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WO2020063863A1 - Utilisation d'un inhibiteur d'ezh2 en combinaison avec un inhibiteur de point de contrôle immunitaire dans la préparation d'un médicament pour le traitement de tumeurs - Google Patents

Utilisation d'un inhibiteur d'ezh2 en combinaison avec un inhibiteur de point de contrôle immunitaire dans la préparation d'un médicament pour le traitement de tumeurs Download PDF

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WO2020063863A1
WO2020063863A1 PCT/CN2019/108535 CN2019108535W WO2020063863A1 WO 2020063863 A1 WO2020063863 A1 WO 2020063863A1 CN 2019108535 W CN2019108535 W CN 2019108535W WO 2020063863 A1 WO2020063863 A1 WO 2020063863A1
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cancer
antibody
once
tumor
inhibitor
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PCT/CN2019/108535
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English (en)
Chinese (zh)
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张岚
蒋家骅
廖成
张连山
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江苏恒瑞医药股份有限公司
苏州盛迪亚生物医药有限公司
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Priority to CN201980049896.3A priority Critical patent/CN112512580B/zh
Publication of WO2020063863A1 publication Critical patent/WO2020063863A1/fr

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    • 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
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/495—Heterocyclic 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol

Definitions

  • the present disclosure relates to the use of an EZH2 inhibitor combined with an immune checkpoint inhibitor in the manufacture of a medicament for treating tumors.
  • Protein programmed death 1 is an inhibitory member of the CD28 receptor family, which also includes CD28, CTLA-4, ICOS, and BTLA. PD-1 is expressed on activated B cells, T cells, and myeloid cells (Agata et al., Supra; Okazaki et al. (2002) Curr. Opin. Immunol. 14: 391779-82; Bennett et al. (2003) J Immunol 170: 711-8). The original members of the family, CD28 and ICOS (Hutloff et al. (1999) Nature397: 263-266; Hansen et al.
  • PD-1 was discovered by screening for differential expression in apoptotic cells (Ishida et al. (1992) EMBOJ11: 3887-95).
  • Nivolumab by Ono and Pembrolizumab by Merck have been successfully approved for marketing for the treatment of unresectable or metastatic melanoma, non-small cell lung cancer, advanced renal cell carcinoma, Hodgkin lymphoma, recurrent or metastatic Squamous cell carcinoma.
  • PD-1 has two ligands, PD-L1 and PD-L2.
  • PD-L1 is mainly expressed on T cells, B cells, macrophages and dendritic cells (DCs).
  • the expression of PD-L1 on activated cells can be up-regulated.
  • PD-L1 inhibits the immune system by combining with PD-1 and B7-1.
  • Many tumor cells and immune cells in the tumor tissue microenvironment express PD-L1.
  • New research finds high PD-L1 in human tumor tissues such as breast cancer, lung cancer, stomach cancer, intestinal cancer, kidney cancer, melanoma, non-small cell lung cancer, colon cancer, bladder cancer, ovarian cancer, pancreatic cancer and liver cancer Protein expression, and the expression level of PD-L1 is closely related to the clinical and prognosis of patients.
  • WO2017084495 discloses a series of PD-L1 antibodies, which can effectively improve the effect of suppressing tumorigenesis and development.
  • the histone methyltransferase encoded by the EZH2 gene is a catalytic component of the polycomb inhibitory complex 2 (PRC2).
  • PRC2 polycomb inhibitory complex 2
  • EZH2 levels are abnormally elevated in cancer tissues, while EZH2 expression levels are highest in advanced or poor prognosis of cancer.
  • overexpression of EZH2 occurs simultaneously with amplification of the EZH2 gene.
  • si / shRNA experiments have found that reducing EZH2 expression in tumor cell lines can inhibit tumor cell proliferation, migration and invasion or angiogenesis, and cause apoptosis.
  • Tazemetostat developed by Eisai is used to treat non-Hodgkin B-cell lymphoma. It is currently in the clinical stage II.
  • -1205 is used for the treatment of B-cell lymphoma, which is currently in the clinical stage I.
