WO2022111618A1 - Composition pharmaceutique combinée d'un anticorps anti-pd-l1 et d'un inhibiteur de la kinase c-met pour le traitement du cancer du poumon - Google Patents

Composition pharmaceutique combinée d'un anticorps anti-pd-l1 et d'un inhibiteur de la kinase c-met pour le traitement du cancer du poumon Download PDF

Info

Publication number
WO2022111618A1
WO2022111618A1 PCT/CN2021/133386 CN2021133386W WO2022111618A1 WO 2022111618 A1 WO2022111618 A1 WO 2022111618A1 CN 2021133386 W CN2021133386 W CN 2021133386W WO 2022111618 A1 WO2022111618 A1 WO 2022111618A1
Authority
WO
WIPO (PCT)
Prior art keywords
lung cancer
antibody
pharmaceutical composition
seq
compound
Prior art date
Application number
PCT/CN2021/133386
Other languages
English (en)
Chinese (zh)
Inventor
张喜全
王训强
于鼎
刘涛
湛筱乐
吴乃营
Original Assignee
正大天晴药业集团股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 正大天晴药业集团股份有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to MX2023005930A priority Critical patent/MX2023005930A/es
Priority to CN202180078291.4A priority patent/CN116437957A/zh
Publication of WO2022111618A1 publication Critical patent/WO2022111618A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents

