Nothing Special   »   [go: up one dir, main page]

CN110680919A - Application of CDK4/6 inhibitor in preparation of medicine for treating tumors in combination with immunotherapy - Google Patents

Application of CDK4/6 inhibitor in preparation of medicine for treating tumors in combination with immunotherapy Download PDF

Info

Publication number
CN110680919A
CN110680919A CN201910602910.XA CN201910602910A CN110680919A CN 110680919 A CN110680919 A CN 110680919A CN 201910602910 A CN201910602910 A CN 201910602910A CN 110680919 A CN110680919 A CN 110680919A
Authority
CN
China
Prior art keywords
antibody
seq
ser
cancer
thr
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201910602910.XA
Other languages
Chinese (zh)
Inventor
王泉人
戴宗飞
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jiangsu Hengrui Medicine Co Ltd
Suzhou Suncadia Biopharmaceuticals Co Ltd
Original Assignee
Jiangsu Hengrui Medicine Co Ltd
Suzhou Suncadia Biopharmaceuticals Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jiangsu Hengrui Medicine Co Ltd, Suzhou Suncadia Biopharmaceuticals Co Ltd filed Critical Jiangsu Hengrui Medicine Co Ltd
Publication of CN110680919A publication Critical patent/CN110680919A/en
Pending legal-status Critical Current

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/395Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents

Landscapes

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

Abstract

The present disclosure relates to the use of a CDK4/6 inhibitor in combination with immunotherapy for the preparation of a medicament for the treatment of tumors. Specifically, the application of the compound shown in the formula I or the pharmaceutically acceptable salt thereof in combination with an anti-PD-1 antibody or an antigen binding fragment thereof in preparing a medicament for treating tumors such as lung cancer, melanoma, breast cancer, liver cancer, stomach cancer, intestinal cancer and kidney cancer is provided, and the scheme shows the synergistic effect of combined medication.
Figure DDA0002119791330000011