  • GSK-2816126 developed by GlaxoSmithKline is used to treat diffuse large B-cell lymphoma and follicular lymphoma, which is currently in the clinical stage I
  • T cell infiltration selectively interacts with high EZH2-PRC2 complex activity in human skin melanoma Related.
  • TNF- ⁇ tumor necrosis factor- ⁇
  • EZH2 inactivation reversed this resistance and inhibited melanoma growth in synergy with anti-CTLA-4 and IL-2 immunotherapy.
  • EZH2 is used as a molecular switch to control melanoma escape during T-cell targeted immunotherapy (Cells Reports, Volume 20, Issue 4, 25 July 2017, Pages 854-867).
  • the present disclosure provides the use of an EZH2 inhibitor combined with an immune checkpoint inhibitor in the manufacture of a medicament for treating tumors.
  • the EZH2 inhibitor may be a polypeptide, including but not limited to a peptide or an antibody.
  • the EZH2 inhibitor may also be a small molecule, and is specifically selected from CPI-0209, CPI-1205, GSK126, valemetostat, tazemetostat, PF-06821497, DS- 3201GSK-2816126, 3-deazaneplanocin A, HKMT-I-005, KM-301 or a compound represented by formula (I) or a complex thereof or a pharmaceutically acceptable salt thereof, preferably a compound represented by formula (I) or a complex thereof or Its pharmaceutically acceptable salts,
  • the immune checkpoint inhibitors described in this disclosure may be selected from the group consisting of a programmed death-1 (PD-1) receptor inhibitor, a programmed death ligand-1 (PD-L1) inhibitor, or a cytotoxic-T-lymph Cell-associated protein-4 (CTLA-4) inhibitor.
  • PD-1 programmed death-1
  • PD-L1 programmed death ligand-1
  • CTLA-4 cytotoxic-T-lymph Cell-associated protein-4
  • the PD-1 receptor inhibitor described in the present disclosure is an antibody or an antigen-binding fragment thereof that specifically binds PD-1 and inhibits PD-1 activity;
  • the PD-L1 inhibitor is An antibody or antigen-binding fragment thereof capable of specifically binding PD-L1 and inhibiting PD-L1 activity;
  • the CTLA-4 inhibitor is an antibody or antigen-binding thereof capable of specifically binding CTLA-4 and inhibiting CTLA-4 activity Fragment.
  • the antibody or antigen-binding fragment thereof that specifically binds PD-1 and inhibits PD-1 activity described in the present disclosure is an anti-PD-1 antibody or an antigen-binding fragment thereof.
  • the antibodies or antigen-binding fragments thereof that can specifically bind PD-L1 and inhibit the activity of PD-L1 described in the present disclosure are anti-PD-L1 antibodies or antigen-binding fragments thereof.
  • the antibody or antigen-binding fragment thereof that specifically binds CTLA-4 and inhibits CTLA-4 activity described in the present disclosure is an anti-CTLA-4 antibody or antigen-binding fragment thereof.
  • the anti-PD-1 antibodies provided in this disclosure may be selected from sintilimab, cemipilimab, pembrolizumab, tisselizumab, nivolumab, JS-001, AK-103, dostarlimab, PD1-PIK, GLS-010, geneolimzumab, BI- 754091, spartalizumab, MGA-012, PF-06801591, XmAb-20717, CS-1003, Sym-021, AGEN-2034, MEDI-5752, MGD-013, AK-105, AK-104, BCD-100, PF- 06753512, HLX-10, AMP-224, LZM-009.
  • the anti-PD-L1 antibodies provided in this disclosure may be selected from the group consisting of avelumab, atezolizumab, durvalumab, CS-1001, M-7824, KL-A167, CX-072, BGB-A333, GNS-1480, CA-170, BMS-936559, preferably avelumab, atezolizumab, durvalumab.
  • the anti-CTLA-4 antibody provided in the present disclosure is selected from the group consisting of ipilimumab, vertremimumab, AGEN-1884, CS-1002, XmAb-20717, REGN-4659, BCD-145, MEDI-5752, AK-104, MK-1308, BMS-986249, BMS-986218, and PF-06753512, preferably ipilimumab and extremelumumab.
