[go: up one dir, main page]

WO2020249018A1 - Composition pharmaceutique combinée pour le traitement du cancer du poumon positif aux gènes "conducteurs" - Google Patents

Composition pharmaceutique combinée pour le traitement du cancer du poumon positif aux gènes "conducteurs" Download PDF

Info

Publication number
WO2020249018A1
WO2020249018A1 PCT/CN2020/095417 CN2020095417W WO2020249018A1 WO 2020249018 A1 WO2020249018 A1 WO 2020249018A1 CN 2020095417 W CN2020095417 W CN 2020095417W WO 2020249018 A1 WO2020249018 A1 WO 2020249018A1
Authority
WO
WIPO (PCT)
Prior art keywords
seq
pharmaceutical composition
antibody
amino acid
lung cancer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2020/095417
Other languages
English (en)
Chinese (zh)
Inventor
于浩
潘茂琼
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Nanjing Shunxin Pharmaceutical Co Ltd
Original Assignee
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Nanjing Shunxin Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chia Tai Tianqing Pharmaceutical Group Co Ltd, Nanjing Shunxin Pharmaceutical Co Ltd filed Critical Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority to CN202410318299.9A priority Critical patent/CN118267469A/zh
Priority to CN202080039208.8A priority patent/CN113905761A/zh
Publication of WO2020249018A1 publication Critical patent/WO2020249018A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • 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