Definitions

  • the present disclosure belongs to the technical field of medicine, and in particular relates to anti-PD-L1 antibodies and N-(4-((7-((1-(cyclopentylamino)cyclopropanyl)methoxy)-6-methoxyquinoline Norrin-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide combined pharmaceutical composition, and its use in the treatment of lung cancer the use of.
  • c-Met kinase is a prototypical member of the subfamily of heterodimeric receptor tyrosine kinases (RTKs), which includes Met, Ron, and Sea.
  • RTKs heterodimeric receptor tyrosine kinases
  • the antiangiogenic and antiproliferative activities of c-Met make it an attractive target.
  • the endogenous ligand of c-Met is hepatocyte growth factor (HGF), also known as scatter factor (SF) because of its ability to interfere with colony formation in vitro.
  • HGF hepatocyte growth factor
  • SF scatter factor
  • Anti-HGF antibodies or HGF antagonists have also been shown to inhibit tumor metastasis.
  • WO2012034055 discloses N-(4-((7-((1-(cyclopentylamino)cyclopropanyl)methoxy)-6-methoxyquinoline-4 as c-Met kinase inhibitors -yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (hereinafter referred to as the compound of formula (I)) and its tyrosine kinase inhibitory activity the use of,
  • the PD-1 immune checkpoint is an inhibitory cell surface receptor, and its corresponding ligand PD-L1 can be up-regulated on the surface of tumor cells and immune cells in the tumor environment, allowing tumor cells to escape immune cell attack.
  • the use of anti-PD-1 or PD-L1 antibodies can block this response, resulting in an anti-tumor effect.
  • Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have significantly improved the prognosis of patients with non-small cell lung cancer, but most patients have poor treatment outcomes due to primary drug resistance.
  • Nivolumab Nivolumab (Gettinger S et al (2016) ClinOncol.
  • the present disclosure provides a combined pharmaceutical composition for treating lung cancer, the combined pharmaceutical composition comprising an anti-PD-L1 antibody and a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the anti-PD-L1 antibody
  • the 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; The amino acid sequence shown has at least 80% homology in the heavy chain CDR2 region; the heavy chain CDR3 region with at least 80% homology with the amino acid sequence shown in SEQ ID NO: 3 or SEQ ID NO: 6; and SEQ ID NO: 6
  • the amino acid sequence shown in NO:7 or SEQ ID NO:10 has at least 80% homology to the light chain CDR1 region; and the amino acid sequence shown in SEQ ID NO:8 or SEQ ID NO:11 has at least 80% homology and a light chain CDR3 region having at least 80% homology with the amino acid sequence shown in SEQ
  • the combination pharmaceutical composition is packaged in the same kit, and the kit further comprises an anti-PD-L1 antibody in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof to treat lung cancer in a patient. illustrate.
  • the combination pharmaceutical composition wherein the anti-PD-L1 antibody and the compound of formula (I) or a pharmaceutically acceptable salt thereof are packaged separately in separate kits, the kit further comprising an anti-PD-L1 antibody.
  • the combination pharmaceutical composition includes a pharmaceutical composition of an anti-PD-L1 antibody and a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the anti-PD-L1 antibody and the compound of formula (I) or a pharmaceutically acceptable salt thereof are each in the form of a pharmaceutical composition, which can be simultaneously, sequentially or at intervals Dosing.
  • the combination pharmaceutical composition is a fixed combination.
  • the fixed composition is in the form of a solid pharmaceutical composition or a liquid pharmaceutical composition.
  • the combination pharmaceutical composition is a non-fixed combination.
  • the anti-PD-L1 antibody and the compound of formula (I) or a pharmaceutically acceptable salt thereof in the non-fixed combination are each in the form of a pharmaceutical composition.
  • the anti-PD-L1 antibody in the non-fixed combination, is in the form of a liquid pharmaceutical composition and the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the form of a solid pharmaceutical composition.
  • the combination pharmaceutical composition wherein the anti-PD-L1 antibody comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 4 (e.g. 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% , 98%, 99% or 100%) homology to the heavy chain CDR1 region; with the amino acid sequence shown in SEQ ID NO: 2 or SEQ ID NO: 5 at least 80% (e.g.
  • the combination pharmaceutical composition wherein the anti-PD-L1 antibody comprises: the heavy chain CDR1 region shown in SEQ ID NO: 1 or SEQ ID NO: 4, SEQ ID NO: 2 or The heavy chain CDR2 region shown in SEQ ID NO:5, the heavy chain CDR3 region shown in SEQ ID NO:3 or SEQ ID NO:6, the light chain CDR1 region shown in SEQ ID NO:7 or SEQ ID NO:10 , the light chain CDR2 region shown in SEQ ID NO: 8 or SEQ ID NO: 11, and the light chain CDR3 region shown in SEQ ID NO: 9 or SEQ ID NO: 12.
  • the combination pharmaceutical composition wherein the anti-PD-L1 antibody comprises: a heavy chain CDR1 region having the amino acid sequence shown in SEQ ID NO:1, having a heavy chain CDR1 region having the amino acid sequence shown in SEQ ID NO:2
  • the heavy chain CDR2 region of the amino acid sequence shown has the heavy chain CDR3 region of the amino acid sequence shown in SEQ ID NO: 3
  • the light chain CDR1 region of the amino acid sequence shown in SEQ ID NO: 7 has the SEQ ID NO: 7 region.
  • the combination pharmaceutical composition wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is 13C5, 5G11, ch13C5-hIgG1, ch13C5-hIgG4, ch5G11-hIgG1, ch5G11-hIgG4, hu13C5 - hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4 monoclonal antibodies or antigen-binding fragments thereof (see WO2016022630 or CN107001463A; incorporated herein by reference).
  • the combination pharmaceutical composition wherein the anti-PD-L1 antibody comprises a heavy chain complementarity determining region (CDR) selected from a 13C5 or 5G11 antibody, and a heavy chain complementarity determining region (CDR) selected from a 13C5 or 5G11 antibody Light chain complementarity determining regions.
  • CDR heavy chain complementarity determining region
  • CDR heavy chain complementarity determining region
  • the present disclosure provides an anti-PD-L1 antibody comprising a heavy chain variable region selected from the group consisting of ch5G11-hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, ch13C5-hIgG4 chimeric antibodies, and selected from ch5G11- Light chain variable regions of hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, ch13C5-hIgG4 chimeric antibodies.
  • the present disclosure provides an anti-PD-L1 antibody comprising a heavy chain variable region selected from the group consisting of hu13C5-hlgG1, hu13C5-hlgG4, hu5G11-hlgG1 or hu5G11-hlgG4 humanized antibody, and selected from hu13C5 - the light chain variable region 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 NO: 5 ), 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 described in the present disclosure comprises the following amino acid sequence: at least 80% (eg 81%, 82%, 83%, 84%) of the amino acid sequence shown in SEQ ID NO: 13 or SEQ ID NO: 14 %, 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% (e.g.
  • the combination pharmaceutical composition wherein the anti-PD-L1 antibody comprises the following amino acid sequence: the heavy chain variable region as shown in SEQ ID NO: 13; and as shown in SEQ ID NO: Light chain variable region shown in 15.
  • the combination pharmaceutical composition wherein the anti-PD-L1 antibody comprises the following amino acid sequence: the heavy chain variable region shown in SEQ ID NO: 14; and the heavy chain variable region shown in SEQ ID NO: Light chain variable region shown in 16.
  • the anti-PD-L1 antibody described in the present disclosure comprises the following amino acid sequence: at least 80% (eg, 81%, 82%, 82%, 82%, 82%, 80%, 80%, 80%, 80%, 80%, 80%, 80%, 80%, 80%, 80%, 80%, 80%, 80%, 80%, 80%, 80%, 80%, 80%, 80%, 80%, 2, 1, 1, 2, and 8% back apart) to %, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, A heavy chain of 99% or 100% homology; at least 80% (e.g.
  • the combination pharmaceutical composition wherein the anti-PD-L1 antibody comprises the heavy chain amino acid sequence shown in SEQ ID NO: 17, and the light chain shown in SEQ ID NO: 18 amino acid sequence.
  • the combined pharmaceutical composition wherein the anti-PD-L1 antibody comprises the heavy chain amino acid sequence shown in SEQ ID NO: 19 and the light chain shown in SEQ ID NO: 20 amino acid sequence.
  • the combined pharmaceutical composition wherein the anti-PD-L1 antibody comprises the heavy chain amino acid sequence shown in SEQ ID NO: 21 and the light chain shown in SEQ ID NO: 18 amino acid sequence.
  • the combined pharmaceutical composition wherein the anti-PD-L1 antibody is hu5G11-hIgG1, which comprises the heavy chain amino acid sequence shown in SEQ ID NO: 17, and SEQ ID NO : the light chain amino acid sequence shown in 18.
  • the combination pharmaceutical composition comprises about 20 mg to about 2400 mg of anti-PD-L1 antibody. In some embodiments, the combination pharmaceutical composition comprises about 600 mg to about 2400 mg of anti-PD-L1 antibody. In some embodiments, the combination pharmaceutical composition comprises about 1000 mg to about 1500 mg of anti-PD-L1 antibody.
  • the combination pharmaceutical composition comprises about 100 mg, about 300 mg, about 600 mg, about 900 mg, about 1000 mg, about 1200 mg, about 1500 mg, about 1800 mg, about 2100 mg, or about 2400 mg of anti-PD-L1 Antibody. In some specific embodiments, the combination pharmaceutical composition comprises about 1200 mg of anti-PD-L1 antibody.
  • the combination pharmaceutical composition wherein the pharmaceutical composition of the anti-PD-L1 antibody is a single dose or multiple doses, in some embodiments, multiple doses.
  • the combined pharmaceutical composition comprises a pharmaceutical composition of an anti-PD-L1 antibody in a single dose of 100 mg-2000 mg, 100 mg-1200 mg, 1000 mg-2000 mg, 100 mg-600 mg, or 600 mg-1200 mg. In some embodiments, the combination pharmaceutical composition comprises a pharmaceutical composition of an anti-PD-L1 antibody in a single dose of 100 mg or 600 mg.
  • the combination pharmaceutical composition wherein the pharmaceutical composition of the anti-PD-L1 antibody is a multi-dose, and the multi-dose consists of a single dose of 100 mg or 600 mg of the pharmaceutical composition of the anti-PD-L1 antibody .
  • the combination pharmaceutical composition, wherein the mass volume concentration of the pharmaceutical composition of the anti-PD-L1 antibody is about 1-150 mg/mL, or about 10-60 mg/mL, or about 10 mg/mL, or about 30 mg/mL.
  • the combination pharmaceutical composition, wherein the anti-PD-L1 antibody is formulated to be suitable for 1 mg/kg, 2 mg/kg, 3 mg/kg, 5 mg/kg, 6 mg/kg, 9 mg/kg
  • the combination pharmaceutical composition wherein the dose of the anti-PD-L1 antibody is a fixed dose in the pharmaceutical composition.
  • the combined pharmaceutical composition, wherein the content of anti-PD-L1 antibody is a daily dose.
  • the combined pharmaceutical composition, wherein the content of anti-PD-L1 antibody is a unified dose.
  • the combined pharmaceutical composition wherein the content of the anti-PD-L1 antibody is a dose of one cycle, and each cycle is 21 days.
  • the combined pharmaceutical composition wherein the anti-PD-L1 antibody exists in the form of a pharmaceutical composition, the pharmaceutical composition comprises an anti-PD concentration of about 1-150 mg/mL by mass and volume -L1 antibody, 3-50 mM buffer, 2-150 mg/mL isotonicity modifier/stabilizer and 0.01-0.8 mg/mL surfactant, and pH about 4.5-6.8.