  • the light chain variable region of the PD-1 antibody described in the present disclosure 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 of the PD-1 antibody comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively.
  • the PD-1 antibody is a humanized antibody or a fragment thereof.
  • the anti-PD-1 antibody or antigen-binding fragment thereof described in the present disclosure is selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab ') 2 fragments of antibody fragments.
  • Immunoglobulins can be derived from any generally known isotype, including but not limited to IgA, secreted IgA, IgG, and IgM.
  • IgG subclasses are also well known to those skilled in the art and include, but are not limited to, IgG1, IgG2, IgG3, and IgG4.
  • Isotype refers to an Ab species or subclass (eg, IgM or IgG1) encoded by a heavy chain constant region gene.
  • the anti-PD-1 antibody or antigen-binding fragment thereof described in the present disclosure comprises a heavy chain constant region of human IgG1, IgG2, IgG3, or IgG4 isotype, preferably comprising the IgG1 or IgG4 isotype Heavy chain constant region.
  • the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain constant region of a light chain constant region of kappa or lambda.
  • the humanized antibody light chain variable region sequence is preferably a sequence as shown in SEQ ID NO: 10 or a variant thereof, and the variant preferably has a 0-10 amino acid change in the light chain variable region, more Preferably it is an amino acid change of A43S; the sequence of the humanized antibody heavy chain variable region is the sequence shown in SEQ ID NO: 9 or a variant thereof, and the variant preferably has 0-10 in the heavy chain variable region
  • the amino acid change is more preferably an amino acid change of G44R.
  • sequences of the heavy and light chains of the aforementioned humanized antibodies are as follows:
  • the humanized antibody light chain sequence is the sequence shown in SEQ ID NO: 8 or a variant thereof; the variant preferably has an amino acid change of 0-10 in the variable region of the light chain, more preferably A43S amino acid changes; the humanized antibody heavy chain sequence is the sequence shown in SEQ ID NO: 7 or a variant thereof, the variant preferably has a 0-10 amino acid change in the heavy chain variable region, more An amino acid change of G44R is preferred.
  • the light chain sequence of the humanized antibody is the sequence shown in SEQ ID NO: 8
  • the heavy chain sequence is the sequence shown in SEQ ID NO: 7.
  • sequences of the heavy and light chains of the humanized antibody are as follows:
  • the heavy chain variable region of the PD-L1 antibody or antigen-binding fragment comprises HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 11-13, respectively, the PD-L1 antibody or antigen
  • the light chain variable region of the binding fragment comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NOs: 14-16, respectively;
  • HCDR1 is selected from:
  • HCDR2 is selected from:
  • HCDR3 is selected from:
  • LCDR1 is selected from:
  • LCDR2 is selected from:
  • LCDR3 is selected from:
  • the PD-L1 antibody or antigen-binding fragment comprises an amino acid sequence: SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16 has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity light chain variable region CDR sequences, and amino acids Sequence: SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 have at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94% , 95%, 96%, 97%, 98%, or 99% sequence identity heavy chain variable region CDR sequences.
  • the PD-L1 antibody or antigen-binding fragment may be selected from a murine antibody, a chimeric antibody, a humanized antibody, a human antibody, preferably a humanized antibody.
  • the PD-L1 antibody or antigen-binding fragment comprises and the amino acid sequence SEQ ID NO: 17 has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92 %, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity heavy chain variable region sequences, and the amino acid sequence SEQ ID NO: 18 has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity light chain variable region sequences.
  • the PD-L1 antibody or antigen-binding fragment further comprises a heavy chain constant region of human IgG1, IgG2, IgG3 or IgG4 or a variant thereof, preferably a human IgG2 or IgG4 heavy chain constant region More preferably, the IgG4 heavy chain constant region comprises F234A and L235A mutations; the humanized antibody light chain further comprises a constant region of a human-derived kappa, lambda chain, or a variant thereof.