Description

Application of CDK4/6 inhibitor in preparation of medicine for treating tumors in combination with immunotherapy
Technical Field
The disclosure relates to the use of a CDK4/6 inhibitor in combination with immunotherapy for the preparation of a medicament for the treatment of tumors.
Background
Numerous studies have found that tumors are associated with cell cycle deregulation, and most tumors have a number of mutations in mitotic signaling proteins/antimitotic signaling protein defects, Genomic Instability (GIN) and genomic instability (CIN), all three basic cell cycle defects being caused directly or indirectly by deregulation of Cyclin Dependent Kinases (CDKs). Cyclins Cyclin B/CDK1, Cyclin A/CDK2, Cyclin E/CDK2, Cyclin D/CDK4, Cyclin D/CDK6 and other heterodimers (including CDK3 and CDK7) are important regulators of cell cycle progression. Several CDK inhibitors have been disclosed, among which CDK4/6 inhibitors are abemaciclib, ribociclib, palbociclib, etc. W02014183520 provides a potent CDK4/6 inhibitor having the structure shown in formula I, WO2016124067 discloses isethionate salts of the aforementioned novel CDK4/6 inhibitors,
tumor immunotherapy has focused on methods to enhance the anti-tumor immune response by adoptive transfer of activated effector cells, immunization against relevant antigens, or providing non-specific immune stimulators such as cytokines. The development of specific immune checkpoint pathway inhibitors has begun to become a new immunotherapeutic approach for the treatment of cancer, e.g., the CTLA antibody Ipilimumab for the treatment of advanced melanoma
Figure BDA0002119791310000012
(Hodi et al, 2010) that specifically binds programmed death receptor (PD-1) nivolumab or pembrolizumab. WO2015085847A also discloses a novel anti-PD-1 antibody, which is in clinical trials and has been shown to be somewhat anti-tumorAnd (4) acting.
In recent years, tumor immunotherapy has made a breakthrough. Several clinical studies have shown that anti-PD-1/PD-L1 antibody shows unusual therapeutic effects in several advanced solid tumors, such as melanoma, renal carcinoma, non-small cell lung cancer, triple negative breast cancer, etc., with an objective effective rate (ORR) of about 10% -40% among different solid tumors, with the highest (about 36% -53%) among malignant melanoma. However, many patients with advanced colorectal cancer do not obtain good curative effect by using the anti-PD-1/PD-L1 antibody alone, so that the finding of a targeted drug which can be combined with the anti-PD-1/PD-L1 antibody and enhance the curative effect is urgent.
Studies by Zhang et al (Nature vol 553, pages 91-95) have found that the abundance of PD-L1 protein is regulated by cyclin D-CDK4 kinase and Cullin 3-SPOP E3 ligase, and the regulation process belongs to a classical proteasome mediated degradation pathway. In vivo studies found that CDK4/6 inhibitors promote FZR1 to degrade SPOP and increase PD-L1 expression by blocking cyclin D-CDK4 from mediating the phosphorylation of speckle-type poz (SPOP) proteins. This article lays the theoretical foundation for the enhancement of anti-tumor immunotherapy by the PD-L1 antibody in combination with CDK4/6 inhibitors.
Recently, the compendium and the mershadong company developed a clinical trial of the CDK4/6 inhibitor, bmaxinib (Abemaciclib), in combination with specific binding to the programmed death receptor (PD-1) Pembrolizumab for the treatment of breast and non-small cell lung cancer (NCT 02779751).
These studies have generated significant interest to scientists in the field of immunotherapy involving the administration of CDK4/6 inhibitors in combination.
Disclosure of Invention
The disclosure provides an application of a compound shown in a formula I or a pharmaceutically acceptable salt thereof in combination with an anti-PD-1 antibody or an antigen binding fragment thereof in preparing a medicament for treating tumors,
in alternative embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof in the present disclosure is selected from the group consisting of AMP-224, GLS-010, IBI-308, REGN-2810, PDR-001, BGB-A317, Pidilizumab, PF-06801591, Genolimzumab, CA-170, MEDI-0680, JS-001, TSR-042, Camrelizumab, Pembrolizumab, LZM-009, AK-103, and Nivolumab.
In some embodiments, the light chain variable region of the anti-PD-1 antibody or antigen-binding fragment thereof comprises LCDR1, LCDR2, and LCDR3 as shown in SEQ ID No. 4, SEQ ID No. 5, and SEQ ID No. 6, respectively; the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO 1, SEQ ID NO 2, and SEQ ID NO 3, respectively.
Wherein, the CDR sequences are shown in the following table:
Figure BDA0002119791310000022
Figure BDA0002119791310000031
preferably, the PD-1 antibody is a humanized antibody.
Further, it is preferred that the humanized antibody light chain variable region sequence is the sequence shown in SEQ ID NO 10 or a variant thereof, said variant preferably having 0 to 10 amino acid changes in the light chain variable region, more preferably the amino acid change of A43S; the humanized antibody heavy chain variable region sequence is shown as SEQ ID NO. 9 or its variant, and the variant has preferably amino acid change of 0-10, preferably G44R in the heavy chain variable region.
The variable region sequences of the heavy and light chains of the humanized antibody are shown as follows:
heavy chain variable region
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISGGGANTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARQLYYFDYWGQGTTVTVSS
SEQID NO:9
Light chain variable region
DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIK
SEQ ID NO:10 in an alternative embodiment, the humanized antibody light chain sequence is that shown as SEQ ID NO. 8 or a variant thereof; the variant preferably has 0-10 amino acid changes in the light chain variable region, more preferably the amino acid change of A43S; the humanized antibody heavy chain sequence is shown as SEQ ID NO. 7 or its variant, and the variant has preferably amino acid change of 0-10, more preferably G44R in the heavy chain variable region.
In a preferred embodiment, the light chain sequence of the humanized antibody is as shown in SEQ ID NO 8 and the heavy chain sequence is as shown in SEQ ID NO 7.
The sequences of the heavy chain and the light chain of the humanized antibody are shown as follows:
heavy chain