Definitions

  • This application belongs to the field of biomedicine, and relates to a combined pharmaceutical composition for treating driver gene-positive lung cancer.
  • Tyrosine kinases are a group of enzymes that catalyze the phosphorylation of protein tyrosine residues. They play an important role in intracellular signal transduction. They are involved in the regulation, signal transmission and development of normal cells, and 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 antibody 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 role of killing and inhibiting tumor cells. Because anti-PD-L1 antibody can directly act on tumor tissues, it has high specificity and safety.
  • Lung cancer is a common cause of death from cancer in men, and second only to breast cancer in women.
  • Lung cancer driver genes mainly include epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ROS proto-oncogene 1 receptor tyrosine kinase (ROS1), MET gene receptor tyrosine kinase (MET ) And human epidermal growth factor receptor 2 (HER-2).
  • EGFR epidermal growth factor receptor
  • ALK anaplastic lymphoma kinase
  • ROS1 c-ROS proto-oncogene 1 receptor tyrosine kinase
  • MET MET gene receptor tyrosine kinase
  • HER-2 human epidermal growth factor receptor 2
  • WO2016022630 discloses a class of PD-L1 antibodies that have 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 for the treatment of driver gene-positive lung cancer, which includes an anti-PD-L1 antibody and anlotinib.
  • Anlotinib is in the form of a free base, or in the form of a pharmaceutically acceptable salt thereof.
  • 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 with the amino acid sequence shown in SEQ ID NO: 3; and the light chain CDR1 region with the amino acid sequence shown in SEQ ID NO: 7, and the light chain CDR1 region with 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 instructions for the combined use of PD-L1 antibody and anlotinib to treat driver-positive lung cancer.
  • the present application provides a combined 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.
  • this 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 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 present application provides a combination pharmaceutical composition, which is a preparation 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 combination 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 application also provides the use of the combined pharmaceutical composition herein in the preparation of a medicament for the treatment of driver gene-positive lung cancer.
  • the present application also provides a method for treating driver gene-positive lung cancer, which comprises administering to a subject an effective amount of the combined pharmaceutical composition of the present application.
  • the application also provides the use of the combined pharmaceutical composition of the application for the treatment of driver gene-positive 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 the preparation of drugs for the treatment of gene-positive lung cancer.
  • the present application also provides a method for treating driver gene-positive lung cancer, including administering an effective amount of anti-PD-L1 antibody and anlotinib to the subject.
  • the application also provides the use of the combination of anti-PD-L1 antibody and anlotinib to treat driver gene-positive lung cancer.
  • this application also provides a combination of anti-PD-L1 antibody and anlotinib for the treatment of driver gene-positive 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 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.
  • the present application provides a kit for the treatment of driver gene-positive lung cancer
  • the kit includes an anti-PD-L1 antibody pharmaceutical composition and anlotinib pharmaceutical composition, and an anti-PD-L1 antibody and anlotinib Instructions for the treatment of driver gene-positive lung cancer in combination with Nicolas.
  • 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.
  • the present application provides a combination pharmaceutical composition for the treatment of driver gene-positive lung cancer, which includes an anti-PD-L1 antibody and anlotinib.
  • the combination 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 driver-positive lung cancer.
  • a combination pharmaceutical composition for the treatment of driver gene-positive 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 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 driver gene-positive lung 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 , 8mg, 10mg and/or 12mg anlotinib pharmaceutical composition.
  • a combination pharmaceutical composition for the treatment of driver gene-positive lung cancer which includes 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 driver gene-positive lung cancer which includes an anti-PD-L1 antibody pharmaceutical composition and an anlotinib pharmaceutical composition, wherein the anti-PD-L1
  • the pharmaceutical composition of 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, and the pharmaceutical composition of anlotinib is prepared to be suitable for continuous 14 A single dose of 6mg, 8mg, 10mg and/or 12mg of Anlotinib was given to the patient every day.
  • a combination pharmaceutical composition for the treatment of driver gene-positive 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 The dosage is 6mg, 8mg, 10mg and/or 12mg of the pharmaceutical composition of Anlotinib.
  • a combination pharmaceutical composition for the treatment of driver gene-positive lung cancer which comprises an anti-PD-L1 antibody concentration of 10 mg/mL and a single dose of the anti-PD-L1 antibody pharmaceutical composition
  • a pharmaceutical composition of 8mg and/or 10mg and/or 12mg anlotinib is provided.
  • a combination pharmaceutical composition for the treatment of driver gene-positive 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 a pharmaceutical composition of 10mg and/or 12mg Anlotinib.
  • the application also provides the use of the combined pharmaceutical composition in the preparation of a drug for the treatment of driver gene-positive lung cancer.
  • the application also provides a method for treating driver gene-positive 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 the treatment of driver gene-positive lung cancer.
  • the combination pharmaceutical composition includes an anti-PD-L1 humanized monoclonal antibody and anlotinib.
  • this application also provides the use of anti-PD-L1 antibody and Anlotinib in the preparation of drugs for the treatment of gene-positive lung cancer.
  • This application also provides a method for treating driver gene-positive lung cancer, including administering an effective amount of anti-PD-L1 antibody and anlotinib to the subject.
  • the application also provides the use of the combination of anti-PD-L1 antibody and anlotinib to treat driver gene-positive lung cancer.
  • the application also provides a combination of anti-PD-L1 antibody and anlotinib for the treatment of driver gene-positive lung cancer.
  • the present application provides a kit for treating driver gene-positive lung cancer.
  • the kit includes a pharmaceutical composition of anti-PD-L1 antibody and a pharmaceutical composition of anlotinib, as well as an anti-PD-L1 antibody and an anti-PD-L1 antibody. Instructions for the combined use of Rotinib in the treatment of driver gene-positive lung cancer.
