义为：ER＜1％阳性，PR＜1％阳性。Her-2阴性定义为：免疫组化检测Her-2(-)或(1+)，其中Her-2(2+)者必须进行FISH检测且结果为阴性，如Her-2(-)或(1+)者可选择进行FISH检测，但结果必须为阴性。
3)患者至少具有一个可测量病灶(RECIST 1.1)。
4)既往至少接受过一线系统治疗且已使用过蒽环类和/或紫杉类药物，最后一次治疗后疾病进展；如果在治疗期间或停止治疗后6个月内出现复发或疾病进展，应将其算作治疗失败。
5)实验室检查需满足：血常规检查：血红蛋白(Hb)≥80g/L(14天内未输血)；绝对中性粒细胞计数(ANC)≥1.5×10 9/L；血小板(PLT)≥75×10 9/L；生化检查：谷丙转氨酶(ALT)及谷草转氨酶(AST)≤2.5×ULN(肿瘤肝脏转移者，≤5×ULN)；血清总胆红素(TBIL)≤1.5×ULN(Gilbert综合症患者，≤3×ULN)；血清肌酐(Cr)≤1.5×ULN，且肌酐清除率＞50μmol/L；凝血功能：活化部分凝血活酶时间(APTT)、国际标准化比值(INR)、凝血酶原时间(PT)≤1.5×ULN；多普勒超声评估：左室射血分数(LVEF)≥50％。
6)女性应同意在研究期间和研究结束后6个月内必须采用避孕措施(如宫内节育器[IUD]、避孕药或避孕套)；在研究入组前的7天内血清或尿妊娠试验阴性，且必须为非哺乳期患者；男性应同意在研究期间和研究期结束后6个月内必须采用避孕措施的患者。
7)患者自愿加入本研究，签署知情同意书，依从性好。
3.2试验药
抗PD-L1抗体注射剂hu5G11-hIgG1：1200mg抗PD-L1抗体注射液(100mg/10mL)用生理盐水稀释至250mL，输注时间60±5min，输注完成后按医院常规要求进行生理盐水冲管，每21天给药一次。
盐酸安罗替尼胶囊(活性成分为安罗替尼二盐酸盐)：抗PD-L1抗体注射液开始输注±5min内空腹服用盐酸安罗替尼胶囊10mg，连续口服2周停1周，即21天为一治疗周期。
规格：12mg、10mg、8mg。
3.3评价标准
根据RECIST 1.1/irRECIST判定疾病状态。以RECIST 1.1评价标准为主。
3.4终点指标
客观缓解率(ORR)＝(完全缓解(CR)+部分缓解(PR))；
抗肿瘤疗效指标：无进展生存期(PFS)、疾病控制率(DCR＝CR+PR+疾病稳定(SD))、总生存期(OS)等。
3.5结果
Figure PCTCN2020073957-appb-000006
Figure PCTCN2020073957-appb-000007
患者用药规格：C01001和C01003患者联用1200mg抗PD-L1抗体注射剂hu5G11-hIgG1和10mg盐酸安罗替尼胶囊。C01004、C01005、C01006、C01007、C01008和C01009患者联用1200mg抗PD-L1抗体注射剂hu5G11-hIgG1和12mg盐酸安罗替尼胶囊。
患者情况：
C01001患者：左乳浸润性乳腺癌，淋巴结转移，先后接受过根治术，化疗(AT方案(阿霉素+多西他赛，3周期)，AC方案(阿霉素+环磷酰胺，3周期)，GP方案(吉西他滨+卡铂，4周期))和放疗(100Gy，50Gy)。
C03003患者：右乳浸润性乳腺癌，淋巴结转移，先后接受过根治术，化疗(吡柔比星+环磷酰胺+多西他赛，8周期)和放疗。
C01004：右乳浸润性乳腺癌，肺转移，骨转移可能，先后接受过根治术，化疗(AC-T方案(吡柔比星+环磷酰胺+紫杉醇，8周期)，卡培他滨(6周期)，TC方案(多西他赛+卡铂，8周期)，多西他赛(2周期))和放疗(50Gy)。