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISGGGANTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARQLYYFDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
SEQID NO:7
Light chain
DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQID NO:8
Further, in alternative embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof of the present disclosure is administered at a dose of 0.1-10.0 mg/kg, which may be 0.1mg/kg, 0.2mg/kg, 0.3mg/kg, 0.4mg/kg, 0.5mg/kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg, 1.0mg/kg, 1.2mg/kg, 1.4mg/kg, 1.6mg/kg, 1.8mg/kg, 2.0mg/kg, 2.2mg/kg, 2.4mg/kg, 2.6mg/kg, 2.8mg/kg, 3.0mg/kg, 3.2mg/kg, 3.4mg/kg, 3.6mg/kg, 3.8mg/kg, 4.0mg/kg, 4.2mg/kg, 4.6mg/kg, 4mg/kg, 4.5 mg/kg, 4mg/kg, 4.6mg/kg, 4mg/kg, 5.2mg/kg, 5.4mg/kg, 5.6mg/kg, 5.8mg/kg, 6.0mg/kg, 6.2mg/kg, 6.4mg/kg, 6.6mg/kg, 6.8mg/kg, 7.0mg/kg, 7.2mg/kg, 7.4mg/kg, 7.6mg/kg, 7.8mg/kg, 8.0mg/kg, 8.2mg/kg, 8.4mg/kg, 8.6mg/kg, 8.8mg/kg, 9.0mg/kg, 9.2mg/kg, 9.4mg/kg, 9.6mg/kg, 9.8mg/kg, 10.0 mg/kg.
In another alternative embodiment, the PD-1 antibody or antigen-binding fragment thereof is present in an amount of 1-600 mg, which may be 1.0mg, 1.2mg, 1.4mg, 1.6mg, 1.8mg, 2.0mg, 2.2mg, 2.4mg, 2.6mg, 2.8mg, 3.0mg, 3.2mg, 3.4mg, 3.6mg, 3.8mg, 4.0mg, 4.2mg, 4.4mg, 4.6mg, 4.8mg, 5.0mg, 5.2mg, 5.4mg, 5.6mg, 5.8mg, 6.0mg, 6.2mg, 6.4mg, 6.6mg, 6.8mg, 7.0mg, 7.2mg, 7.4mg, 7.6mg, 7.8mg, 8.0mg, 8.2mg, 8.4mg, 8.6mg, 6.8mg, 7.0mg, 7.2mg, 7.4mg, 7.6mg, 7.8mg, 9.120 mg, 9.25 mg, 9.95 mg, 9.45 mg, 20mg, 100mg, 6mg, 9.95 mg, 6mg, 9.95 mg, 6mg, 6.95 mg, 100mg, 6mg, 25mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 305mg, 310mg, 315mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg, 365mg, 370mg, 375mg, 380mg, 385mg, 540mg, 395mg, 400mg, 405mg, 410mg, 415mg, 420mg, 425mg, 430mg, 435mg, 440mg, 445mg, 450mg, 455mg, 460mg, 465mg, 470mg, 475mg, 485mg, 490mg, 505mg, 500mg, 505mg, 520mg, 535mg, 530mg, 565mg, 530mg, 150mg, 545mg, 575mg, 580mg, 585mg, 590mg, 595mg, 600 mg.
The anti-PD-1 antibody or antigen-binding fragment thereof in the present disclosure is administered once a week, once a three week, once a four week, or once a month; the compound shown in the formula I or the pharmaceutically acceptable salt thereof is administered once a day, twice a day, three times a day, once a week, once a three week, once a four week or once a month.
The combination of a compound of formula I or a pharmaceutically acceptable salt thereof as described in this disclosure has a synergistic pharmacodynamic effect with an anti-PD-1 antibody or antigen-binding fragment thereof.
In alternative embodiments, the dosage of a compound of formula I, or a pharmaceutically acceptable salt thereof, as described in this disclosure is selected from 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 175mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, 1000 mg.
Further, in an alternative embodiment, the dosage of the anti-PD-1 antibody or the antigen-binding fragment thereof is 1-600 mg, and the dosage of the compound represented by the formula I or the pharmaceutically acceptable salt thereof is 20-500 mg.
In an alternative embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof is dosed at 1-600 mg once every 1-4 weeks; the dosage of the compound shown in the formula I or the pharmaceutically acceptable salt thereof is 20-500 mg once a day.
In alternative embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is dosed at 200 mg; the compound shown in the formula I or the pharmaceutically acceptable salt thereof is 20-500 mg.
The route of administration described in the present disclosure may be oral, parenteral, transdermal, including but not limited to intravenous, subcutaneous, intramuscular.
In an alternative embodiment, the PD-1 antibody or antigen-binding fragment thereof is administered by injection, e.g., subcutaneously or intravenously, formulated in an injectable form prior to injection. Particularly preferred injectable forms of the PD-1 antibody or antigen-binding fragment thereof are injectable solutions or lyophilized powders, for example injectable forms of the PD-1 antibody comprising the PD-1 antibody, a buffer, a stabilizer, optionally further comprising a surfactant. The buffer can be one or more selected from acetate, citrate, succinate and phosphate. The stabilizer may be selected from sugars or amino acids, preferably disaccharides, such as sucrose, lactose, trehalose, maltose. The surfactant is selected from polyoxyethylene hydrogenated castor oil, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, preferably the polyoxyethylene sorbitan fatty acid ester is polysorbate 20, 40, 60 or 80, most preferably polysorbate 20.
The pharmaceutically acceptable salts of the drugs described in this disclosure may be hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, acetate, oxalate, malonate, valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, methanesulfonate, isethionate, maleate. Malate, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate, succinate, gluconate, lactobionate or laurylsulfonate salts, and the like.
In some embodiments, the pharmaceutically acceptable salt of the compound of formula I is selected from isethionate.
In some embodiments, the isethionate salt of the compound of formula I is administered in combination with the PD-1 antibody or antigen-binding fragment thereof, thereby enhancing anti-tumor activity and improving the therapeutic efficacy of the tumor disease.
Further, in an alternative embodiment, the tumor patient in the present disclosure has received a tumor therapy selected from one or more of chemotherapy, immunotherapy, surgery, radiotherapy or vaccine, preferably from chemotherapy.
In some embodiments, the tumor patient has a relative reduction in target lesion diameter of at least 30%.
In some embodiments, the tumor patient has a relative increase in target lesion diameter of at least 20% or the appearance of one or more new lesions.
In some embodiments, the tumor patient has a relative increase in target lesion diameter of at most 20% or a relative decrease in target lesion diameter of at most 30%.
Further, the tumor patient failed the treatment.