  • the present application also provides an anti-PD-L1 antibody for the treatment of driver gene-positive lung cancer.
  • the application also provides a method for treating driver gene-positive 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 driver gene-positive lung cancer.
  • the application also provides the use of the anti-PD-L1 antibody in the preparation of a medicine for treating lung cancer with positive driver genes.
  • the present invention provides a combination pharmaceutical composition, which includes an anti-PD-L1 antibody and anlotinib.
  • 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 at intervals.
  • the antibody and anlotinib are administered in the same or different dosing schedules. In some embodiments, the administration is performed in different dosing schedules.
  • 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 once 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 days 1-14 of each cycle
  • Anlotinib 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 is 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.
  • the anti-PD-L1 antibody and anlotinib are administered to the subject at a weight ratio of 1, wherein the anti-PD-L1 antibody and anlotinib are administered in a single dose and multiple doses, respectively.
  • 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.
  • 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.
  • 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 anti-PD-L1 antibody pharmaceutical composition is calculated in w/v, and the anti-PD-L1 monoclonal antibody concentration is about 5-150 mg/mL; preferably about 10-60 mg/mL; More preferably, it is about 10-30 mg/mL.
  • the mass volume concentration of anti-PD-L1 monoclonal antibody is 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 or about 60 mg/mL, more preferably about 10 mg/mL, about 20 mg/mL, or about 30 mg/mL.
  • the mass volume concentration of anti-PD-L1 monoclonal antibody is 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 has a concentration of about 10 mM.
  • the histidine salt buffer has a concentration of about 15 mM.
  • the histidine salt buffer has a concentration of 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 the 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, 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 embodiments, 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 some 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 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 value 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 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, 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, 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, (e) optional hydrochloric acid, and adjust the pH of the composition to about 5.5.
  • the pharmaceutical composition comprises: (a) 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) 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) optional acetic acid, and 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 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 formulation of the present application can also be dried by other methods known in the art, such as spray drying and bubble drying.
  • a 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 pharmaceutical composition of anlotinib administered in each cycle includes 84-168 mg according to a treatment cycle of administration for 2 weeks and stop for 1 week.
  • the total dose of the pharmaceutical composition of Anlotinib includes a range selected from 84mg, 112mg, 140mg, 168mg or any of the above values.
  • the total dose of the pharmaceutical composition of Anlotinib 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%, 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
  • the heavy chain CDR2 region it has at least 80% (for example, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%) of the amino acid sequence shown in
  • 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 a heavy chain CDR1 region having an amino acid sequence 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% (for example, 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 light chain variable region.
  • 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 a humanized antibody of hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4, and a variable heavy chain selected from hu13C5 -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-hIgG4
  • the anti-PD-L1 antibody in the drug combination may be selected from one or more.
  • the term "plurality" can 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 shown in SEQ ID NO: 14 and the light chain variable region 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.
  • anlotinib 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methyl Oxyquinolin-7-yl]oxy]methyl]cyclopropylamine, which has the following structural formula:
  • the anlotinib includes its non-salt form (for example, free base), and also includes its pharmaceutically acceptable salt, and the non-salt form or salt is included in the protection scope of this 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 driver gene-positive lung cancer is selected from driver gene-positive non-small cell lung cancer.
  • the driver gene-positive non-small cell lung cancer includes lung squamous cell carcinoma or lung adenocarcinoma.
  • the driver gene-positive non-small cell lung cancer is non-squamous non-small cell lung cancer.
  • the driver gene-positive non-small cell lung cancer is advanced and/or metastatic lung cancer.
  • the driver gene-positive lung cancer includes, but is not limited to, EGFR mutation (for example, EGFR-T790M), ALK mutation, ROS1 mutation, KRAS mutation, MET mutation, HER-2 mutation, BRAF mutation, KIF5B mutation, RET mutation Or any two or more of lung cancers with mutations.
  • the driver gene-positive lung cancer is non-small cell lung cancer that has failed treatment with at least one platinum-based drug.
  • the driver gene-positive lung cancer is lung cancer that has failed treatment with platinum drugs and at least one other chemotherapeutic drug. In some embodiments, the driver gene-positive lung cancer is lung cancer that has failed treatment with platinum drugs and one other chemotherapeutic drug.
  • the driver gene-positive lung cancer is a lung cancer that has failed prior treatment with one or more kinase inhibitors.
  • the driver gene-positive lung cancer is a lung cancer that has failed treatment with platinum drugs and at least one other chemotherapeutic drug
  • the driver gene-positive includes but is not limited to EGFR mutation, ALK mutation, ROS1 mutation, KRAS mutation, MET One or more of mutations, HER-2 mutations, BRAF mutations, KIF5B mutations, RET mutations, and NTRK fusion mutations.
  • the driver gene-positive lung cancer is a lung cancer that has failed treatment with one or more kinase inhibitors
  • the driver gene-positive includes but is not limited to EGFR mutation, ALK mutation, ROS1 mutation, KRAS mutation, MET mutation , HER-2 mutation, BRAF mutation, KIF5B mutation, RET mutation, one or more mutations.
  • the driver gene-positive lung cancer is lung cancer that has previously received platinum drugs, at least one other chemotherapeutic drug, and one or more kinase inhibitors
  • the driver gene-positive lung cancer includes but is not limited to EGFR One or more of mutations, ALK mutations, ROS1 mutations, KRAS mutations, MET mutations, HER-2 mutations, BRAF mutations, KIF5B mutations, and RET mutations.