  • the PD-L1 antibody or antigen-binding fragment comprises and the amino acid sequence SEQ ID NO: 19 has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92 %, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity heavy chain sequence, and the amino acid sequence SEQ ID NO: 21 has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity light chain sequences.
  • the heavy chain sequence of the PD-L1 antibody or antigen-binding fragment is SEQ ID NO: 19, and the light chain sequence is SEQ ID NO: 21.
  • EZH2 inhibitors and immune checkpoint inhibitors provided in the present disclosure can adjust the dosage regimen to provide the optimal desired response, for example, maximum therapeutic response and / or minimal adverse effects.
  • the EZH2 inhibitor in the present disclosure is a compound represented by formula (I) or a complex thereof or a pharmaceutically acceptable salt thereof.
  • the EZH2 inhibitor can be used with a uniform dose or a weight-based dose.
  • the EZH2 inhibitor is administered as a uniform dose, specifically selected from 1-1600 mg, 10-800 mg, for example: 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg , 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg , 190mg, 195mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg,
  • the dose in order to administer an anti-PD-1 antibody or antigen-binding fragment thereof, may be in the following range: 0.1-10.0 mg / kg, 0.1-5 mg / kg, 1-5 mg / kg, 2- 5mg / kg, for example, the specific dose 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, for example,
  • the dose may also be in the range of 1-1000 mg, 80-800 mg, 80-700 mg, 80-600 mg, 80-500 mg, 80-400 mg, 80-300 mg in order to administer an anti-PD-1 antibody. , 100-300mg or 200-300mg.
  • the specific dose can be selected from 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, 8.8mg, 9.0mg, 9.2mg, 9.4mg, 9.6mg, 9.8mg, 10.0mg, 15mg, 20mg, 25mg, 30mg ,
  • An exemplary treatment regimen for the anti-PD-1 antibody or antigen-binding fragment thereof in the present disclosure requires once a week, once every two weeks, once every three weeks, once every four weeks, once a month, every 3-6 Dosing at monthly or longer dosing.
  • the anti-PD-1 antibody or antigen-binding fragment thereof is administered every 2 weeks.
  • the antibody is administered once every three weeks. The dose may vary during the course of treatment.
  • the dosage regimen of an anti-PD-1 antibody or antigen-binding fragment thereof described in the present disclosure comprises intravenous or subcutaneous or intraperitoneal administration, 0.3-10 mg / kg, 1-5 mg / kg, or 1- 3 mg / kg, or 80-800 mg, the antibody is administered every 14-21 days over a period of up to 6 or 12 weeks until a complete response or confirmation of progressive disease.
  • the anti-PD-1 antibody or antigen-binding fragment thereof is administered at 200 mg every 2 weeks.
  • any combination therapy disclosed in the present disclosure lasts for at least 3 weeks, or at least 1 month, or at least 3 months, or at least 6 months, or 9 months, or at least 1 year, or at least 18 Month, or at least 24 months, or at least 3 years, or at least 5 years.
  • the dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 200-300 mg
  • the frequency of administration is once every two or three weeks
  • the dose of the EZH2 inhibitor is 10-800 mg.
  • the frequency is once a day or twice a day.
  • the dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 200 mg
  • the frequency of administration is once every two or three weeks
  • the dose of EZH2 inhibitor is 10-800 mg
  • the frequency of administration is Once a day or twice a day.
  • the dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 200 mg
  • the frequency of administration is once every 2 weeks or once every 3 weeks
  • the dose of the EZH2 inhibitor is 50 mg, 100 mg, 200 mg, 250 mg, 300mg, 350mg, 400mg, 450mg or 800mg
  • the frequency of administration is once a day or twice a day.
  • the PD-L1 antibody or antigen-binding fragment dose is selected from 50-3000 mg, preferably 180 mg, 225 mg, 600 mg, 750 mg, 1200 mg, 1500 mg, more preferably 600 mg, 750 mg, and the PD-L1 antibody.
  • the frequency of administration of the antigen-binding fragment may be once every week, once every two weeks, once every three weeks or once every four weeks.