Chemotherapy in the present disclosure refers to the treatment by administering a compound for the treatment of tumors selected from, but not limited to, alkylating agents, such as thiotepa, cyclophosphamide, ifosfamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as bendazol, carbaquinone, meteedopa and uredopa; methylmelamines including altretamine, triethyleneamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethlamelamine; beta-lapachone (beta-lapachone); camptothecin (camptothecin) (including the synthetic analogs topotecan (topotecan), CPT-11 (irinotecan), acetylcamptothecin (acetylcamptothecin), scolecitin (scopolectin) and 9-aminocamptothecin), bryocin (bryostatin), calystatin (callystatin), CC-1065 (including adozelesin), cazelesin (carzelesin), nitrogen mustards such as chlorambucil, chlorambucil (chloremazine), estramustine (estramustine), anticancer metabolites such as methotrexate and 5-fluorouracil (5-fluorouracil) (5-FU), folic acid analogs such as denopterin, pterin, pteropterin (tripterytin), triptolide (triptolide), testosterone (5-fluorouracil), androgenic acid analogs such as nortriptolide (dinoteosine), steroids (testosterone (medrysothiazine), steroids (such as testosterone), steroids (medrysothiazine), steroids (medryptone), steroids (such as testosterone), steroids (medryptone), steroids (testosterone), steroids (5-fluorotestosterone) (5-FU), such as retinoic acid (retinic acid); capecitabine (capecitabine); PARP inhibitors, such as olaparib, fluxaparib; VEGFR-2 inhibitors, such as at least one of Foretinib and Tafetinib, or pharmaceutically acceptable salts, acids or derivatives thereof.
The combinations described in this disclosure optionally also contain other components including, but not limited to, other antineoplastic agents and the like.
Also provided in the present disclosure is a method of treating a tumor, comprising: administering an effective dose of an anti-PD-1 antibody or an antigen-binding fragment thereof and a compound of formula I or a pharmaceutically acceptable salt thereof to a patient with a tumor.
Further, the tumor patient has also received a tumor treatment, preferably chemotherapy.
In alternative embodiments, the tumor patient has a relative increase in target lesion diameter of at least 20% or the appearance of one or more new lesions.
In an alternative embodiment, the tumor patient has a relative reduction in target lesion diameter of at least 30%.
In alternative embodiments, the tumor patient has a relative increase in target lesion diameter of at most 20% or a relative decrease in target lesion diameter of at most 30%.
Preferably, the tumor patient has failed therapy.
The tumors in the present disclosure are selected from lung cancer (e.g., non-small cell lung cancer (NSCLC) including squamous carcinoma, adenocarcinoma (e.g., large cell carcinoma) and bronchoalveolar carcinoma), melanoma (e.g., advanced melanoma), breast cancer, liver cancer (e.g., hepatocellular carcinoma), gastric cancer, intestinal cancer (e.g., advanced colorectal cancer), renal cancer (e.g., renal cell carcinoma), preferably from non-small cell lung cancer, advanced colorectal cancer, hepatocellular carcinoma, advanced melanoma, metastatic renal cell carcinoma.
The present disclosure also provides a method of reducing adverse effects caused by an anti-PD-1 antibody or an antigen-binding fragment thereof, a compound of formula I, or a pharmaceutically acceptable salt thereof, comprising administering to a patient having a tumor an effective amount of an anti-PD-1 antibody or an antigen-binding fragment thereof and a compound of formula I, or a pharmaceutically acceptable salt thereof, simultaneously.
Also provided in the present disclosure is a method of reducing the separate administered doses of a PD-1 antibody or antigen-binding fragment thereof, a compound of formula I, or a pharmaceutically acceptable salt thereof, comprising simultaneously administering to a patient having a tumor an effective dose of an anti-PD-1 antibody or antigen-binding fragment thereof and a compound of formula I, or a pharmaceutically acceptable salt thereof.
Unless otherwise explained, terms in this disclosure have the following meanings:
the term "humanized antibody" in the present disclosure, also referred to as CDR-grafted antibody (CDR-grafted antibody), refers to an antibody produced by grafting mouse CDR sequences into a human antibody variable region framework, i.e., a framework sequence of a different type of human germline antibody. Can overcome the strong antibody variable antibody reaction induced by the chimeric antibody because of carrying a large amount of mouse protein components. Such framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences. Germline DNA Sequences of genes such as the human heavy and light chain variable regions can be found in the "VBase" human germline sequence database (available on the Internet www.mrccpe.com.ac.uk/VBase), as well as in Kabat, E.A. et al, 1991Sequences of Proteins of Immunological Interest, 5 th edition. In a preferred embodiment of the disclosure, the CDR sequences of the humanized antibody PD-1 are selected from the group consisting of SEQ ID NO 1, 2, 3, 4, 5, 6.
The term "antigen-binding fragment" as used in the present disclosure refers to Fab fragments, Fab 'fragments, F (ab') 2 fragments, and Fv fragments, sFv fragments, which bind to human PD-1, having antigen-binding activity; comprising one or more CDR regions selected from SEQ ID NO 1 to SEQ ID NO 6 of an antibody described in the present disclosure. The Fv fragment contains the variable regions of the antibody heavy and light chains, but lacks the constant region, and has the smallest antibody fragment with the entire antigen-binding site. Generally, Fv antibodies also comprise a polypeptide linker between the VH and VL domains and are capable of forming the structures required for antigen binding. Two antibody variable regions can also be joined together with different linkers into a single polypeptide chain, known as single chain antibodies (scFv) or single chain fv (sFv). The term "binds to PD-1" in the present disclosure means capable of interacting with human PD-1. The term "antigen binding site" in the present disclosure refers to a three-dimensional spatial site that is not contiguous on an antigen and is recognized by an antibody or antigen binding fragment of the present disclosure.
The term "immunotherapy" as used in the present disclosure refers to the immunotherapy of diseases by using the immune system, and in the present disclosure mainly refers to the stimulation and enhancement of the anti-tumor immune response of the body by increasing the immunogenicity and sensitivity of tumor cells to killing by effector cells, and the infusion of immune cells and effector molecules into the host body, which cooperate with the immune system of the body to kill tumor and inhibit tumor growth.