  • the driver gene-positive lung cancer is non-small cell lung cancer with EGFR gene mutation that has previously received at least one EGFR inhibitor treatment failure; in some embodiments, the driver gene-positive lung cancer is EGFR gene mutation non-small cell lung cancer that has previously received at least one EGFR-TKI inhibitor (EGFR tyrosine kinase inhibitor) treatment failure; in some embodiments, the driver gene-positive lung cancer is previously received At least one EGFR inhibitor and at least one chemotherapeutic drug have failed to treat non-small cell lung cancer with mutations in the EGFR gene; in some embodiments, the driver gene-positive lung cancer is previously received at least one EGFR inhibitor and at least A platinum-based drug treatment failed non-small cell lung cancer with EGFR mutation.
  • EGFR-TKI inhibitor EGFR tyrosine kinase inhibitor
  • the driver gene-positive lung cancer is an EGFR mutant non-small cell that has previously received platinum drugs, at least one other chemotherapeutic drug, and one or more EGFR tyrosine kinase inhibitors. Lung cancer.
  • the driver gene-positive lung cancer is an EGFR-T790M mutation that has previously received platinum drugs, at least one other chemotherapeutic drug, and one or more EGFR-T790M tyrosine kinase inhibitors.
  • platinum drugs at least one other chemotherapeutic drug
  • one or more EGFR-T790M tyrosine kinase inhibitors are included in non-small cell lung cancer.
  • the driver gene-positive lung cancer is ALK-mutated non-small cell lung cancer that has previously received at least one ALK inhibitor treatment failure; in some embodiments, the driver gene-positive lung cancer is in First received at least one ALK inhibitor treatment failure ALK mutant non-small cell lung cancer; in some embodiments, the driver gene positive lung cancer is previously received at least one ALK inhibitor and at least one chemotherapeutic drug Treatment failed ALK-mutated non-small cell lung cancer; in some embodiments, the driver gene-positive lung cancer is ALK-mutated non-small cell that has previously received at least one ALK inhibitor and at least one platinum-based drug treatment failure Lung cancer. In some embodiments, the driver gene-positive lung cancer is ALK-mutated non-small cell lung cancer that has previously received platinum drugs, at least one other chemotherapeutic drug, and at least one ALK inhibitor treatment.
  • the driver gene-positive lung cancer is a patient who has previously received platinum drugs, at least one other chemotherapeutic drug, and two or more ALK inhibitors including crizotinib. ALK mutant non-small cell lung cancer.
  • the driver gene-positive lung cancer is ROS1 mutant non-small cell lung cancer that has previously received at least one ROS1 inhibitor treatment failure; in some embodiments, the driver gene-positive lung cancer is in ROS1 mutant non-small cell lung cancer that has received at least one ROS1 inhibitor treatment failure; in some embodiments, the driver gene-positive lung cancer has previously received at least one ROS1 inhibitor and at least one chemotherapeutic drug Treatment failure of ROS1 mutant non-small cell lung cancer; in some embodiments, the driver gene-positive lung cancer is a ROS1 mutant non-small cell that has previously received at least one ROS1 inhibitor and at least one platinum-based drug treatment failure Lung cancer. In some embodiments, the driver gene-positive lung cancer is ROS1 mutant non-small cell lung cancer that has previously received platinum drugs, at least one other chemotherapeutic drug, and one or more ROS1 inhibitors.
  • the driver gene-positive lung cancer is KRAS-mutated non-small cell lung cancer that has previously received platinum-based drugs and at least one other chemotherapeutic drug that has failed treatment.
  • the driver gene-positive lung cancer is non-small cell lung cancer with KRAS mutation that has previously received platinum drugs, at least one other chemotherapeutic drug, and one or more KRAS inhibitors.
  • the driver gene-positive lung cancer is a MET-mutated non-small cell lung cancer that has previously received platinum-based drugs and at least one other chemotherapeutic drug. In some embodiments, the driver gene-positive lung cancer is MET-mutated non-small cell lung cancer that has previously received platinum drugs, at least one other chemotherapeutic drug, and one or more c-MET inhibitors.
  • the driver gene-positive lung cancer is a HER-2 mutant non-small cell lung cancer that has previously received platinum-based drugs and at least one other chemotherapeutic drug that has failed treatment. In some embodiments, the driver gene-positive lung cancer is a HER-2 mutant non-small cell that has previously received platinum drugs, at least one other chemotherapeutic drug, and one or more HER-2 inhibitors. Lung cancer.
  • the driver gene-positive lung cancer is BRAF-mutated non-small cell lung cancer that has previously been treated with platinum drugs and at least one other chemotherapeutic drug. In some embodiments, the driver gene-positive lung cancer is BRAF mutant non-small cell lung cancer that has previously received platinum drugs, at least one other chemotherapeutic drug, and one or more BRAF inhibitors.
  • the driver gene-positive lung cancer is KIF5B mutant non-small cell lung cancer that has previously received platinum-based drugs and at least one other chemotherapeutic drug that has failed treatment.
  • the driver gene-positive lung cancer is non-small cell lung cancer with a KIF5B mutation that has previously received platinum drugs, at least one other chemotherapeutic drug, and one or more KIF5B inhibitors.
  • the driver gene-positive lung cancer is RET-mutated non-small cell lung cancer that has previously been treated with platinum drugs and at least one other chemotherapeutic drug. In some embodiments, the driver gene-positive lung cancer is RET-mutated non-small cell lung cancer that has previously received platinum drugs, at least one other chemotherapeutic drug, and one or more RET inhibitors.
  • the EGFR mutations include, but are not limited to, exon 19 deletion mutation 19DEL, exon 20 T790M mutation, exon 20 C797S mutation, exon 21 L858R mutation, and copy number amplified EGFR mutation One or more mutations in.
  • the ALK mutations include, but are not limited to, one or more mutations in EML4-ALK, NPM-ALK fusion gene positive.
  • the ROS1 mutation includes, but is not limited to, one or more mutations in CD74-ROS1, SDC-ROS1 fusion gene positive.
  • the KRAS mutation includes but is not limited to one or more of exon 2 G12C mutation, exon 2 G12V mutation, exon 2 G12A mutation, and exon 3 G61H mutation.
  • the BRAF mutation includes, but is not limited to, the mutation of exon 15 V600E.
  • the Met gene mutations include but are not limited to exon 14 skipping mutations, Met gene amplification, and the Met gene mutations cause c-Met abnormalities.
  • the chemotherapeutic drugs include but are not limited to alkylating agents, including but not limited to bendamustine, carmustine, chlorambucil, chlorambucil, rolazine Mustard, carboplatin, cisplatin, oxaliplatin, cyclophosphamide, ifosfamide, dacarbazine, temozolomide), antimetabolites, including but not limited to azacitidine, cytarabine, 5 -Fluorouracil, 6-mercaptopurine, capecitabine, decitabine, gemcitabine, fluorouridine, fludarabine, nelarabine, hydroxyurea, methotrexate, pratroxa, pemetrexed , Pentostatin, trifluridine/dipiforin combination), plant alkaloid (including but not limited to camptothecin) and antitumor antibiotics, including but not limited to daunorubicin