  • the combined pharmaceutical composition wherein the pharmaceutical composition of the anti-PD-L1 antibody comprises: (a) a mass-volume concentration of about 10 mg/mL or about 30 mg/ml Anti-PD-L1 antibody, (b) sucrose at a concentration of about 80 mg/mL by volume, (c) polysorbate 80 at a concentration of about 0.2 mg/mL by volume, (d) histidine at a molar concentration of about 10 mM , (e) optionally an appropriate amount of hydrochloric acid to adjust the pH of the composition to about 5.5.
  • the combined pharmaceutical composition wherein the pharmaceutical composition of the anti-PD-L1 antibody comprises: (a) a mass-volume concentration of about 10 mg/mL or about 30 mg/mL hu5G11-hIgG1, (b) sucrose at a concentration of about 80 mg/mL by volume, (c) polysorbate 80 at a concentration of about 0.2 mg/mL by volume, (d) histidine at a molar concentration of about 10 mM, ( e) optionally an appropriate amount of hydrochloric acid to adjust the pH of the composition to about 5.5.
  • the combined pharmaceutical composition, wherein the pharmaceutical composition of the anti-PD-L1 antibody is a water-soluble injection includes, but is not limited to, a water-soluble preparation that is not lyophilized or frozen Dry powder reconstituted water-soluble formulation.
  • the combined pharmaceutical composition, wherein the pharmaceutical composition of the anti-PD-L1 antibody is a lyophilized preparation.
  • the lyophilized preparation refers to the preparation of an aqueous solution through a freeze-drying process, a stabilization process in which the substance is first frozen, and then the amount of solvent is first reduced by sublimation (primary drying process), and then the amount of solvent is reduced by desorption (secondary drying process) until the amount of solvent is at a value that no longer supports biological activity or chemical reaction.
  • the combined pharmaceutical composition wherein the pharmaceutical composition of the anti-PD-L1 antibody is hu5G11-hIgG1 injection, with a specification of 100 mg/10 mL or 600 mg/20 mL.
  • the present disclosure provides a pharmaceutical composition preparation of an anti-PD-L1 antibody, the polymer is not more than 1.1%, preferably not more than 0.9%, more preferably not more than 1.1% when stored at 2-8°C or 25°C for at least 6 months more than 0.5%.
  • the combination pharmaceutical composition contains a pharmaceutical composition of an anti-PD-L1 antibody in multiple doses of about 20 mg to about 2400 mg, about 600 mg to about 2400 mg, or about 1000 mg to about 1500 mg, wherein The content of the anti-PD-L1 antibody is a unified dose, and the multiple doses consist of a single dose of 100 mg or 600 mg of the pharmaceutical composition of the anti-PD-L1 antibody.
  • the combination pharmaceutical composition contains multiple doses of about 100 mg, about 300 mg, about 600 mg, about 900 mg, about 1000 mg, about 1200 mg, about 1500 mg, about 1800 mg, about 2100 mg, or about 2400 mg
  • a pharmaceutical composition of an anti-PD-L1 antibody wherein the content of the anti-PD-L1 antibody is a uniform dose, and the multiple doses are composed of a single dose of the pharmaceutical composition of an anti-PD-L1 antibody of 100 mg or 600 mg.
  • the combination pharmaceutical composition contains a pharmaceutical composition of about 1200 mg of anti-PD-L1 antibody in multiple doses, wherein the content of the anti-PD-L1 antibody is a uniform dose, and the multiple doses are composed of A single dose of 100 mg or 600 mg of a pharmaceutical composition of an anti-PD-L1 antibody.
  • the combined pharmaceutical composition contains 90 mg-180 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the combined pharmaceutical composition contains 90 mg-120 mg, 90 mg-150 mg, 120 mg-150 mg, 120 mg-180 mg, or 150 mg-180 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the combined pharmaceutical composition contains 90 mg, 120 mg, 150 mg, or 180 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the combined pharmaceutical composition contains 120 mg or 150 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the combination pharmaceutical composition wherein the pharmaceutical composition of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a single dose or multiple doses; in some embodiments, multiple doses.
  • the combination pharmaceutical composition contains a single dose of 30 mg or 60 mg of the pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the combination pharmaceutical composition wherein the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof, is in multiple doses consisting of a single dose of 30 mg or 60 mg of formula (I) A pharmaceutical composition of a compound or a pharmaceutically acceptable salt thereof.
  • the combined pharmaceutical composition wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in a daily dose.
  • the combined pharmaceutical composition wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in a once-daily dose.
  • the combined pharmaceutical composition wherein the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a once-a-day dose, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is Single or multiple doses.
  • the combined pharmaceutical composition contains multiple doses of 90mg-180mg, 90mg-120mg, 90mg-150mg, 120mg-150mg, 120mg-180mg or 150mg-180mg of the compound of formula (I) or its A pharmaceutical composition of a pharmaceutically acceptable salt, wherein the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a once-a-day dose, and the multiple doses are composed of a single dose of 30 mg or 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • Pharmaceutical compositions with salts are composed of a single dose of 30 mg or 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the combination pharmaceutical composition contains multiple doses of 90 mg, 120 mg, 150 mg, or 180 mg of a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I)
  • the content of a pharmaceutically acceptable salt thereof is a once-a-day dose, and the multiple doses consist of a single dose of 30 mg or 60 mg of the pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the combined pharmaceutical composition contains multiple doses of 120 mg or 150 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof
  • the salt is present in a once-daily dose, and the multiple doses consist of a single dose of 30 mg or 60 mg of the pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the compounds of formula (I) of the present disclosure can be administered in their free base form, as well as in the form of their pharmaceutically acceptable salts, hydrates and prodrugs, which are converted in vivo to the free form of compounds of formula (I) base form.
  • pharmaceutically acceptable salts of the compounds of formula (I) are within the scope of the present disclosure, and the salts can be generated from various organic and inorganic acids according to methods well known in the art, for example, the inorganic acids can be selected from the group consisting of hydrochloric acid, hydrobromic acid, Sulfuric acid, nitric acid or phosphoric acid, the organic acid may be selected from succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid or naphthalene sulfuric acid.
  • the compound of formula (I) is administered in its free base form.
  • the "compound of formula (I)" described in the present disclosure may be a “pharmaceutical composition of the compound of formula (I)".
  • the "compound of formula (I) or a pharmaceutically acceptable salt thereof” described in the present disclosure may be a "pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof".
  • the method of administration can be comprehensively determined according to the activity of the drug, the toxicity and the patient's tolerance.
  • the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof of the present disclosure further contains a pharmaceutically acceptable adjuvant.
  • a pharmaceutical composition of a compound of formula (I) of the present disclosure, or a pharmaceutically acceptable salt thereof, is administered orally.
  • the pharmaceutical composition of the compound of formula (I) of the present disclosure, or a pharmaceutically acceptable salt thereof is a solid pharmaceutical composition.
  • the formulation form of a solid pharmaceutical composition of a compound of formula (I) of the present disclosure, or a pharmaceutically acceptable salt thereof is a capsule.
  • the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a capsule of the compound of formula (I) or a pharmaceutically acceptable salt thereof in 30 mg and 60 mg strengths.
  • composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing method, dissolving method, granulation method, sugar-coated pilling method, grinding method, emulsifying method method, freeze-drying method, etc.
  • Solid oral compositions can be prepared by conventional mixing, filling or tabletting methods. It can be obtained, for example, by mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to give tablets or icing core.
  • Suitable adjuvants include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • the pharmaceutical composition of the compound of formula (I) can be a capsule of the compound of formula (I) containing the compound of formula (I), cornstarch, calcium carboxymethylcellulose, hypromellose, and hard Magnesium Fatty Acid.
  • the pharmaceutical composition of the compound of formula (I) can be a capsule of the compound of formula (I) containing the compound of formula (I), lactose, microcrystalline cellulose, sodium starch glycolate, and magnesium stearate .
  • the pharmaceutical composition of the compound of formula (I) is a capsule of the compound of formula (I) containing: (a) about 30 mg or about 60 mg of the compound of formula (I), (b) about 93 mg or about 63 mg of corn starch, (c) about 22.5 mg of calcium carboxymethylcellulose, (d) about 3 mg of hypromellose, and (e) about 1.5 mg of magnesium stearate; total weight of 150mg.
  • the pharmaceutical composition of the compound of formula (I) is a capsule of the compound of formula (I) containing: (a) about 30 mg or about 60 mg of the compound of formula (I), (b) about 40 mg of lactose, (c) about 72.5 mg or about 42.5 mg of microcrystalline cellulose, (d) about 6 mg of sodium starch glycolate, and (e) about 1.5 mg of magnesium stearate; total weight 150 mg.
  • the present disclosure also provides a kit for a pharmaceutical composition for treating lung cancer, which contains (a) a first pharmaceutical composition comprising the anti-PD-L1 antibody described in the present disclosure as an active ingredient; and ( b) A second pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present disclosure also provides a method of treating lung cancer comprising administering to a subject suffering from lung cancer a therapeutically effective amount of the combination pharmaceutical composition of the present disclosure.
  • the present disclosure also provides the use of the combined pharmaceutical composition in the preparation of a medicament for the treatment of lung cancer, and the combined pharmaceutical composition is the combined pharmaceutical composition of the present disclosure.
  • the present disclosure also provides the use of a combined pharmaceutical composition for treating lung cancer, and the combined pharmaceutical composition is the combined pharmaceutical composition of the present disclosure.
  • the present disclosure also provides a combination therapy for treating a subject suffering from lung cancer, the combination therapy comprising administering to the subject alone a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and A therapeutically effective amount of an anti-PD-L1 antibody described in the present disclosure is administered alone.
  • the anti-PD-L1 antibody is administered at 1 mg/kg, 2 mg/kg, 3 mg/kg, 5 mg /kg, 6 mg/kg, 9 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 30 mg/kg of body weight, continuous administration.