The disclosure with respect to "combination" is a mode of administration and refers to the administration of at least one dose of a CDK4/6 inhibitor compound of formula I or a pharmaceutically acceptable salt thereof and at least one dose of a PD-1 antibody or antigen-binding fragment thereof, wherein both substances exhibit pharmacological effects over a period of time. The time period may be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours, more preferably within 12 hours. The CDK4/6 inhibitor compound of formula I or a pharmaceutically acceptable salt thereof and the PD-1 antibody or antigen-binding fragment thereof may be administered simultaneously or sequentially. Such term includes treatments in which the CDK4/6 inhibitor compound of formula I or a pharmaceutically acceptable salt thereof and the PD-1 antibody or antigen-binding fragment thereof are administered by the same route of administration or different routes of administration. The mode of administration of the combinations described in this disclosure is selected from simultaneous administration, independently formulated and co-administered or independently formulated and administered sequentially.
An "effective amount" as referred to in this disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on the following factors: such as the condition to be treated, the general health of the patient, the method and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.
As used in this disclosure, "treatment failure" refers to a subject at baseline with measurable tumor lesions, either disease Progression (PD) or intolerance according to RECIST1.1 efficacy assessment criteria.
The term "intolerant" in this disclosure means that adverse effects due to the drug are not amenable to further treatment.
Overall Survival (OS) refers to the period from random to death due to any cause. Subjects who survived the last visit had OS scored as data loss at the time of the last visit. Subjects who were missed their OS were data loss as the last confirmed survival time before the missed visit. The OS of data erasure is defined as the time from random grouping to erasure.
Objective Response Rate (ORR) refers to the proportion of patients whose tumors have shrunk to a certain extent and are maintained for a certain period of time, including cases of CR and PR. Objective tumor remission was assessed using the criteria for tumor remission assessment (RECIST1.1 criteria). Subjects must be accompanied by measurable tumor lesions at baseline, and the criteria for efficacy assessment are divided into Complete Remission (CR), Partial Remission (PR), Stable (SD), Progression (PD) according to RECIST1.1 criteria.
Disease Control Rate (DCR) refers to the percentage of confirmed cases of complete remission, partial remission, and stable Disease (> 8 weeks) among patients with evaluable efficacy.
Complete Remission (CR): all target lesions disappeared and the short diameter of all pathological lymph nodes (including target and non-target nodes) had to be reduced to < 10 mm.
Partial Remission (PR): the sum of the target lesion diameters is reduced by at least 30% from baseline levels.
Disease Progression (PD): the diameter and relative increase is at least 20% with respect to the minimum of the sum of all measured target lesion diameters throughout the experimental study (baseline values are referenced if the baseline measurement is minimal); in addition to this, it must be satisfied that the absolute value of the sum of the diameters increases by at least 5mm (the appearance of one or more new lesions is also considered as disease progression).
Disease Stability (SD): the target lesion was decreased to a degree that did not reach PR and increased to a degree that did not reach PD levels, between which the minimum of the sum of the diameters was considered for the study.
Isethionates of compounds of formula I of the present disclosure may be prepared according to the method described in WO2016124067, and other equipment or reagents used may be commercially available.
Drawings
FIG. 1: tumor volume change trend of four groups of mice after administration;
FIG. 2: body weight trend of four groups of mice after administration.
Detailed Description
The disclosure is further described below in conjunction with the following examples, which, however, do not limit the scope of the disclosure.
Example 1: curative effect of PD-1 antibody and CDK inhibitor on mouse colon cancer cell MC-38 transplantation tumor C57 human PD-1 transgenic mouse singly or in combination
1. Test antibodies and compounds
Compound A (PD-1 antibody, heavy and light chain sequences as in the present disclosure SEQ ID NO:7 and SEQ ID NO:8, 200 mg/vial, 20mg/mL for use): PBS is used for preparing 0.03mg/mL concentration, and the volume of the intraperitoneal injection is 10 mL/kg;
compound B (isethionate salt of the compound of formula I, prepared according to the method disclosed in CN201780000891.2, molecular weight: 572.67, purity: 99.22%): adopting 0.05mol/L citric acid, 0.5 percent CMC-Na and 0.5 percent Tween 80 to prepare 3mg/mL suspension, wherein the intragastric administration volume is 10 mL/kg;
control group was dosed with hIgG4(0.3 mg/kg): the stock solution of 13.0mg/mL is diluted to 0.03mg/mL by PBS and then is administered, and the volume of intraperitoneal injection is 10 mL/kg.
2. Laboratory animal
Human PD-1 transgenic C57 mouse, SPF, body weight 23-30 g, male. Purchased from south Beijing Galaxy Biopharmaceutical Co.
3. Test method
3.1C 57 human PD-1 transgenic mice were acclimatized in the laboratory for at least 5 days.
3.2 cell culture
Culturing mouse colon cancer cell MC38 in RPMI1640 medium containing 10% fetal calf serum, digesting the cell with EDTA-containing trypsin according to conventional method, passaging twice per week, placing at 37 deg.C and 5% CO2And continuing culturing in the incubator. Tumor cells in logarithmic growth phase will be used for in vivo establishment of transplanted tumor model. 3.3 tumor cell transplantation
Resuspended MC38 cells in PBS at 5X 1050.1 mL/volume was inoculated subcutaneously in the right flank of C57BL/6 mice when the average tumor volume reached 100-3At the same time, mice with moderate individual tumor volume were selected and divided into 4 groups of 7 mice each, and administration was started on the day of the division.