  • the chemotherapeutic drugs include but are not limited to platinum drugs, fluoropyrimidine derivatives, camptothecins, taxanes, vinblastines, anthracyclines, antibiotics, podophyllum One or more of tumors and antimetabolites.
  • platinum drugs such as oxaliplatin, miplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin
  • Lobaplatin triplatin tetranitrate, phenanthroplatin, picoplatin, satraplatin, lobaplatin
  • fluoropyrimidine derivatives e.g.
  • gemcitabine capecitabine, amphibin Fluorouridine, tegafur, carmofur, trifluorouridine), taxanes (e.g. paclitaxel, albumin-bound paclitaxel and docetaxel, camptothecins (e.g.
  • the platinum-based drugs include but are not limited to cisplatin, carboplatin, nedaplatin, oxaliplatin, miplatin, bicycloplatin, picoplatin, satraplatin, phenanthroplatin, tetranitrotriazine One or more of platinum or lobaplatin.
  • the other chemotherapeutic drugs refer to chemotherapeutic drugs other than platinum drugs, including but not limited to gemcitabine, paclitaxel, docetaxel, vinorelbine, pemetrexed, etoposide, irinote Kang, or topotecan.
  • the platinum-based drug and one other chemotherapeutic drug are selected from a combination of: cisplatin and gemcitabine, cisplatin and docetaxel, cisplatin and paclitaxel, cisplatin and vinorelbine, cisplatin And pemetrexed, cisplatin and etoposide, cisplatin and irinotecan, cisplatin and topotecan, carboplatin and gemcitabine, carboplatin and docetaxel, carboplatin and paclitaxel, carboplatin and vinorelbine , Carboplatin and pemetrexed, carboplatin and etoposide, carboplatin and irinotecan, or carboplatin and topotecan.
  • the patient of the driver gene-positive lung cancer has previously received other drug treatment, and the other drug is selected from the group consisting of docetaxel and nedaplatin, pemetrexed and nedaplatin, pemetrexed One or more of carboplatin, pemetrexed, pemetrexed, carboplatin and bevacizumab, pemetrexed and bevacizumab, bevacizumab and osimertinibkind of combination.
  • the kinase inhibitor includes, but is not limited to, Brigatinib, Osimertinib, Dacomitinib, Gefitinib, Afatinib, Erlotinib (Eerlotinib), Necitumumab, Icotinib, Olmutinib, Alectinib, Crizotinib, Lorlatinib, Certinib, Omedinib, Cabozantinib, Dacomitinib , Dabrafenib, Elpercatinib, Vorolanib, Pontatinib, Sitravatinib, Lenvatinib, or dovitinib.
  • the EGFR inhibitor includes, but is not limited to, Brigatinib, Osimertinib, Dacomitinib, Gefitinib, Afatinib, Erlotinib , Necitumumab, Icotinib, or Olmutinib.
  • the EGFR-T790M inhibitor includes Osimertinib.
  • the ALK inhibitor includes but is not limited to Brigatinib, Alectinib, Crizotinib, Lorlatinib, or Certinib.
  • the ROS1 inhibitor includes but is not limited to Brigatinib, Crizotinib, Lorlatinib, or Certinib.
  • the c-MET inhibitor includes, but is not limited to, Crizotinib, or Cabozantinib.
  • the HER-2 inhibitor includes, but is not limited to, Dacomitinib, or Afatinib.
  • the BRAF inhibitor includes but is not limited to Dabrafenib.
  • the RET inhibitor includes, but is not limited to, Selpercatinib, Vorolanib, Pontatinib, Sitravatinib, Lenvatinib, or Dovitinib.
  • the driver gene-positive lung cancer is lung adenocarcinoma, and the driver gene-positive is BRAF p.V600E mutation.
  • the driver gene-positive lung cancer is lung adenocarcinoma, the driver gene-positive is BRAF p.V600E mutation, and the driver gene-positive lung cancer patient has received one or more of the following protocols Treatment of: 1) docetaxel and nedaplatin, 2) pemetrexed and nedaplatin, 3) pemetrexed and carboplatin, 4) pemetrexed, 5) erlotinib.
  • the driver gene-positive lung cancer is lung adenocarcinoma, and the driver gene-positive is EGFR del mutation and/or EGFR-T790M mutation.
  • the driver gene-positive lung cancer is lung adenocarcinoma, the driver gene positive is EGFR del mutation and/or EGFR-T790M mutation, and the driver gene-positive lung cancer patient has received one of the following protocols Or any two or more treatments: 1) pemetrexed, carboplatin and bevacizumab, 2) pemetrexed and bevacizumab, 3) bevacizumab and osimertinib, 4) Gefitinib, 5) Osimertinib.
  • the driver gene-positive lung cancer is lung adenocarcinoma, and the driver gene-positive is KIF5B-RET fusion gene positive. In some embodiments, the driver gene-positive lung cancer is lung adenocarcinoma, the driver gene-positive is KIF5B-RET fusion gene positive, and the driver-gene-positive lung cancer patient has received one or two of the following protocols Treatment: 1) Pemetrexed and carboplatin, 2) Pemetrexed.
  • the patient suffering from the driver gene-positive lung cancer has received anti-VEGFR monoclonal antibodies (e.g. bevacizumab), antimetabolites (e.g. pemetrexed), taxanes (e.g. Docetaxel), platinum drugs (e.g. nedaplatin and/or carboplatin) and/or EGFR inhibitors (e.g.
  • anti-VEGFR monoclonal antibodies e.g. bevacizumab
  • antimetabolites e.g. pemetrexed
  • taxanes e.g. Docetaxel
  • platinum drugs e.g. nedaplatin and/or carboplatin
  • EGFR inhibitors e.g.
  • Non-small cell lung cancer patients with failed BRAF mutation, KIF5B mutation, RET mutation and/or EGFR mutation such as BRAF p.V600E mutation, EGFR del mutation and/or EGFR-T790M mutation, KIF5B-RET fusion gene mutation.
  • the components of 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 may be individually administered orally or by injection, such as intravenous injection or intraperitoneal injection.
  • the components of the combined pharmaceutical composition of the present application may be independent of each other, or part or all of them may be a suitable dosage form together, including but not limited to tablets, troches, pills, capsules (such as hard capsules, soft capsules). Capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and for oral or non- The dosage form of a sustained-release preparation for oral administration.
  • the components in the combined drug combination of the present application may each independently, or part or all of them together contain a pharmaceutically acceptable carrier and/or excipient.
  • the combined drug combination of the present application may also include additional therapeutic agents.
  • the additional therapeutic agent may be a cancer therapeutic agent known in the art, preferably a lung cancer therapeutic agent.
  • the treated patients have a longer survival period (such as median survival, progression-free survival or overall survival);
  • 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). In this context, the terms “combined pharmaceutical composition” and “drug 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 anti-PD-L1 antibodies and fragments thereof of the present invention can be derived from any species, including but not limited to mice, rats, rabbits, primates, llamas and humans.
  • the anti-PD-L1 antibody and its fragments can be chimeric antibodies, humanized antibodies or fully human antibodies.
  • the anti-PD-L1 antibody is an antibody produced by a hybridoma cell line derived from 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.
  • a “humanized antibody” is an antibody that contains a complementarity determining region (CDR) derived from a non-human antibody; and a framework region and constant region derived from a human antibody.