C01005：右乳浸润性乳腺癌，肺转移，肝转移，先后接受过根治术，化疗(AC-T方案(吡柔比星+环磷酰胺+紫杉醇，8周期)，TX+尼妥珠单抗(多西他赛+卡培，6周期)，GP方案(吉西他滨+顺铂，4周期)，(吉西他滨+卡铂，1周期)和IMP4297胶囊(PARP抑制剂))和放疗。
C01006：右乳浸润性乳腺癌，先后接受过根治术，化疗(TEC方案(紫杉醇+表阿霉素+环磷酰胺)，GP方案(吉西他滨+顺铂，6周期)，TX方案(多西他赛+卡培他滨，1周期))和放疗。
C01007：左乳浸润性乳腺癌，淋巴结转移，先后接受过根治术，化疗(TC方案(紫杉醇+卡铂，6周期)，(紫杉醇+卡培他滨，3周期))和放疗(223.4Gy)。
C01008：左乳浸润性乳腺癌，先后接受过根治术，化疗(EC-T方案(表阿霉素+环磷酰胺+紫杉醇，8周期))和放疗。
C01009：左乳浸润性导管癌，淋巴结转移，先后接受过根治术，化疗(TAC方案(吡柔比星+环磷酰胺+紫杉醇，6周期)，紫杉醇(9周期)，卡铂(1周期))。
实施例4肺癌的临床试验
4.1入选标准
1)年满18周岁；ECOG体力状况：0～1分；预计生存期超过3个月。
2)组织学或细胞学确诊为非小细胞肺癌。
3)至少接受过一线标准化疗失败或无法耐受化疗的晚期(IIIB/IV期)患者，根据实体瘤疗效评价标准RECIST 1.1，至少具有一个可测量病灶。
4)肿瘤表达PD-L1阳性(肿瘤比例评分TPS≥1％)。
组织样本要求：福尔马林固定、石蜡包埋的存档肿瘤样品用于PD-L1分析。组织样品必须在随机入组前被中心服务商接收并评估。不接受细针抽吸样品。接受粗针或切除活检组织样品、或已切除的组织。
5)主要器官功能正常，即符合下列标准：
a)血常规检查：血红蛋白(Hb)≥90g/L(14天内未输血)；绝对中性粒细胞计数(ANC)≥1.5×10 9/L；血小板(PLT)≥80×10 9/L；
b)生化检查：谷丙转氨酶(ALT)及谷草转氨酶(AST)≤2.5×ULN(肿瘤肝脏转移者，≤5×ULN)；血清总胆红素(TBIL)≤1.5×ULN(Gilbert综合症患者，≤3×ULN)；血清肌酐(Cr)≤1.5×ULN，或肌酐清除率计算值≥50mL/min；
肌酐清除率计算公式：Ccr＝(140-年龄)×体重(kg)/72×Scr(mg/dl)
Ccr＝[(140-年龄)×体重(kg)/[0.818×Scr(μmol/L)]
(女性受试者按计算结果)×0.85；1mg/dL＝88.41μmol/L。
c)凝血功能：活化部分凝血活酶时间(APTT)、国际标准化比值(INR)、凝血酶原时间(PT)≤1.5×ULN。
6)女性应同意在研究期间和研究结束后6个月内必须采用避孕措施(如宫内节育器[IUD]、避孕药或避孕套)；在研究入组前的7天内血清或尿妊娠试验阴性，且必须为非哺乳期患者；男性应同意在研究期间和研究期结束后6个月内必须采用避孕措施的患者。
7)患者自愿加入本研究，签署知情同意书，依从性好。
4.2排除标准
1)既往使用了盐酸安罗替尼、其它PD-1/PD-L1抗体治疗或其它针对PD-1/PD-L1的免疫治疗；
2)其它单克隆抗体给药后出现重度超敏反应者；
3)5年内受试者既往或同时患有其它恶性肿瘤(已治愈的皮肤基底细胞癌和宫颈原位癌除外)；
4)存在任何活动性自身免疫病或有自身免疫病病史(如以下，但不局限于：自身免疫性肝炎、间质性肺炎、肠炎、血管炎、肾炎；受试者需要支气管扩张剂进行医学干预的哮喘则不能纳入)；但以下患者允许入组：无需进行全身治疗的白癜风、银屑病、脱发，控制良好的I型糖尿病，经替代治疗甲状腺功能正常的甲减。
5)需使用免疫抑制剂、或全身治疗以达到免疫抑制目的(剂量>10mg/天泼尼松或其它等疗效激素)，并首次给药2周内仍在继续使用的。
6)具有影响口服药物的多种因素(比如无法吞咽、胃肠道切除术后、慢性腹泻和肠梗阻等)者。
7)不能控制的需要反复引流的胸腔积液、心包积液或腹水。