  • the anti-PD-L1 antibody or antigen-binding fragment is administered every two weeks at a dose of 600 mg or 750 mg.
  • the dose of the anti-PD-L1 antibody or antigen-binding fragment is selected from 50-3000 mg, and the frequency of administration can be once every two or three weeks; the dose of EZH2 inhibitor is 10-800 mg, and the frequency of administration is Once a day or twice a day.
  • the dose of the anti-PD-L1 antibody or antigen-binding fragment is selected from 180 mg, 225 mg, 600 mg, 750 mg, 1200 mg, and 1500 mg, and the frequency of administration may be once every two weeks and once every three weeks; the dose of the EZH2 inhibitor is 50mg, 100mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg or 800mg, the frequency of administration is once a day or twice a day.
  • the dose of the anti-PD-L1 antibody or antigen-binding fragment is selected from 600 mg, 750 mg, and the frequency of administration is once every two weeks; the EZH2 inhibitor dose is 50 mg, 100 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg Or 800 mg twice daily.
  • the tumor described in the present disclosure is selected from the group consisting of adrenocortical cancer, anal cancer, anorectal cancer, anal canal cancer, appendix cancer, cerebellar astrocytoma, cerebral astrocytoma, basal cell cancer, and skin cancer (non-melanoma).
  • Biliary tract cancer extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, bone and joint cancer, osteosarcoma, malignant fibrous histiocytoma, brain cancer, brain tumor, brain stem glioma, ependymal tumor, neural tube Cell tumor, visual pathway and hypothalamic glioma, breast cancer, bronchial adenoma, nervous system cancer, nervous system lymphoma, central nervous system cancer, central nervous system lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloma Cell leukemia leukemia, chronic myeloproliferative disease, colon cancer, colorectal cancer, skin T-cell lymphoma, lymphoma, mycosis fungoides, Sezary syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumor, gonadal External germ cell tumor, eye cancer, intraocular melanoma, retinoblastoma,
  • the tumor described in the present disclosure refers to the aforementioned tumor that is resistant to the treatment of a single EZH2 inhibitor or an immune checkpoint inhibitor, and the immune checkpoint inhibitor is selected from the PD-1 receptor Inhibitor, PD-L1 inhibitor or CTLA-4 inhibitor.
  • the present disclosure provides the use of a compound represented by formula (I) or a complex thereof or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor in the preparation of a medicament for treating tumors.
  • the present disclosure provides the use of a compound represented by formula (I) or a complex thereof or a pharmaceutically acceptable salt thereof in combination with the above-mentioned anti-PD-1 antibody or an antigen-binding fragment thereof in the manufacture of a medicament for treating tumors.
  • the present disclosure provides the use of a compound represented by formula (I) or a complex thereof or a pharmaceutically acceptable salt thereof and the above-mentioned anti-PD-L1 antibody or an antigen-binding fragment thereof in the manufacture of a medicament for treating tumors.
  • Routes of administration of immune checkpoint inhibitors in the present disclosure include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes of administration, such as by injection or infusion.
  • the "parenteral administration” refers to an administration mode other than enteral and local administration by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, Intracystic, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injections and infusions, and intracorporeal electricity perforation.
  • the immune checkpoint inhibitor (eg, an anti-PD-1 antibody) is administered by a non-parenteral route, and in certain embodiments, is administered orally.
  • non-parenteral routes include topical, epidermal or mucosal routes of administration, for example, intranasally, vaginally, rectally, sublingually or locally.
  • compositions for example, a pharmaceutical composition containing an antibody and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the carrier for the antibody-containing composition is suitable for intravenous, intramuscular, subcutaneous, parenteral, abdominal, spinal or epidermal administration (e.g., by injection or infusion), and the pharmaceutical composition of the present disclosure may include One or more pharmaceutically acceptable salts, antioxidants, aqueous and non-aqueous carriers, and / or adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents.
  • the PD-1 antibody or antigen-binding fragment thereof is administered by injection, for example, subcutaneously or intravenously or intraperitoneally. Before injection, the PD-1 antibody or antigen-binding fragment thereof is required.