  • the anti-PD-L1 antibody is administered in one or more uniform doses effective to treat the cancer. In some embodiments, wherein the uniform dose is in the range of about 20 mg to about 2400 mg, or about 600 mg to about 2400 mg, or about 1000 mg to about 1500 mg of anti-PD-L1 antibody.
  • the unitary dose is selected from about 100 mg, about 300 mg, about 600 mg, about 900 mg, about 1000 mg, about 1200 mg, about 1500 mg, about 1800 mg, about 2100 mg, or about 2400 mg of anti-PD-L1 antibody. In some embodiments, the unitary dose is selected from about 1200 mg of anti-PD-L1 antibody.
  • a uniform dose (the dose administered to the patient regardless of the patient's weight) may be used.
  • a unified dose of 13C5, ch13C5-hIgG1, ch13C5-hIgG4, hu13C5-hIgG1, hu13C5-hIgG4, 5G11, ch5G11-hIgG1, ch5G11-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4 mAbs can be about 1200 mg.
  • the anti-PD-L1 antibody is administered at a dose of about 1800 mg. In certain embodiments, the anti-PD-L1 antibody is administered at a dose of about 1200 mg. In certain embodiments, the anti-PD-L1 antibody is administered at a dose of about 900 mg. In certain embodiments, the anti-PD-L1 antibody is administered at a dose of about 600 mg. In one embodiment, 900 mg of the anti-PD-L1 antibody is administered once every 3 weeks. In another embodiment, 1200 mg of the anti-PD-L1 antibody is administered once every 4 weeks. In another embodiment, 1200 mg of the anti-PD-L1 antibody is administered once every 3 weeks.
  • the combination pharmaceutical composition or some embodiments of the method, use, or combination therapy, about every week (q1w), about every 2 weeks (q1w), about every 3 weeks (q1w) ), or anti-PD-L1 antibodies were administered approximately every 4 weeks (q1w).
  • the patient is administered a uniform dose of anti-PD-L1 antibody approximately every 3 weeks (21 days).
  • the anti-PD-L1 antibody is administered at a dose of 1200 mg per patient approximately every 3 weeks (21 days) for continuous administration.
  • the anti-PD-L1 antibody is administered as an intravenous infusion. In some embodiments, the anti-PD-L1 antibody is administered as an intravenous infusion over about 1-2 hours, preferably as an intravenous infusion over about 1 hour ( ⁇ 5 minutes).
  • the anti-PD-L1 antibody is hu5G11-hIgG1 injection, the hu5G11-hIgG1 injection
  • the packaging specification is 100mg: 10mL or 600mg: 20mL; the dosing plan is an intravenous infusion of 1200mg of hu5G11-hIgG1 (diluted to 250mL with normal saline), and the infusion time is 60 ⁇ 5 minutes. Dosing every 21 days.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combination pharmaceutical composition is The amount is a daily dose, which is administered by administering a compound of formula (I) or a pharmaceutically acceptable salt thereof once a day.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combination pharmaceutical composition is The amount is a daily dose, which is administered by administering a compound of formula (I) or a pharmaceutically acceptable salt thereof once a day for 21 consecutive days.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combination pharmaceutical composition is The amount is a daily dose wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a single dose or in multiple doses. In some embodiments, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered in multiple doses.
  • combination pharmaceutical composition or in some embodiments of the method, use, or combination therapy, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered by administering to a subject
  • the subjects received daily doses of 90 mg, 120 mg, 150 mg or 180 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, administered continuously daily.
  • the daily dose is 90 mg, 120 mg, 150 mg or 180 mg, once a day.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is administered orally; in some embodiments Among them, the compound of formula (I) or a pharmaceutically acceptable salt thereof is orally administered within ⁇ 5 minutes of administration of the pharmaceutical composition of the anti-PD-L1 antibody.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is administered at a fixed time each day.
  • administration is by administering the anti-PD-L1 antibody within ⁇ 5 minutes of administration of formula (I ) compound or a pharmaceutically acceptable salt thereof.
  • administration is by: within ⁇ 5 minutes of administration of the pharmaceutical composition of the anti-PD-L1 antibody
  • a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered.
  • administration is by fasting within ⁇ 5 minutes of administration of the anti-PD-L1 antibody injection
  • Capsules of a compound of formula (I) or a pharmaceutically acceptable salt thereof are administered.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is administered in combination with an anti-PD- L1 antibody administration, every 21 days is a treatment cycle, and the administration is as follows: 1200 mg of anti-PD-L1 antibody is infused on the first day, and the infusion time is 60 ⁇ 5 minutes; the compound of formula (I) or its compound is administered once a day. 120 mg or 150 mg of a pharmaceutically acceptable salt for 21 days.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is administered in combination with hu5G11-hIgG1 Administration, every 21 days is a treatment cycle, and the administration is as follows: 1200 mg of hu5G11-hIgG1 antibody is infused on the first day, the infusion time is 60 ⁇ 5 minutes; the compound of formula (I) or a pharmaceutically acceptable compound thereof is administered once a day Salt 120 mg for 21 days.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is administered in combination with hu5G11-hIgG1 Administration, every 21 days is a treatment cycle, and the administration is as follows: 1200 mg of hu5G11-hIgG1 antibody is infused on the first day, the infusion time is 60 ⁇ 5 minutes; the compound of formula (I) or a pharmaceutically acceptable compound thereof is administered once a day Salt 150 mg for 21 days.
  • 1200 mg of the hu5G11-hlgG1 antibody is administered diluted to 250 mL with normal saline.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is administered on day one, and is administered on an empty stomach within ⁇ 5 minutes of the start of the hu5G11-hIgG1 antibody infusion.
  • the lung cancer is refractory, relapsed or metastatic lung cancer.
  • the lung cancer is advanced lung cancer. In some aspects of the present disclosure, the lung cancer is locally advanced lung cancer.
  • the lung cancer is metastatic lung cancer.
  • the metastatic lung cancer is metastatic cancer metastasized from kidney cancer, liver cancer, gastric cancer, rectal cancer, colon cancer, colorectal cancer, prostate cancer, pancreatic cancer, or breast cancer.
  • the lung cancer is advanced, recurrent and/or metastatic lung cancer. In some aspects of the present disclosure, the lung cancer is locally advanced, recurrent and/or metastatic lung cancer.
  • the lung cancer is small cell lung cancer or non-small cell lung cancer.
  • the lung cancer is squamous cell non-small cell lung cancer or non-squamous cell non-small cell lung cancer (eg, lung adenocarcinoma).
  • the lung cancer is lung adenocarcinoma, lung squamous cell carcinoma, or lung large cell carcinoma.
  • the lung cancer is non-small cell lung cancer with histologically predominant squamous cell carcinoma.
  • the lung cancer is recurrent and/or metastatic non-small cell lung cancer. In some embodiments, the lung cancer is recurrent and/or metastatic small cell lung cancer.
  • the lung cancer is advanced non-small cell lung cancer. In some specific schemes, the lung cancer is advanced small cell lung cancer.
  • the lung cancer is advanced (or locally advanced), recurrent and/or metastatic non-small cell lung cancer or small cell lung cancer.
  • the lung cancer is advanced, recurrent and/or metastatic non-small cell lung cancer. . In some embodiments of the present disclosure, the lung cancer is advanced, recurrent and/or metastatic squamous cell non-small cell lung cancer or non-squamous cell non-small cell lung cancer (eg, lung adenocarcinoma).
  • the lung cancer is locally advanced, recurrent and/or metastatic non-small cell lung cancer. In some embodiments of the present disclosure, the lung cancer is locally advanced, recurrent and/or metastatic squamous cell non-small cell lung cancer or non-squamous cell non-small cell lung cancer (eg, lung adenocarcinoma).
  • the subject of lung cancer has not previously received surgery, chemotherapy, and/or radiation therapy. In some embodiments of the present disclosure, the subject of lung cancer has previously received surgery, chemotherapy, and/or radiation therapy. In some embodiments, the subject of lung cancer has relapsed after achieving a complete remission following surgery, chemotherapy and/or radiation therapy. In some embodiments, the subject of lung cancer is not in complete remission or in partial remission after surgery, chemotherapy and/or radiation therapy. In some embodiments, the subject of lung cancer has metastasized cancer following surgery, chemotherapy and/or radiation therapy. In some aspects of the present disclosure, the subject of lung cancer has not previously received systemic chemotherapy. In some aspects of the present disclosure, the subject of lung cancer has previously received systemic chemotherapy.
  • the subject of lung cancer has previously received surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy. In some embodiments, the subject of lung cancer has not previously received systemic chemotherapy, but has received surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy and/or adjuvant chemotherapy. In some specific embodiments, the subject of lung cancer relapses after achieving complete remission after surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy and/or adjuvant chemotherapy. In some specific embodiments, the subject of lung cancer fails to achieve complete remission or partial remission after surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy and/or adjuvant chemotherapy. In some embodiments, the subject of lung cancer develops cancer metastasis after surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy and/or adjuvant chemotherapy.
  • the subject of lung cancer is the subject of non-small cell lung cancer (NSCLC) of UICC/AJCC 8th edition lung cancer TNM stage, conforming to stage IIIB/IIIC/IV.
  • NSCLC non-small cell lung cancer
  • the subject of lung cancer is a subject who has previously received PD-1 or PD-L1 inhibitor therapy alone or in combination with platinum-based chemotherapy (eg, treatment failure).
  • the subject of lung cancer is non-small cell lung cancer that has previously received a PD-1 or PD-L1 inhibitor alone or in combination with platinum-based chemotherapy (eg, treatment failure). main body.
  • the subject of lung cancer is an advanced, relapsed patient who has previously received a PD-1 or PD-L1 inhibitor alone or in combination with platinum-based chemotherapy (eg, treatment failure). and/or subjects with metastatic non-small cell lung cancer.
  • the subject of lung cancer is locally advanced, recurrent, and previously treated with PD-1 or PD-L1 inhibitor alone or in combination with platinum-based chemotherapy (eg, treatment failure).
  • the subject of lung cancer is an advanced, relapsed patient who has previously received a PD-1 or PD-L1 inhibitor alone or in combination with platinum-based chemotherapy (eg, treatment failure). and/or metastatic squamous cell non-small cell lung cancer subjects.
  • the subject of lung cancer is an advanced, relapsed patient who has previously received a PD-1 or PD-L1 inhibitor alone or in combination with platinum-based chemotherapy (eg, treatment failure). and/or metastatic and histologically predominant squamous cell carcinoma of the body of non-small cell lung cancer.
  • the subject of lung cancer is an advanced, relapsed patient who has previously received a PD-1 or PD-L1 inhibitor alone or in combination with platinum-based chemotherapy (eg, treatment failure). and/or metastatic non-squamous non-small cell lung cancer subjects.