8)影像学(CT或MRI)显示肿瘤侵犯大血管或与血管分界不清。
9)在首次给药前4周内，出现任何出血或流血事件≥CTCAE 3级的患者，或存在未愈合窗口、溃疡或骨折。
10)首次给药前8周内出现不可控制的脑转移症状，脊髓压迫、癌性脑膜炎，或筛选时CT或MRI检查发现脑或者软脑膜的疾病者。
11)先前接受放疗、化疗、手术，在治疗完成后(末次用药)，距首次给药不足4周，口服靶向药不足5个药物半衰期者；或口服氟尿嘧啶类药物不足14天，丝裂霉素C以及亚硝基脲不足6周者；先前治疗引起的不良事件(脱发除外)未恢复至≤CTCAE 1度的患者。
12)存在任何重度和/或未能控制的疾病的患者，包括：
a)血压控制不理想的(收缩压≥150mmHg，舒张压≥90mmHg)患者；
b)首次给药6个月内出现不稳定心绞痛、心梗、≥2级充血性心功能衰竭，或需治疗的心律失常(包括QTc≥480ms)；
c)活动性或未能控制的严重感染(≥CTCAE 2级感染)；
d)肝硬化、失代偿性肝病，活动性肝炎*或慢性肝炎需要接受抗病毒治疗；
*活动性肝炎(乙肝参考：HBsAg阳性，且HBV DNA检测值超过正常值上限；丙肝参考：HCV抗体阳性，且HCV病毒滴度检测值超过正常值上限)；
e)HIV检测阳性；
f)糖尿病控制不佳(空腹血糖≥CTCAE 2级)；
g)尿常规提示尿蛋白≥++，且证实24小时尿蛋白定量＞1.0g者。
13)首次给药4周内接种过预防疫苗或减毒疫苗。
14)经研究者判断，受试者有其它可能导致本研究被迫中途终止的因素，如，其它的严重疾病(含精神疾病)需要合并治疗，有严重的实验室检查异常，伴有家庭或社会等因素，会影响到受试者的安全，或资料及样品的收集。
4.3试验药
抗PD-L1抗体注射剂hu5G11-hIgG1：1200mg抗PD-L1抗体注射液(100mg/10mL)用生理盐水稀释至250mL，输注时间60±5min，输注完成后按医院常规要求进行生理盐水冲管，每21天给药一次。
盐酸安罗替尼胶囊(活性成分为安罗替尼二盐酸盐)：抗PD-L1抗体注射液开始输注±5min内空腹服用盐酸安罗替尼胶囊10mg，连续口服2周停1周，即21天为一治疗周期。
规格：12mg、10mg、8mg。
4.4评价标准
根据RECIST 1.1/irRECIST判定疾病状态。以RECIST 1.1评价标准为主。
4.5终点指标
无进展生存期(PFS)；
抗肿瘤疗效指标：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))、总生存期(OS)等。
4.6结果
Figure PCTCN2020073957-appb-000008
患者状况：
01患者：左上肺中至低分化腺癌，淋巴结和双肺转移。基因型：BRAF p.V600E。
08患者：左肺腺癌。基因型：EGFR del/EGFR-T790M。
011患者：肺腺癌，复发转移IVA期。基因型：EGFR。
上述实施例中，每个给药周期均为21天，C2、C4、C6、C8、C10分别表示给药2个周期、4个周期、6个周期、8个周期和10个周期。上述实施例中，靶病灶大小(基线)是指给药前，影像学检查时靶病灶的最长径。

Claims (20)

  1. 一种联用药物组合物，其包括抗PD-L1抗体和安罗替尼。
  2. 根据权利要求1所述的联用药物组合物，其中，所述联用药物组合物用于治疗胆道系统肿瘤、肝癌、三阴乳腺癌或肺癌。
  3. 根据权利要求1或2所述的联用药物组合物，其中，所述联用药物组合物包括抗PD-L1抗体的药物组合物和安罗替尼的药物组合物。
  4. 根据权利要求1-3中任一所述的联用药物组合物，其中，所述联用药物组合物包装于同一试剂盒中，所述试剂盒还包括PD-L1抗体和安罗替尼联合使用治疗胆道系统肿瘤、肝癌、三阴乳腺癌和/或肺癌的说明。