3.4 dosage and method of administration
Compound a, i.p., BIW × 6 (2 times weekly, 6 total doses);
compound B, oral gavage, QD × 19 (once daily for a total of 19 administrations). Specific drug dosing regimens are shown in table 1.
3.5 transplant tumor volume and mouse body weight determination
Tumor volume and body weight were measured 2 times per week and data were recorded.
3.6 data statistics
Using Excel 2010 statistical software: the average is calculated as Ave; the SD value is calculated as STDEV; SEM values were calculated as STDEV/SQRT; p-values for differences between groups were calculated as TTEST.
Tumor volume (V) was calculated as: v1/2 xlLong and long×LShort length 2
Relative volume (RTV) ═ VT/V0
Tumor inhibition rate (%) ═ CRTV-TRTV)/CRTV(%)
Wherein V0、VTTumor volumes at the beginning and end of the experiment, respectively. CRTV、TRTVRelative tumor volumes of the blank control group and the experimental group at the end of the experiment, respectively.
4. Test results
The experimental result shows that the compound A is injected into the abdominal cavity with 0.3mg/kg (BIW multiplied by 6), the tumor inhibition rate reaches 37.25 percent on the 19 th day, and compared with a control group, the compound A has no statistical difference; the compound B is orally administrated, and the gastric lavage is carried out at 30mg/kg (QD multiplied by 19), the tumor inhibition rate of the compound B when being singly used at 19 days can reach 42.16 percent, and the compound B has significant difference (P is less than 0.05) compared with a control group; the tumor inhibition rate of the compound A (0.3mg/kg) and the compound B (30mg/kg) combined group can reach 75.68 percent, and the compound A and the compound B show statistical difference (P is less than 0.05) with the control group and the compound B single group. In conclusion, the combination of the compound A (0.3mg/kg) and the compound B (30mg/kg) has a synergistic anti-tumor effect, and the drug effect is obviously better than that of the compound A and the compound B which are used singly. The weight of each group of mice after administration is normal, and the medicament has no obvious toxic or side effect. The data are shown in Table 1 and FIGS. 1-2.
TABLE 1
Figure BDA0002119791310000101
Figure BDA0002119791310000111
Example 2:
grouping standard:
the subjects included are patients with histologically or cytologically confirmed advanced and/or metastatic colorectal cancer, advanced (IIIB/IV) non-small cell lung cancer; or patients with advanced liver cancer that are histologically or cytologically confirmed or clinically confirmed;
or
Subjects who were enrolled were patients who failed second-line and above-second-line treatment of advanced colorectal cancer and non-small cell lung cancer, and patients who failed first-line and above-first-line treatment of liver cancer, who had not been treated with either the PD-1 antibody or CDK4/6 inhibitor.
The administration scheme is as follows:
drug a (PD-1, prepared according to the method in patent application WO 2017054646A): dose 200mg, intravenous injection, 1 dose for 2 weeks, 1 cycle every 4 weeks;
drug B (isethionate tablet of the compound of formula I, prepared according to the method disclosed in CN 107405350A): 125 mg/tablet, is taken orally 1 time a day, 1 time each time, and is taken continuously for 3 weeks and 1 week, 4 weeks are 1 cycle.
And (4) conclusion: of the 6 subjects evaluated for therapeutic effect, 4 patients with colorectal cancer showed Stable Disease (SD), 1 patient with colorectal cancer showed disease Progression (PD), 1 patient with liver cancer showed disease Progression (PD), and Disease Control Rate (DCR) was 66.7%.
Sequence listing
<110> Hengrui pharmaceutical Co., Ltd of Jiangsu
Suzhou Shengdiya biomedical Co Ltd
<120> use of CDK4/6 inhibitor in combination with immunotherapy for the preparation of a medicament for the treatment of tumors
<160>10
<170>SIPOSequenceListing 1.0
<210>1
<211>5
<212>PRT
<213> mouse source (Mus musculus)
<400>1
Ser Tyr Met Met Ser
1 5
<210>2
<211>17
<212>PRT
<213> mouse source (Mus musculus)
<400>2
Thr Ile Ser Gly Gly Gly Ala Asn Thr Tyr Tyr Pro Asp Ser Val Lys
1 5 10 15
Gly
<210>3
<211>7
<212>PRT
<213> mouse source (Mus musculus)
<400>3
Gln Leu Tyr Tyr Phe Asp Tyr
1 5
<210>4
<211>11
<212>PRT
<213> mouse source (Mus musculus)
<400>4
Leu Ala Ser Gln Thr Ile Gly Thr Trp Leu Thr
1 5 10
<210>5
<211>7
<212>PRT
<213> mouse source (Mus musculus)
<400>5
Thr Ala Thr Ser Leu Ala Asp
1 5
<210>6
<211>9
<212>PRT
<213> mouse source (Mus musculus)
<400>6
Gln Gln Val Tyr Ser Ile Pro Trp Thr
1 5
<210>7
<211>443
<212>PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221>PEPTIDE
<222>(1)..(443)
<223> heavy chain sequence
<400>7
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Met Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Gly Gly Gly Ala Asn Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Leu Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
210 215 220
Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
290 295 300
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210>8
<211>214
<212>PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221>PEPTIDE
<222>(1)..(214)
<223> light chain sequence
<400>8
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Leu Ala Ser Gln Thr Ile Gly Thr Trp
20 25 30
Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Thr Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Tyr Ser Ile Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210>9
<211>116
<212>PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221>PEPTIDE
<222>(1)..(116)
<223> heavy chain variable region
<400>9
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Met Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Gly Gly Gly Ala Asn Thr Tyr Tyr Pro Asp Ser Val
5055 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Leu Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210>10
<211>107
<212>PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221>PEPTIDE
<222>(1)..(10)
<223> light chain variable region
<400>10
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Leu Ala Ser Gln Thr Ile Gly Thr Trp
20 25 30
Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Thr Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Tyr Ser Ile Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105