  • the anti-PD-L1 antibodies provided herein can include 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 the present invention.
  • 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 position 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.
  • the amino acids at positions 24 and/or 28 and/or 30 and/or 49 and/or 73 and/or 83 and/or 94 of the heavy chain variable region are backmutated to 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, in which the amino acid at position 24 is mutated from Phe(F) to Val(V), and the amino acid at position 49 is mutated from Ala(A) to Gly(G), The amino acid at position 73 was mutated from Thr(T) to Asn(N), and the amino acid at position 83 was mutated from Thr(T) to Asn(N).
  • the humanized 13C5 antibody comprises a light chain variable region in which the amino acid at position 53 is mutated from Tyr (Y) to Lys (K); and a heavy chain variable region in which the amino acid at position 28
  • 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 present invention also includes humanized antibodies that bind to PD-L1 and include 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 hybridomas that produce the antibodies disclosed herein.
  • the invention also provides isolated polynucleotides encoding the antibodies and fragments thereof provided herein.
  • the present invention also includes an expression vector containing the isolated polynucleotide, and a host cell containing the expression vector.
  • isolated antibody refers to an antibody that contains substantially no other antibodies with different antigen specificities (for example, an isolated antibody that specifically binds PD-1 contains substantially no specific binding other than PD-1 Antibodies to other antigens). However, an isolated antibody that specifically binds PD-1 may have cross-reactivity with other antigens, such as PD-1 molecules from different species. 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 is partially or completely stable or cures the disease and/or side effects due to the disease, and can be therapeutic.
  • 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 given disease, condition, or disorder, (ii) reducing, ameliorating or eliminating one or more symptoms of a particular disease, condition, or disorder, or (iii) delaying what is described herein
  • the amount of the compound of the present application for the onset of one or more symptoms of a particular 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” may 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 routes of administration, 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).
  • BSA body surface area
  • 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).
  • 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 draw 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 administration, 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 drug is discontinued for 2 days for 5 consecutive 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, methyl Acid salt, acetate, trifluoroacetate, fumarate, oxalate, maleate, citrate, succinate, methanesulfonate, benzenesulfonate or p-toluenesulfonate Acid salt, preferably hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, methanesulfonate, p-toluenesulfonate Acid salt, sodium salt, potassium salt, ammonium salt, amino acid salt, etc.
  • the molar ratio of the free acid to the base ion is about 1:0.5 to 1:5, preferably 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7 or 1:8.
  • the terms “subject” or “patient” or “subject” 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.
  • combination or “combination” 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 present 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 application or its pharmaceutical combination to a subject.
  • the ECOG score is 0 to 1, and the expected survival time is ⁇ 12 weeks;
  • definitions include but not limited to the following:
  • EGFR gene sensitive mutation positive it needs to undergo at least one EGFR-TKI inhibitor treatment failure, and at least one chemotherapy regimen including platinum-containing dual-drug regimen has failed treatment; if there is a patient with EGFR-T790M mutation, it must have been accepted Can be selected after the third-generation EGFR inhibitor treatment fails;
  • the curative effect evaluation standard for solid tumors at least one measurable lesion
  • the main organs function during the screening period are normal, that is, they meet the following criteria:
  • Hemoglobin (Hb) ⁇ 80g/L
  • TBIL Total bilirubin
  • ALT Alanine aminotransferase
  • AST aspartate aminotransferase
  • Serum/urinary pregnancy test results were negative before enrollment in this study; during the entire study period, agreed to adopt an approved method of contraception (for example: oral contraception, injection contraception or implanted, barrier-effect contraceptive method, spermicide And condoms, or intrauterine contraceptive devices), and the contraceptive method remained unchanged throughout the study period.
  • an approved method of contraception for example: oral contraception, injection contraception or implanted, barrier-effect contraceptive method, spermicide And condoms, or intrauterine contraceptive devices
  • Anti-PD-L1 antibody injection hu5G11-hIgG1 1200 mg of anti-PD-L1 antibody injection is diluted with normal saline to 250mL, the infusion time is 60 ⁇ 10min, after the infusion is completed, the normal saline flushing tube is performed according to the hospital's routine requirements, and it is given every 21 days The medicine is given once, that is, 21 days as a treatment cycle.
  • anti-PD-L1 antibody injection 100mg/10mL.
  • Anlotinib hydrochloride capsules active ingredient is Anlotinib dihydrochloride: the starting dose is 12 mg.
  • the anti-PD-L1 antibody injection was administered on an empty stomach within ⁇ 5min, and anlotinib hydrochloride capsules were taken on an empty stomach, one capsule per day, oral administration for 2 weeks and 1 week stop, ie 21 days is a treatment cycle.
  • Anlotinib Hydrochloride Capsules 3 dose levels are designed, starting dose 12mg, dose level 1 is 10mg, and dose level 2 is 8mg. Any subject who needs to reduce the dose of Anlotinib Hydrochloride Capsules will continue to receive reduced dose treatment in subsequent cycles.
  • ORR Objective Response Rate
  • PFS Progress-Free Survival
  • OS all survival: the time from randomization to death from all causes. For subjects who were alive at the last follow-up, their OS was counted as data censored based on the last follow-up time. For subjects who are lost to follow-up, their OS is counted as data censorship based on the last confirmed survival time before loss to follow-up;
  • DCR Disease Control Rate
  • Health-related quality of life (EORTC QLQ-C30 and EORTC QLQ-LC13): Observe the changes in clinical symptoms and objective examination results of tumor patients before and after treatment to score, and score the results of each area of the scale according to the requirements of the quality of life scale Recorded in EDC.
  • Patient 001 has previously received chemotherapy and targeted therapy:
  • Targeted therapy drug Erlotinib.
  • Patient 008 has previously received chemotherapy and targeted therapy:
  • Targeted therapy drugs gefitinib and osimertinib.
  • the amount of anlotinib hydrochloride capsules is based on the weight of anlotinib free base contained therein, and each dosing cycle is 21 days, and C6, C14, and C17 indicate 6 administration cycles, 14 cycles and 17 cycles.

