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
  • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
  • C07K16/2827—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
  • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
  • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

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

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