  • An injectable form of an anti-PD-1 antibody in a particularly preferred embodiment of the present disclosure is an injection or a lyophilized powder injection, which comprises a PD-1 antibody or an antigen-binding fragment thereof, a buffer, a stabilizer, and optionally a surface Active agent.
  • the buffer may be selected from one or more of 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 Of these, polysorbate 20 is most preferred.
  • the most preferred injectable form of the PD-1 antibody or antigen-binding fragment thereof comprises the PD-1 antibody or antigen-binding fragment thereof, an acetate buffer, trehalose, and polysorbate 20.
  • the EZH2 inhibitor described in this disclosure may be a hydrochloride, a phosphate, a hydrogen phosphate, a sulfate, a hydrogen sulfate, a sulfite, an acetate, an oxalate, a malonate, a valerate, a valley Carbamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, mesylate, isethionate, maleate, malate Salt, tartrate, benzoate, paraben, salicylate, vanillate, mandelate, succinate, gluconate, lactobionate or laurylsulfonate.
  • the route of administration of the EZH2 inhibitor described in the present disclosure may be the same as or different from the above immune checkpoint inhibitors, and specifically includes oral, nasal, topical, intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other gastrointestinal External application route.
  • the EZH2 inhibitor is administered orally and is formulated in the form of a composition.
  • the carrier of the composition includes, but is not limited to, a filler, a lubricant, a disintegrant, an adhesive, and the like.
  • the present disclosure provides a method for treating a tumor, comprising administering to a patient a therapeutically effective amount of the above-mentioned EZH2 inhibitor and an immune checkpoint inhibitor.
  • the tumor in the method for treating a tumor refers to the above-mentioned tumor that is resistant to the treatment of a single EZH2 inhibitor or an immune checkpoint inhibitor.
  • the method includes administering to a patient a therapeutic effect. Amounts of the above EZH2 inhibitors and immune checkpoint inhibitors.
  • the EZH2 inhibitor and the immune checkpoint inhibitor are administered simultaneously; in one embodiment, the EZH2 inhibitor and the immune checkpoint inhibitor are administered sequentially; in one embodiment, the EZH2 inhibitor The agent is administered before the immune checkpoint inhibitor.
  • the method of treating tumors provided by this disclosure in one embodiment, is administered parenterally with an immune checkpoint inhibitor.
  • the EZH2 inhibitor is administered orally and the immune checkpoint inhibitor is administered intravenously.
  • the PD-L1 antibody or antigen-binding fragment thereof is administered by injection, such as subcutaneously or intravenously.
  • the present disclosure also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an EZH2 inhibitor, an immune checkpoint inhibitor, and one or more pharmaceutically acceptable carriers, excipients, and diluents.
  • the pharmaceutical composition can be made into any pharmaceutically acceptable dosage form. For example, they can be formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injections and concentrated solutions for injections), suppositories, inhalants or sprays Agent.
  • frequency of administration means the frequency of the administered dose of a drug disclosed herein at a given time.
  • the frequency of dosing can be indicated as the number of doses per given time, for example, once a week, once every two weeks.
  • flat dose refers to the dose administered to a patient regardless of the patient's weight or body surface area (BSA). For example, a 60 kg person and a 100 kg person will receive the same dose of antibody (eg, 240 mg of anti-PD-1 antibody).
  • BSA body surface area
  • weight-based dose refers to a dose calculated to be administered to a patient based on the weight of the patient. For example: 10.0mg / kg refers to 10.0mg per kg based on the weight of the subject.
  • the “combination” described in the present disclosure is a mode of administration, which means that at least one dose of an immune checkpoint inhibitor and an EZH2 inhibitor is administered within a certain period of time, and both of the drugs show a pharmacological effect.
  • the time period may be within a dosing cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours.
  • the immune checkpoint inhibitor and the EZH2 inhibitor can be administered simultaneously or sequentially. This term includes treatment in which immune checkpoint inhibitors and EZH2 inhibitors are administered by the same route or different routes of administration.