  5. 根据权利要求1-4中任一所述的联用药物组合物，其中，所述联用药物组合物包括含600～2400mg的抗PD-L1抗体的药物组合物和单剂量为6mg、8mg、10mg和/或12mg安罗替尼的药物组合物。
  6. 根据权利要求1-5中任一所述的联用药物组合物，其中，所述联用药物组合物包括重量比为(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。
  7. 根据权利要求1-6中任一所述的联用药物组合物，其中，所述联用药物组合物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。
  8. 权利要求1-7中任一所述的联用药物组合物在制备用于治疗胆道系统肿瘤、肝癌、三阴乳腺癌和/或肺癌的药物的用途。
  9. 抗PD-L1抗体和安罗替尼在制备用于治疗胆道系统肿瘤、肝癌、三阴乳腺癌和/或肺癌的药物的用途。
  10. 根据权利要求8或9所述的用途，其中，所述抗PD-L1抗体和安罗替尼各自呈药物组合物的形式，可同时、顺序或间隔给药。
  11. 根据权利要求8-10中任一所述的用途，其中，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，每次以600～2400mg的剂量施用。
  12. 根据权利要求8-11中任一所述的用途，其中，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。
  13. 用于治疗胆道系统肿瘤、肝癌、三阴乳腺癌和/或肺癌的试剂盒，所述试剂盒包括抗PD-L1抗体的药物组合物和安罗替尼的药物组合物，以及抗PD-L1抗体和安罗替尼联合使用治疗胆道系统肿瘤、肝癌、三阴乳腺癌和/或肺癌的说明。
  14. 根据权利要求13所述的试剂盒，其中，所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。
  15. 根据权利要求1-7中任一所述的联用药物组合物、或权利要求8-12中任一所述的用途、或权利要求13或14所述的试剂盒，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。
  16. 根据权利要求1-7中任一所述的联用药物组合物、或权利要求8-12中任一所述的用途、或权利要求13或14所述的试剂盒，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。
  17. 根据权利要求1-7中任一所述的联用药物组合物、或权利要求8-12中任一所述的用途、或权利要求13或14所述的试剂盒，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。
  18. 根据权利要求1-7中任一所述的联用药物组合物、或权利要求8-12中任一所述的用途、或权利要求13或14所述的试剂盒，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。
  19. 根据权利要求1-7中任一所述的联用药物组合物、或权利要求8-12中任一所述的用途、或权利要求13或14所述的试剂盒，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。
  20. 根据权利要求1-7中任一所述的联用药物组合物、或权利要求8-12中任一所述的用途、或权利要求13或14所述的试剂盒，其中，安罗替尼处于自由碱形式、或处于其药学上可接受的盐的形式。
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