  • the subject of lung cancer is locally advanced, recurrent, and previously treated with PD-1 or PD-L1 inhibitor alone or in combination with platinum-based chemotherapy (eg, treatment failure).
  • the subject of lung cancer is locally advanced, recurrent, and previously treated with PD-1 or PD-L1 inhibitor alone or in combination with platinum-based chemotherapy (eg, treatment failure).
  • the subject of lung cancer is locally advanced, recurrent, and previously treated with PD-1 or PD-L1 inhibitor alone or in combination with platinum-based chemotherapy (eg, treatment failure). subjects with non-squamous and/or metastatic non-squamous non-small cell lung cancer.
  • the PD-1 inhibitor in the previously received PD-1 or PD-L1 inhibitor therapy, is an anti-PD-1 antibody, such as Nivolumab, Pembrolizumab (Pembrolizumab), Toripalizumab (JS-001), Sintilimab (IBI308), Camrelizumab (Camrelizumab), Tislelizumab (BGB-A317) ), balstilimab, AK105, genusumab (GB226), LZM009, HLX10, AK103 (HX008), CS1003, SCT-I10A, F520, SG001, or sepalimumab (GLS-010) .
  • an anti-PD-1 antibody such as Nivolumab, Pembrolizumab (Pembrolizumab), Toripalizumab (JS-001), Sintilimab (IBI308), Camrelizumab (Camrelizumab), Tislelizumab (B
  • the PD-L1 inhibitor in the previously treated PD-1 or PD-L1 inhibitor, is an anti-PD-L1 antibody, such as Atezolizumab , Durvalumab (Durvalumab), Avelumab (Avelumab), Envolumab (KN035), Sugelimab (CS1001), , TQB2450, SHR-1316, Socazolimab (ZKAB001), HS636 , LP002, JS003, MSB2311, KL-A167 or STI-A1014.
  • an anti-PD-L1 antibody such as Atezolizumab , Durvalumab (Durvalumab), Avelumab (Avelumab), Envolumab (KN035), Sugelimab (CS1001), , TQB2450, SHR-1316, Socazolimab (ZKAB001), HS636 , LP002, JS003, MSB2311, K
  • the lung cancer is driver gene-negative lung cancer.
  • the lung cancer is driver gene-negative non-small cell lung cancer.
  • the driver gene negative includes, but is not limited to, EGFR mutation negative, ALK mutation negative, ROS1 mutation negative, BRAF mutation negative, NTRK mutation negative, MET mutation negative, and/or KRAS mutation negative.
  • the lung cancer is selected from i) EGFR, ALK and/or ROS1 wild type squamous cell non-small cell lung cancer, and ii) EGFR, ALK and/or ROS1 wild type non-squamous non-small cell lung cancer Small cell lung cancer (eg lung adenocarcinoma).
  • the lung cancer is non-small cell lung cancer (eg, advanced non-small cell lung cancer) that has failed previous PD-1 or PD-L1 inhibitor therapy alone or in combination with platinum-based chemotherapy lung cancer).
  • the cancer therapy is first-line therapy for relapsed or refractory non-small cell lung cancer.
  • the lung cancer is metastatic non-small cell lung cancer, eg, non-small cell lung cancer that is lymphatic, brain, and/or bone metastases.
  • the subject is a driver gene-negative (including EGFR, ALK, and ROS1 mutation-negative) patient with advanced, metastatic, or recurrent non-small cell lung cancer.
  • the subject is a driver gene-negative (including EGFR, ALK, and ROS1 mutation-negative) locally advanced (IIIB), metastatic, or recurrent (stage IV) non-small cell lung cancer patient.
  • the subject is driver gene-negative (including EGFR, ALK, and ROS1 mutation-negative) advanced, metastatic, or recurrent squamous cell non-small cell lung cancer or non-squamous cell non-small cell lung cancer (such as lung adenocarcinoma).
  • the subject is driver gene-negative (including EGFR, ALK, and ROS1 mutation-negative) locally advanced, metastatic, or recurrent squamous cell non-small cell lung cancer or non-squamous cell non-small cell lung cancer (eg lung adenocarcinoma).
  • the patient is treated with a PD-1 or PD-L1 inhibitor alone or in combination with platinum-based chemotherapy (eg, treatment failure).
  • the patient is histologically or cytologically inoperable and ineligible for curative concurrent chemoradiotherapy.
  • the EGFR mutation includes, but is not limited to, exon 19 or 21 mutations.
  • the combined pharmaceutical composition of the present application has one or more of the following effects:
  • the treated patient has a longer survival (eg, median survival, progression-free survival, or overall survival) compared to standard chemotherapy;
  • the combined pharmaceutical composition and its treatment scheme of the present disclosure have a good curative effect in the treatment of lung cancer, especially non-small cell lung cancer. wherein there is a beneficial effect on at least one of ORR, DCR, DoR, PFS, OS, tolerability and side effects.
  • the term "antibody” refers to an antigen-binding protein having at least one antigen-binding domain.
  • the antibodies and fragments thereof of the present disclosure can be whole antibodies or any fragments thereof. Accordingly, the antibodies and fragments thereof of the present disclosure 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)'2 fragments, Fv fragments, isolated CDR regions, single chain Fv molecules (scFv) and other antibody fragments known in the art. Antibodies and fragments thereof can also include recombinant polypeptides, fusion proteins, and bispecific antibodies.
  • the anti-PD-L1 antibodies and fragments thereof disclosed herein can be of the IgG1, IgG2, IgG3, or IgG4 isotype.
  • the term "isotype" refers to the species of antibody encoded by the heavy chain constant region genes.
  • treatment generally refers to an operation to obtain a desired pharmacological and/or physiological effect.
  • the effect may be prophylactic in terms of complete or partial prevention of the disease or its symptoms; and/or 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, preventing its progression; or (b) alleviating the symptoms of the disease, ie, causing regression of the disease or symptoms.
  • systemic therapy refers to a therapy in which a drug substance is transported through the bloodstream to reach and affect cells throughout the body.
  • systemic therapy refers to systemic chemotherapy, systemic or local radiation therapy.
  • first-line treatment refers to treatment with a drug that may be first or standardly selected according to the patient's condition.
  • administering means physically introducing a composition comprising a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those skilled in the art. Routes of administration include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, eg, 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, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion , and electroporation in vivo.
  • administration is by non-parenteral routes, in certain embodiments, orally.
  • non-parenteral routes include topical, epidermal or mucosal routes of administration, eg, intranasal, vaginal, rectal, sublingual, or topical. Administration can also be performed, eg, once, multiple times, and/or over one or more extended periods of time.
  • an "adverse event” is any unfavorable and often unintended or undesired sign (including abnormal laboratory findings), symptom, or disease associated with the use of a medical treatment.
  • adverse events can be associated with activation of the immune system or expansion of immune system cells (eg, T cells) in response to treatment.
  • a medical treatment may have one or more associated AEs, and each AE may be of the same or a different level of severity.
  • Reference to a method capable of "modifying an adverse event” refers to a treatment regimen that reduces the incidence and/or severity of one or more AEs associated with the use of a different treatment regimen.
  • dosing interval refers to the amount of time that elapses between multiple doses of a formulation disclosed herein administered to a subject.
  • the dosing interval can thus be indicated as a range.
  • Dosing frequency refers to how often a dose of a formulation disclosed herein is administered at a given time. Dosing frequency can be indicated as the number of administrations per given time, eg, once a week or once every two weeks.
  • flat dose refers to a dose administered to a patient regardless of the patient's weight or body surface area (BSA).
  • the uniform dose is therefore specified as an absolute amount of an agent (eg, anti-PD-L1 antibody) rather than as a mg/kg dose.
  • an agent eg, anti-PD-L1 antibody
  • mg/kg dose e.g. a 60kg person and a 100kg person will receive the same dose of antibody (eg, 240mg anti-PD-L1 antibody).
  • fixed dose means that two or more different antibodies in a single composition are present in the composition in a specific (fixed) ratio to each other.
  • the fixed dose is based on the weight (eg, mg) of the antibody.
  • the fixed dose is based on the concentration of the antibody (eg, mg/ml).
  • body weight-based dose refers to a dose administered to a patient calculated based on the patient's weight.
  • body weight-based dose refers to a dose administered to a patient calculated based on the patient's weight.
  • a patient with a body weight of 60 kg requires 3 mg/kg of anti-PD-L1 antibody and 1 mg/kg of anti-CTLA-4 antibody
  • daily dose refers to the dose administered to a patient for one day.
  • single dose refers to the smallest packaging unit containing a certain amount of medicine, for example, a box of medicine contains seven capsules, each capsule is a single dose; for example, a box of medicine contains seven tablets, each medicine is a single dose; Or each vial of injection is a single dose.
  • multi-dose consists of multiple single doses.
  • day When referring to dosing regimens, the terms “day”, “every day” and the like refer to the time within a calendar day, beginning at midnight and ending at the next midnight.
  • immunotherapy refers to the treatment of a subject afflicted with or at risk of infection or relapse of a disease by a method that includes inducing, enhancing, suppressing or otherwise altering an immune response.
  • Treatment or “therapy” of a subject means any type of intervention or procedure performed on the subject, or administration of an active agent to the subject, for the purpose of reversing, alleviating, ameliorating, inhibiting, slowing or preventing a symptom, complication or disorder onset, progression, progression, severity, or recurrence of disease, or disease-related biochemical markers.
  • P-L1 Programmed Death Ligand-1 (PD-L1) is one of two cell surface glycoprotein ligands for PD-1 (the other being PD-L2), which downregulates T cells upon binding to PD-1 activation and cytokine secretion.
  • Subject includes any human or non-human animal.
  • non-human animal includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs.
  • the subject is a human.
  • Subject means mammals such as rodents, felines, canines, and primates.
  • the subject of the present disclosure is a human.
  • the terms "subject”, “subject” and “patient” are used interchangeably in certain contexts herein.
  • a “therapeutically effective amount” or “therapeutically effective dose” of a drug or therapeutic agent is any amount of a drug that, when used alone or in combination with another therapeutic agent, protects a subject from the onset of disease or promotes regression of disease, said Disease regression is evidenced by a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, or prevention of injury or disability caused by disease affliction.
  • the ability of therapeutic agents to promote disease regression can be assessed using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predicting efficacy in humans, or by in vitro assays The activity of the agent was determined.
  • a therapeutically effective amount of an anticancer drug can inhibit cell growth or tumor growth by at least a About 10%, at least about 20%, at least about 40%, at least about 60%, or at least about 80%.
  • tumor regression can be observed for a period of at least about 20 days, at least about 40 days, or at least about 60 days.