  • the "humanized antibody” in the present disclosure also known as CDR-grafted antibody, refers to the transplantation of mouse CDR sequences into the human antibody variable region framework, that is, different types Antibodies produced in human germline antibody framework sequences. It can overcome the strong antibody variable antibody response induced by the chimeric antibody because it carries a large amount of mouse protein components.
  • Such framework sequences can be obtained from a public DNA database including germline antibody gene sequences or published references.
  • germline DNA sequences of human heavy chain and light chain variable region genes can be found in the "VBase" human germline sequence database (available on the Internet at www.mrccpe.com.ac.uk/vbase), and in Kabat, EA, etc. People, 1991 Sequences of Proteins of Immunological Interest, 5th edition.
  • the CDR sequence of the PD-1 humanized antibody is selected from the group consisting of SEQ ID NO: 1,2,3,4,5,6.
  • the “antigen-binding fragment” described in the present disclosure refers to a Fab fragment, Fab ′ fragment, F (ab ′) 2 fragment, and Fv fragment sFv fragment that binds to human PD-1;
  • the antibody is selected from one or more CDR regions of SEQ ID NO: 1 to SEQ ID NO: 6.
  • the Fv fragment contains the variable region of the heavy chain and light chain of the antibody, but has no constant region and has the smallest antibody fragment with all antigen-binding sites.
  • Fv antibodies also contain a polypeptide linker between the VH and VL domains and are capable of forming the structure required for antigen binding.
  • variable regions of two antibodies can also be linked into a single polypeptide chain with different linkers, called single chain antibodies (single chain antibodies) or single chain Fv (sFv).
  • binding to PD-1 in this disclosure refers to the ability to interact with human PD-1.
  • antigen-binding site in the present disclosure refers to a three-dimensional spatial site on the antigen that is discontinuous and is recognized by the antibody or antigen-binding fragment in the present disclosure.
  • T / C (%) (Ti-T0) / (Ci-C0) * 100%;
  • Ti and Ci are the average tumor volume of the treatment group and the control day, respectively;
  • T0 and C0 are the treatment group and the control group, respectively Day 0 Mean tumor volume.
  • TGI Tumor growth inhibition
  • % TGI (1- (Ti-T0) / (Ci-C0)) * 100%; Ti and Ci are the average tumor volume on the day of the treatment group and control group; T0 and C0 are the treatment group and control group, respectively Day 0 Mean tumor volume.
  • FIG. 1 Effect of different drugs combined on body weight of B16F10 tumor-bearing mice.
  • Example 1 Evaluation of the inhibitory effect of the compound represented by formula (I) (drug A) and anti-PD-1 (drug B) antibody on the growth of huPD-1 humanized BALB / c mice CT-26 colon cancer xenografts
  • mice PD-1HuGEMM mice, 42 females, 4-8 weeks old.
  • the animals used were from Nanjing University-Nanjing Institute of Biomedicine.
  • Mouse-derived colon cancer cells CT-26 WT were cultured in RPMI1640 medium containing 10% fetal bovine serum. Cells were digested and passaged with trypsin containing EDTA as usual, passaged twice a week, and placed at 37 ° C, The culture was continued in a 5% CO 2 incubator. Tumor cells in the logarithmic growth phase will be used to establish a model of transplanted tumor in vivo.
  • Drug A prepared according to the method provided in patent application WO2017084494A;
  • Drug B prepared according to the method of patent application WO2017054646A, 200mg, lyophilized powder injection;
  • hIgG negative control, derived from Shanghai Hengrui Pharmaceutical Co., Ltd., diluted with PBS.
  • CT-26 WT cells resuspended in PBS were inoculated subcutaneously in the right flank of PD-1HuGEMM BALB / c mice at a concentration of 5 ⁇ 10 6 cells / 0.1 mL at a volume of 0.1 mL / head. A total of 42 cells were transferred. mouse. When the average tumor volume reached about 100 mm 3 , select mice with moderate tumor volume for each group, 7 mice in each group, and start the administration on the day of the group. The specific dosing schedule is shown in Table 1 below.