Claims (12)

1. The application of the compound shown in the formula I or the medicinal salt thereof and anti-PD-1 antibody or antigen binding fragment thereof in preparing the medicament for treating the tumor,
2. the use of claim 1, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is selected from the group consisting of: AMP-224, GLS-010, IBI-308, REGN-2810, PDR-001, BGB-A317, Pidilizumab, PF-06801591, Genolimzumab, CA-170, MEDI-0680, JS-001, TSR-042, Camrelizumab, Pembrolizumab, LZM-009, AK-103, and Nivolumab.
3. The use of claim 1, wherein the light chain variable region of the anti-PD-1 antibody or antigen-binding fragment thereof comprises LCDR1, LCDR2 and LCDR3 as set forth in SEQ ID No. 4, SEQ ID No. 5 and SEQ ID No. 6, respectively, and the heavy chain variable region of the PD-1 antibody comprises HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID No. 1, SEQ ID No. 2 and SEQ ID No. 3, respectively.
4. The use of claim 3, wherein the anti-PD-1 antibody is a humanized antibody.
5. The use of claim 4, wherein the light chain variable region sequence of the humanized antibody is the sequence shown as SEQ ID NO 10 or a variant thereof, preferably having 0-10 amino acid changes in the light chain variable region, more preferably the amino acid change of A43S; the heavy chain variable region sequence of the humanized antibody is shown as SEQ ID NO. 9 or a variant thereof, wherein the variant preferably has 0-10 amino acid changes in the heavy chain variable region, and more preferably has G44R amino acid changes.
6. The use of claim 4, wherein the light chain sequence of the humanized antibody is the sequence shown in SEQ ID NO 8 or a variant thereof, preferably having 0-10 amino acid changes in the light chain variable region, more preferably the amino acid change of A43S; the heavy chain sequence of the humanized antibody is shown as SEQ ID NO. 7 or a variant thereof, wherein the variant preferably has 0-10 amino acid changes in the heavy chain variable region, and more preferably has G44R amino acid changes.
7. The use of claim 6, wherein the humanized antibody has a light chain sequence as set forth in SEQ ID NO 8 and a heavy chain sequence as set forth in SEQ ID NO 7.
8. Use according to any one of claims 1 to 7, wherein the tumor is selected from lung cancer, melanoma, breast cancer, liver cancer, stomach cancer, intestinal cancer, kidney cancer, preferably from non-small cell lung cancer, advanced colorectal cancer, hepatocellular carcinoma, advanced melanoma, metastatic renal cell carcinoma.
9. The use of any one of claims 1-8, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose selected from the group consisting of 0.1-10.0 mg/kg.
10. The use according to any one of claims 1 to 9, wherein the dose of the compound of formula I or the pharmaceutically acceptable salt thereof is selected from 1 to 1000mg
11. The use of any one of claims 1-10, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 1-600 mg.
12. The use according to any one of claims 1 to 11, wherein the pharmaceutically acceptable salt of the compound of formula I is isethionate.
CN201910602910.XA 2018-07-06 2019-07-05 Application of CDK4/6 inhibitor in preparation of medicine for treating tumors in combination with immunotherapy Pending CN110680919A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201810734649 2018-07-06
CN2018107346494 2018-07-06
CN2018113521293 2018-11-14
CN201811352129 2018-11-14