  • a “recurrent” cancer is one that regenerates at the initial site or at a distant site in response to initial treatment (eg, surgery).
  • a “locally recurrent” cancer is one that, after treatment, develops in the same location as the previously treated cancer.
  • Unresectable cancer is one that cannot be removed by surgery.
  • Metalstatic cancer refers to cancer that has spread from one part of the body (eg, the lungs) to another part of the body.
  • Treatment failure means disease progression or intolerable toxicity during or after treatment.
  • Treatment failure with platinum-based chemotherapy refers to disease progression or intolerable toxicity during or after treatment with platinum-based first-line chemotherapy or chemoradiotherapy.
  • First-line or more chemotherapy failure was defined as: disease progression during or after the last treatment; or intolerable toxicity during treatment.
  • about 3 mg can include any number between 2.7 mg and 3.3 mg (for 10%) or between 2.4 mg and 3.6 mg (for 20%).
  • the term may refer to up to an order of magnitude or up to 5 times the value.
  • the terms “about weekly,” “about every two weeks,” or any other similar dosing interval term refer to approximations. “About once a week” can include every 7 days ⁇ 1 day, ie, every 6 days to every 8 days. “About every two weeks” can include every 14 days ⁇ 3 days, ie, every 11 days to every 17 days. Similar approximations apply, for example, about once every 3 weeks, about once every 4 weeks, about once every 5 weeks, about once every 6 weeks, and about once every 12 weeks.
  • a dosing interval of about once every 6 weeks or about once every 12 weeks means that the first dose may be administered on any day of the first week, followed by the administration of the first dose on the sixth or twelfth week, respectively.
  • a second dose is administered on any day.
  • a dosing interval of about once every 6 weeks or about once every 12 weeks means that the first dose is administered on a particular day of the first week (eg, Monday) and then on the sixth or fourth week, respectively. The second dose was administered on the same day (ie, Monday) for twelve weeks. Similar principles apply to phrases including, but not limited to, "about once every 2 weeks," "about once a month,” etc. . . .
  • any concentration range, percentage range, ratio range or integer range should be understood to include any integer value within the recited range and, where appropriate, fractions thereof (such as one-tenths of an integer and one percent) unless otherwise indicated.
  • a pH of about 5.5 means a pH of 5.5 ⁇ 5%, preferably a pH of 5.5 ⁇ 2%, more preferably a pH of 5.5 ⁇ 1%.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are within the scope of sound medical judgment, suitable for use in contact with human and animal tissue without excessive of toxicity, irritation, allergic reactions or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • fixed combination refers to the active components (eg, an anti-PD-L1 antibody or a compound of formula (I) or a pharmaceutically acceptable salt thereof) in a fixed total dose or dose ratio, or simultaneously in the form of a single entity, pharmaceutical composition or formulation given to the subject.
  • active components eg, an anti-PD-L1 antibody or a compound of formula (I) or a pharmaceutically acceptable salt thereof
  • non-fixed combination refers to the simultaneous, concurrent or sequential administration of two or more active components as separate entities (eg, pharmaceutical compositions, formulations) to a subject without a specific time limit, wherein said administration to a subject of the active ingredient to a therapeutically effective level.
  • An example of a non-fixed combination is a cocktail therapy, eg the 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 use of a combination between "fixed combination” or "fixed combination” with any one or more separate entities of the active ingredient.
  • combination or “combination” means that two or more active substances may be administered to a subject together in a mixture, each simultaneously as a single formulation, or each as a single formulation sequentially in any order to a subject By.
  • pharmaceutical composition refers to one or more active ingredients of the present disclosure (eg, an anti-PD-L1 antibody or a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical combination thereof and a pharmaceutically acceptable excipient. mixture.
  • active ingredients of the present disclosure eg, an anti-PD-L1 antibody or a compound of formula (I) or a pharmaceutically acceptable salt thereof
  • pharmaceutical combination thereof e.g., a pharmaceutically acceptable excipient.
  • pharmaceutical composition refers to one or more active ingredients of the present disclosure (eg, an anti-PD-L1 antibody or a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical combination thereof and a pharmaceutically acceptable excipient. mixture.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical combination thereof, to a subject.
  • pharmaceutical composition and “formulation” have the same meaning and are used interchangeably.
  • the components of the pharmaceutical combinations of the present disclosure may each be formulated separately, or some or all of them may be co-formulated.
  • the pharmaceutical combinations of the present disclosure can be formulated as pharmaceutical compositions suitable for single or multiple administration.
  • the components of the pharmaceutical combinations of the present disclosure may each be administered alone, or some or all of them may be co-administered.
  • the components of the pharmaceutical combinations of the present disclosure may not be administered substantially simultaneously, or some or all of them may be administered substantially simultaneously.
  • the components of the pharmaceutical combinations of the present disclosure can be administered individually, or some or all of them together, by various routes as appropriate, including, but not limited to, oral or parenteral (by intravenous, intramuscular, topical, or subcutaneous routes). ).
  • the components of the pharmaceutical combinations of the present disclosure may each be administered independently, or some or all of them may be administered orally or by injection, eg, intravenously or intraperitoneally.
  • the components of the pharmaceutical combinations of the present disclosure may each independently, or some or all of them together be in a suitable dosage form including, but not limited to, tablets, troches, pills, capsules (eg, hard capsules, soft capsules, enteric capsules) capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and for oral or non-oral administration
  • a suitable dosage form including, but not limited to, tablets, troches, pills, capsules (eg, hard capsules, soft capsules, enteric capsules) capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and for oral or non-oral administration
  • a suitable dosage form including, but not limited to, tablets
  • the components of the pharmaceutical combination of the present disclosure may each independently, or some or all of them together contain a pharmaceutically acceptable carrier and/or excipient.
  • the pharmaceutical combinations of the present disclosure may also contain additional therapeutic agents.
  • the additional therapeutic agent may be a cancer therapeutic agent known in the art.
  • Non-small cell lung cancer patients must meet the following criteria at the same time:
  • the central nervous system metastasis has no clinical symptoms or is accompanied by clinical symptoms, and the condition is controlled and stable for ⁇ 4 weeks after treatment;
  • HBVDNA quantification must be ⁇ 500IU/ml or 2500 copies/ml. Patients who need treatment should receive anti-HBV treatment for at least 2 weeks before the start of the study in accordance with the "Guidelines for the Prevention and Treatment of Chronic Hepatitis B (2019 Edition)" and are willing to receive it throughout the study period Antiviral therapy; patients with positive HCV RNA quantification must complete antiviral therapy at least 1 month before the start of the study;
  • At least one measurable lesion (RECIST 1.1);
  • the blood routine examination standards must meet: a) hemoglobin ⁇ 90g/L; b) absolute neutrophil count ⁇ 1.5 ⁇ 10 9 /L; c) platelet count ⁇ 75 ⁇ 10 9 /L; blood transfusion or blood products, not using granulocyte colony-stimulating factor, not using drug correction)
  • Prothrombin time (PT) prolongation is less than or equal to 3 seconds higher than the upper limit of normal
  • Radiotherapy for bone metastases with clinical symptoms must be completed at least 2 weeks before the start of the study;
  • Females of childbearing age should agree to use contraceptive measures (such as intrauterine devices, contraceptives or condoms) during the study period and within 6 months after the end of the study; serum pregnancy test negative within 7 days before study enrollment, and Must be non-breastfeeding; men should agree to use contraception during the study period and for 6 months after the end of the study period;
  • contraceptive measures such as intrauterine devices, contraceptives or condoms
  • Compound capsules of formula (I) Specifications: 30mg/capsule and 60mg/capsule, provided by Chia Tai Tianqing Pharmaceutical Group Co., Ltd.
  • hu5G11-hIgG1 injection Specifications: 100mg/10mL and 600mg/20mL, provided by Chia Tai Tianqing Pharmaceutical Group Co., Ltd.
  • Scheme A Formula (I) compound capsule 120mg/qd+hu5G11-hIgG1 1200mg (first day)
  • Scheme B Formula (I) compound capsule 150mg/qd+hu5G11-hIgG1 1200mg (first day)
  • hu5G11-hIgG1 injection diluted with normal saline to 250mL, the infusion time is 60 ⁇ 5min, administered once every 21 days, and 21 days is a medication cycle.
  • Dose down-regulation (150 mg-120 mg, 120 mg-90 mg) was allowed for adverse events related to compound capsules of formula (I) during the study, but cross-dose down-regulation was not allowed.
  • the main efficacy indicators were evaluated according to the RECIST 1.1 criteria, and the iRECIST evaluation criteria were referred to when pseudo-progression occurred.
  • PFS Progression Free Survival
  • ORR Objective Response Rate
  • DCR disease control rate
  • DoR Duration of Response
  • PR Partial Remission
  • PD disease progression
  • SD stable disease: The target lesion shrinks and does not meet the PR criteria; or the target lesion enlarges and does not meet the PD criteria.
  • the total diameter of the target lesions is the sum of the diameters of the target lesions (including the long diameter of the lesions and the short diameter of the lymph nodes).
  • capsules 120 mg/qd + hu5G11-hIgG1 1200 mg (day 1) in 8 subjects diagnosed with non-small cell lung cancer (including lung adenocarcinoma and lung squamous cell carcinoma) , 3 subjects achieved partial remission PR (37.5%), and the disease control rate DCR reached 100%.
  • Preliminary results show the advantages of the compound of formula (I) in combination with hu5G11-hIgG1 in the treatment of patients with non-small cell lung cancer. Specific results for 3 PR patients (Patient A, Patient B, and Patient C as described below) are shown below.
  • Target lesions 60.53mm; non-target lesions: mediastinal lymph nodes;
  • target lesions 36.87mm
  • non-target lesions mediastinal lymph nodes
  • the best treatment effect of patient A was PR (partial response).
  • Target lesions 29mm
  • non-target lesions hilar and mediastinal pathological lymph nodes, bilateral lung nodules
  • target lesions 13mm
  • non-target lesions Non-CR/Non-PD (non-complete remission/non-disease progression);
  • the best treatment effect of patient B was PR (partial response).
  • target lesions 55.9mm
  • non-target lesions mediastinal lymph nodes, left lower lobe nodules, spleen nodules;
  • target lesions 39mm
  • non-target lesions Non-CR/Non-PD
  • the best treatment effect of patient C was PR (partial response).