  • i.p . intraperitoneal injection
  • p.o . oral gavage
  • BID twice daily
  • Q3D once every three days.
  • Example 2 Efficacy of a combination of a compound represented by formula (I) (drug A) and an anti-PD-1 antibody (drug B) on a subcutaneous transplantation tumor in a mouse melanoma B16F10 model tumor-bearing mouse
  • hIgG negative control, derived from Shanghai Hengrui Pharmaceutical Co., Ltd., diluted with PBS.
  • Drug A is prepared with 0.5% CMC-Na 1% Tween 80 solution
  • Drug B is prepared with 5% glucose solution and diluted with PBS.
  • mice PD-1HuGEMM mice, 6-7 weeks old, tadpoles, purchased from Nanjing Yinhe Biological Medicine Co., Ltd.
  • B16F10 mouse-derived melanoma cells were cultured in RPMI1640 medium containing 10% fetal bovine serum.
  • B16F10 cells resuspended in PBS were inoculated at a concentration of 5 ⁇ 10 5 cells / 0.1 mL in a volume of 0.1 mL / head to PD-1HuGEMM C57BL / 6 mice were subcutaneously in the right posterior flank. After the tumors grew to about 100 mm 3 , the animals were randomly divided into groups (D0) and administered. See Table 3 for the doses and schedules. The tumor volume is measured 2-3 times a week, the weight of the mouse is weighed, and the data is recorded. The combined effect on the subcutaneous transplantation tumor of B16F10 tumor-bearing huPD1 mice is shown in Table 4.
  • i.p . intraperitoneal injection
  • p.o . oral gavage
  • BID twice daily
  • Q3D once every three days.

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Abstract

L'invention concerne l'utilisation d'un inhibiteur d'EZH2 en combinaison avec un inhibiteur de point de contrôle immunitaire dans la préparation d'un médicament pour le traitement de tumeurs. En particulier, l'inhibiteur d'EZH est un composé tel que représenté dans la formule (I) ou un sel pharmaceutiquement acceptable de celui-ci, et l'Inhibiteur de point de contrôle immunitaire est choisi parmi un inhibiteur de PD-1, un inhibiteur de PD-L1 ou un inhibiteur de CTLA-4.
PCT/CN2019/108535 2018-09-29 2019-09-27 Utilisation d'un inhibiteur d'ezh2 en combinaison avec un inhibiteur de point de contrôle immunitaire dans la préparation d'un médicament pour le traitement de tumeurs WO2020063863A1 (fr)

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WO2023244918A1 (fr) 2022-06-13 2023-12-21 Treeline Biosciences, Inc. Agents de dégradation bifonctionnels de quinolone bcl6
WO2023244917A1 (fr) 2022-06-13 2023-12-21 Treeline Biosciences, Inc. Agents dégradant bcl6 hétérobifonctionnels 1,8-naphthyridin-2-one
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CN115364231B (zh) * 2021-10-15 2023-11-17 北京大学第三医院（北京大学第三临床医学院） 一种增强ezh2抑制剂抗肿瘤作用的药物组合物及其用途

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WO2017084494A1 (fr) * 2015-11-19 2017-05-26 江苏恒瑞医药股份有限公司 Dérivé du benzofurane, son procédé de préparation et son utilisation en médecine
WO2018145095A1 (fr) * 2017-02-06 2018-08-09 Bioventures, Llc Procédés de prédiction de la réactivité d'un cancer à un agent immunothérapeutique et procédés de traitement du cancer

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WO2023244918A1 (fr) 2022-06-13 2023-12-21 Treeline Biosciences, Inc. Agents de dégradation bifonctionnels de quinolone bcl6
WO2023244917A1 (fr) 2022-06-13 2023-12-21 Treeline Biosciences, Inc. Agents dégradant bcl6 hétérobifonctionnels 1,8-naphthyridin-2-one
WO2024106878A1 (fr) * 2022-11-17 2024-05-23 인제대학교 산학협력단 Composition pharmaceutique pour prévention ou traitement du cancer, comprenant un inhibiteur d'ezh2 et un anticorps anti-pd-1

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