Landscapes

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

Abstract

L'invention concerne une composition pharmaceutique combinée pour le traitement du cancer du poumon positif aux gènes conducteurs, la composition comprenant un anticorps anti-PD-L1 et de l'anlotinib, et ayant une bonne activité contre le cancer du poumon positif aux gènes "conducteurs".
PCT/CN2020/095417 2019-06-10 2020-06-10 Composition pharmaceutique combinée pour le traitement du cancer du poumon positif aux gènes "conducteurs" Ceased WO2020249018A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN202410318299.9A CN118267469A (zh) 2019-06-10 2020-06-10 治疗驱动基因阳性肺癌的联用药物组合物
CN202080039208.8A CN113905761A (zh) 2019-06-10 2020-06-10 治疗驱动基因阳性肺癌的联用药物组合物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910496033.2 2019-06-10
CN201910496033 2019-06-10

Publications (1)

Publication Number Publication Date
WO2020249018A1 true WO2020249018A1 (fr) 2020-12-17

Family

ID=73781823

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/095417 Ceased WO2020249018A1 (fr) 2019-06-10 2020-06-10 Composition pharmaceutique combinée pour le traitement du cancer du poumon positif aux gènes "conducteurs"

Country Status (2)

Country Link
CN (2) CN118267469A (fr)
WO (1) WO2020249018A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022033585A1 (fr) * 2020-08-13 2022-02-17 正大天晴药业集团股份有限公司 Médicament combiné pour le traitement d'un sarcome des tissus mous
EP3842070A4 (fr) * 2018-07-18 2022-04-20 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Combinaison médicamenteuse de dérivé de quinoléine et d'anticorps
WO2023001283A1 (fr) * 2021-07-22 2023-01-26 正大天晴药业集团股份有限公司 Association médicamenteuse pour le traitement du cancer gastrique et/ou du cancer de la jonction œsogastrique
WO2023098798A1 (fr) * 2021-12-01 2023-06-08 正大天晴药业集团股份有限公司 Association de médicaments pour le traitement du cancer du poumon non à petites cellules
EP4382123A4 (fr) * 2021-08-05 2025-09-17 Chia Tai Tianqing Pharmaceutical Group Co Ltd Composition pharmaceutique pour le traitement du cancer du poumon à petites cellules