Landscapes

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

Abstract

La présente invention concerne une composition pharmaceutique combinée d'un anticorps anti-PD-L1 et d'un inhibiteur de la kinase c-Met pour le traitement du cancer du poumon, et plus particulièrement, une composition pharmaceutique combinée d'un anticorps anti-PD-L1 et de N-(4-((7-((1-(cyclopentylamino)cyclopropyl)méthoxy)-6-méthoxyquinolin-4-yl)oxy)-3-fluorophényl)-N-(4-fluorophényl)cyclopropane-1, 1-diméthylamide pour le traitement du cancer du poumon, et une utilisation de la composition pharmaceutique combinée dans le traitement du cancer du poumon.
PCT/CN2021/133386 2020-11-26 2021-11-26 Composition pharmaceutique combinée d'un anticorps anti-pd-l1 et d'un inhibiteur de la kinase c-met pour le traitement du cancer du poumon WO2022111618A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
MX2023005930A MX2023005930A (es) 2020-11-26 2021-11-26 Composicion farmaceutica combinada de anticuerpo anti-ligando de muerte programada 1 e inhibidor de cinasa c-met para tratar cancer de pulmon.
CN202180078291.4A CN116437957A (zh) 2020-11-26 2021-11-26 用于治疗肺癌的抗PD-L1抗体和c-Met激酶抑制剂的联用药物组合物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202011350770 2020-11-26
CN202011350770.0 2020-11-26