Publications (1)

Publication Number Publication Date
CN110680919A true CN110680919A (en) 2020-01-14

Family

ID=69108143

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201910602910.XA Pending CN110680919A (en) 2018-07-06 2019-07-05 Application of CDK4/6 inhibitor in preparation of medicine for treating tumors in combination with immunotherapy

Country Status (1)

Country Link
CN (1) CN110680919A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114191557A (en) * 2020-09-02 2022-03-18 通化济达医药有限公司 Application of CDK4/6 inhibitor in preparation of anti-cancer drugs in combination with immunotherapy

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014183520A1 (en) * 2013-05-17 2014-11-20 上海恒瑞医药有限公司 Thiophene miazines derivate, preparation method therefor, and medical application thereof
WO2016100882A1 (en) * 2014-12-19 2016-06-23 Novartis Ag Combination therapies
CN106103485A (en) * 2014-01-24 2016-11-09 达纳-法伯癌症研究公司 Antibody molecule of PD 1 and application thereof
CN107003300A (en) * 2014-12-12 2017-08-01 凯尔科迪公司 ERBB signal transduction pathway activity is measured to diagnose the method with treating cancer patient
WO2017181109A1 (en) * 2016-04-15 2017-10-19 Michael Molloy Anti-human vista antibodies and use thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014183520A1 (en) * 2013-05-17 2014-11-20 上海恒瑞医药有限公司 Thiophene miazines derivate, preparation method therefor, and medical application thereof
CN106103485A (en) * 2014-01-24 2016-11-09 达纳-法伯癌症研究公司 Antibody molecule of PD 1 and application thereof
CN107003300A (en) * 2014-12-12 2017-08-01 凯尔科迪公司 ERBB signal transduction pathway activity is measured to diagnose the method with treating cancer patient
WO2016100882A1 (en) * 2014-12-19 2016-06-23 Novartis Ag Combination therapies
WO2017181109A1 (en) * 2016-04-15 2017-10-19 Michael Molloy Anti-human vista antibodies and use thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JIEHUI DENG等: ""CDK4/6 Inhibition Augments Anti-Tumor Immunity by Enhancing T Cell Activation"", 《CANCER DISCOV.》, vol. 8, no. 2, 3 November 2017 (2017-11-03), pages 2 - 3 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114191557A (en) * 2020-09-02 2022-03-18 通化济达医药有限公司 Application of CDK4/6 inhibitor in preparation of anti-cancer drugs in combination with immunotherapy

Similar Documents

Publication Publication Date Title
CN111065411B (en) Use of PD-1 antibody and VEGFR inhibitor for combined treatment of small cell lung cancer
TW202038957A (en) Combination of antibody-drug conjugate and kinase inhibitor
CN113768933B (en) Use of PARP inhibitors for the treatment of chemotherapy-resistant ovarian or breast cancers
WO2022052874A1 (en) Use of chiauranib in combination with immune checkpoint inhibitor in antitumor therapy
WO2018072743A1 (en) Use of pd-1 antibody conjugated with ido inhibitor in preparing anti-tumor drug
CN113811298A (en) Quinoline derivatives for the combined treatment of small cell lung cancer
CN118267469A (en) Combined pharmaceutical composition for treating driving gene positive lung cancer
TW202126302A (en) Use of ezh2 inhibitor in combination with immune checkpoint inhibitor for preparation of medicament for treating tumor diseases
CN111246881B (en) Use of PD-1 antibodies for treating tumors
WO2020239085A1 (en) Combined pharmaceutical composition for treating melanoma
CN112955148B (en) Use of CDK4/6 inhibitors in combination with immunotherapy for the preparation of a medicament for the treatment of lymphoma
CN110680919A (en) Application of CDK4/6 inhibitor in preparation of medicine for treating tumors in combination with immunotherapy
CN113840608A (en) Application of CDK4/6 inhibitor and VEGFR inhibitor in preparation of drugs for treating tumors
WO2021057764A1 (en) Use of pd-1 antibody in combination with taxoid compound in preparation of drugs for treating triple-negative breast cancer
CN118871128A (en) Pharmaceutical combinations of anti-TIM-3 antibodies and anti-PD-L1 antibodies
CN113491769A (en) Pharmaceutical combination
TWI822897B (en) Use of anti-pd-1 antibody in combination with famitinib for preparation of medicament for treating tumor diseases
RU2783846C1 (en) Application of an antibody to pd-1 in combination with famitinib for producing a medicinal product for treating tumours
CN110507820A (en) A kind of purposes of the antibody combined radiotherapy of anti-PD-1 in the drug of preparation treatment tumor patient
WO2021203769A1 (en) Use of anti-pd-1 antibody in preparation of drugs for treating acral lentiginous melanoma
CN118871129A (en) Pharmaceutical combinations of anti-TIM-3 antibodies and demethylated drugs
CN114191557A (en) Application of CDK4/6 inhibitor in preparation of anti-cancer drugs in combination with immunotherapy
WO2023111810A1 (en) Combination therapies and uses for treating cancer
US20220378776A1 (en) Drug combination of quinoline derivative and pd-1 monoclonal antibody
CN115779095A (en) Pharmaceutical composition of quinoline derivative and PD-1 monoclonal antibody for treating colorectal cancer

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20200114

WD01 Invention patent application deemed withdrawn after publication