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107001463A (zh) * 2014-08-05 2017-08-01 中美冠科生物技术（太仓）有限公司 抗pd‑l1抗体
CN107750166A (zh) * 2015-06-16 2018-03-02 默克专利股份有限公司 Pd‑l1 拮抗剂组合治疗
WO2018068691A1 (fr) * 2016-10-10 2018-04-19 苏州盛迪亚生物医药有限公司 Utilisation d'une combinaison d'un anticorps anti-pd-1 et d'un inhibiteur de vegfr dans la préparation d'un médicament pour le traitement de cancers
WO2018160841A1 (fr) * 2017-03-01 2018-09-07 Genentech, Inc. Procédés diagnostiques et thérapeutiques relatifs au cancer
WO2019096194A1 (fr) * 2017-11-16 2019-05-23 江苏恒瑞医药股份有限公司 Utilisation d'un anticorps anti-pd-1 combiné à un inhibiteur de vegfr dans le traitement du cancer du poumon à petites cellules

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109689087B (zh) * 2016-05-13 2023-04-04 奥里尼斯生物科学私人有限公司 靶向性突变干扰素-β及其用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107001463A (zh) * 2014-08-05 2017-08-01 中美冠科生物技术（太仓）有限公司 抗pd‑l1抗体
CN107750166A (zh) * 2015-06-16 2018-03-02 默克专利股份有限公司 Pd‑l1 拮抗剂组合治疗
WO2018068691A1 (fr) * 2016-10-10 2018-04-19 苏州盛迪亚生物医药有限公司 Utilisation d'une combinaison d'un anticorps anti-pd-1 et d'un inhibiteur de vegfr dans la préparation d'un médicament pour le traitement de cancers
WO2018160841A1 (fr) * 2017-03-01 2018-09-07 Genentech, Inc. Procédés diagnostiques et thérapeutiques relatifs au cancer
WO2019096194A1 (fr) * 2017-11-16 2019-05-23 江苏恒瑞医药股份有限公司 Utilisation d'un anticorps anti-pd-1 combiné à un inhibiteur de vegfr dans le traitement du cancer du poumon à petites cellules

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HAN, B.H. ET AL.: "Anlotinib as a Third-Line Therapy in Patients with Refractory Advanced Non-Small-Cell Lung Cancer: a multicentre, randomised phase II trial (ALTER0302)", BRITISH JOURNAL OF CANCER, vol. 118, no. 5, 13 February 2018 (2018-02-13), pages 654 - 661, XP055695984 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3842070A4 (fr) * 2018-07-18 2022-04-20 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Combinaison médicamenteuse de dérivé de quinoléine et d'anticorps
US12390458B2 (en) 2018-07-18 2025-08-19 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Therapeutic combination of quinoline derivative and antibody
WO2022033585A1 (fr) * 2020-08-13 2022-02-17 正大天晴药业集团股份有限公司 Médicament combiné pour le traitement d'un sarcome des tissus mous
WO2023001283A1 (fr) * 2021-07-22 2023-01-26 正大天晴药业集团股份有限公司 Association médicamenteuse pour le traitement du cancer gastrique et/ou du cancer de la jonction œsogastrique
EP4382123A4 (fr) * 2021-08-05 2025-09-17 Chia Tai Tianqing Pharmaceutical Group Co Ltd Composition pharmaceutique pour le traitement du cancer du poumon à petites cellules
WO2023098798A1 (fr) * 2021-12-01 2023-06-08 正大天晴药业集团股份有限公司 Association de médicaments pour le traitement du cancer du poumon non à petites cellules

Also Published As

Publication number Publication date
CN113905761A (zh) 2022-01-07
CN118267469A (zh) 2024-07-02

Similar Documents

Publication Publication Date Title
CN113613674B (zh) 治疗小细胞肺癌的联用药物组合物
CN113347996B (zh) 治疗肿瘤的联用药物组合物
WO2020249018A1 (fr) Composition pharmaceutique combinée pour le traitement du cancer du poumon positif aux gènes "conducteurs"
CN113811298B (zh) 用于联合治疗小细胞肺癌的喹啉衍生物
TW202346342A (zh) 抗tim-3抗體與抗pd-1抗體的藥物組合
CN112168961A (zh) 治疗结直肠癌的联用药物组合物
CN113939315B (zh) 治疗黑色素瘤的联用药物组合物
WO2021219138A1 (fr) Médicament combiné pour le traitement du cancer du rein
CN113018429A (zh) 治疗卵巢癌的药物组合
US20240343807A1 (en) Pharmaceutical composition for treating small cell lung cancer
CN113766917A (zh) 用于治疗头颈癌的喹啉衍生物
CN116370641A (zh) 用于治疗消化系统恶性肿瘤的联用药物
RU2830590C2 (ru) Комбинированный лекарственный препарат для лечения рака почек
RU2829637C2 (ru) Комбинированная фармацевтическая композиция для лечения опухоли
CN120346313A (zh) 治疗肿瘤的药物组合
HK40083393A (en) Combination drug for treating kidney cancer
CN117815387A (zh) Cdk4/6抑制剂和抗pd-l1抗体的联用药物组合物
CN116036265A (zh) 用于癌症的联用药物
CN117642181A (zh) 用于治疗食管癌的药物组合
HK40072142A (en) Quinoline derivative used for combination treatment of small cell lung cancer

Legal Events

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

Ref document number: 20821797

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20821797

Country of ref document: EP

Kind code of ref document: A1