Publications (1)

Publication Number Publication Date
WO2022111618A1 true WO2022111618A1 (fr) 2022-06-02

Family

ID=81755321

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/133386 WO2022111618A1 (fr) 2020-11-26 2021-11-26 Composition pharmaceutique combinée d'un anticorps anti-pd-l1 et d'un inhibiteur de la kinase c-met pour le traitement du cancer du poumon

Country Status (3)

Country Link
CN (1) CN116437957A (fr)
MX (1) MX2023005930A (fr)
WO (1) WO2022111618A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024120483A1 (fr) * 2022-12-08 2024-06-13 正大天晴药业集团股份有限公司 Utilisation d'un composé de quinoléine pour le traitement du cancer de l'ovaire
WO2024120520A1 (fr) * 2022-12-09 2024-06-13 正大天晴药业集团股份有限公司 Utilisation d'un composé de quinoléine dans le traitement du cancer du poumon à petites cellules

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2012200204A1 (en) * 2003-09-22 2012-02-09 Eisai R&D Management Co., Ltd. Hemiasterlin derivatives and uses thereof
CN107750166A (zh) * 2015-06-16 2018-03-02 默克专利股份有限公司 Pd‑l1 拮抗剂组合治疗
CN108883180A (zh) * 2016-02-05 2018-11-23 奥里尼斯生物科学公司 Clec9a结合剂及其用途
WO2019173523A1 (fr) * 2018-03-07 2019-09-12 Genmab A/S Conjugués de médicament et d'anticorps anti-facteur tissulaire, et leur utilisation dans le traitement du cancer
CN111617243A (zh) * 2019-02-28 2020-09-04 正大天晴药业集团股份有限公司 喹啉衍生物与抗体的药物组合
CN111936467A (zh) * 2018-03-02 2020-11-13 正大天晴药业集团股份有限公司 作为c-Met激酶抑制剂的化合物的结晶及其制备方法和用途
CN111973739A (zh) * 2019-05-23 2020-11-24 正大天晴药业集团股份有限公司 抗pd-l1单克隆抗体治疗癌症的用途

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2012200204A1 (en) * 2003-09-22 2012-02-09 Eisai R&D Management Co., Ltd. Hemiasterlin derivatives and uses thereof
CN107750166A (zh) * 2015-06-16 2018-03-02 默克专利股份有限公司 Pd‑l1 拮抗剂组合治疗
CN108883180A (zh) * 2016-02-05 2018-11-23 奥里尼斯生物科学公司 Clec9a结合剂及其用途
CN111936467A (zh) * 2018-03-02 2020-11-13 正大天晴药业集团股份有限公司 作为c-Met激酶抑制剂的化合物的结晶及其制备方法和用途
WO2019173523A1 (fr) * 2018-03-07 2019-09-12 Genmab A/S Conjugués de médicament et d'anticorps anti-facteur tissulaire, et leur utilisation dans le traitement du cancer
CN111617243A (zh) * 2019-02-28 2020-09-04 正大天晴药业集团股份有限公司 喹啉衍生物与抗体的药物组合
CN111973739A (zh) * 2019-05-23 2020-11-24 正大天晴药业集团股份有限公司 抗pd-l1单克隆抗体治疗癌症的用途

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024120483A1 (fr) * 2022-12-08 2024-06-13 正大天晴药业集团股份有限公司 Utilisation d'un composé de quinoléine pour le traitement du cancer de l'ovaire
WO2024120520A1 (fr) * 2022-12-09 2024-06-13 正大天晴药业集团股份有限公司 Utilisation d'un composé de quinoléine dans le traitement du cancer du poumon à petites cellules

Also Published As

Publication number Publication date
CN116437957A (zh) 2023-07-14
MX2023005930A (es) 2023-05-29

Similar Documents

Publication Publication Date Title
US11666572B2 (en) Treatment of HER2 positive cancers
CN113347996B (zh) 治疗肿瘤的联用药物组合物
TW201922793A (zh) Ｐｄ－１抗體和ｖｅｇｆｒ抑制劑聯合治療小細胞肺癌的用途
WO2020187152A1 (fr) Composition pharmaceutique combinée pour le traitement du cancer du poumon à petites cellules
WO2022111618A1 (fr) Composition pharmaceutique combinée d'un anticorps anti-pd-l1 et d'un inhibiteur de la kinase c-met pour le traitement du cancer du poumon
WO2020249018A1 (fr) Composition pharmaceutique combinée pour le traitement du cancer du poumon positif aux gènes "conducteurs"
CN113018429A (zh) 治疗卵巢癌的药物组合
WO2021244551A1 (fr) Composition pharmaceutique combinée d'inhibiteur de kinase c-met et d'anticorps anti-pd-l1
JP2022553041A (ja) Ｈｅｒ２陽性乳がんをカペシタビンおよびトラスツズマブと併用してツカチニブで治療する方法
WO2020239085A1 (fr) Composition pharmaceutique combinée pour le traitement du mélanome
KR20230098279A (ko) Pdx 억제제 또는 독소루비신과 ahr 억제제의 조합
WO2021213523A1 (fr) Utilisations d'une combinaison d'anticorps anti-pd-1 et d'anticorps anti-ctla-4 dans la prévention ou le traitement du cancer
WO2022002153A1 (fr) Médicament pour le traitement de tumeur
CN112915202A (zh) 喹啉衍生物与pd-1单抗的药物组合
CN114667159B (zh) 喹啉衍生物与pd-1单抗的药物组合
WO2023198060A1 (fr) Association pharmaceutique d'inhibiteur de protéasome et d'anticorps anti-pd-1
CN117085124A (zh) 一种包含抗PD-L1抗体和c-Met激酶抑制剂的药物组合
WO2023174278A1 (fr) Composition pharmaceutique d'anticorps anti-tim-3 et d'agent d'hypométhylation
CN117085123A (zh) 抗PD-L1抗体和c-Met激酶抑制剂的药物组合
WO2023230429A1 (fr) Méthodes de traitement du cancer colorectal avec du tucatinib en combinaison avec un anticorps anti-her2
WO2023072043A1 (fr) Médicament combiné pour traitement de tumeurs
CN116761610A (zh) Ahr抑制剂和其用途
JP2023514795A (ja) がんを処置するための方法および組成物
CN116209466A (zh) 抗pd-1抗体在治疗鼻咽癌中的用途

Legal Events

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

Ref document number: 21897118

Country of ref document: EP

Kind code of ref document: A1

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112023009786

Country of ref document: BR

REG Reference to national code

Ref country code: BR

Ref legal event code: B01E

Ref document number: 112023009786

Country of ref document: BR

Free format text: COM BASE NA PORTARIA 48 DE 20/06/2022, SOLICITA-SE QUE SEJA APRESENTADO NOVO CONTEUDO DE LISTAGEM DE SEQUENCIA CONTENDO TODOS OS CAMPOS OBRIGATORIOS, UMA VEZ QUE A LISTAGEM APRESENTADA NA PETICAO NO 870230042914 DE 22/05/2023 ESTA INCOMPLETA, POIS NAO FORAM INCLUIDOS OS CAMPOS 140 / 141 QUE JA ERA CONHECIDO NO MOMENTO DO PROTOCOLO.

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 112023009786

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20230519

122 Ep: pct application non-entry in european phase

Ref document number: 21897118

Country of ref document: EP

Kind code of ref document: A1