WO2021063340A1 - Ezh2抑制剂与免疫检查点抑制剂、酪氨酸激酶抑制剂联合在制备治疗肿瘤药物中的用途 - Google Patents

Ezh2抑制剂与免疫检查点抑制剂、酪氨酸激酶抑制剂联合在制备治疗肿瘤药物中的用途 Download PDF

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WO2021063340A1
WO2021063340A1 PCT/CN2020/118710 CN2020118710W WO2021063340A1 WO 2021063340 A1 WO2021063340 A1 WO 2021063340A1 CN 2020118710 W CN2020118710 W CN 2020118710W WO 2021063340 A1 WO2021063340 A1 WO 2021063340A1
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cancer
once
tumor
day
inhibitor
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French (fr)
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张岚
廖成
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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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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present disclosure relates to the use of the combination of EZH2 inhibitors, immune checkpoint inhibitors, and multi-target tyrosine kinase inhibition in the preparation of drugs 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. The first members of the family, CD28 and ICOS, were discovered based on the functional effect of the addition of monoclonal antibodies on the promotion of T cell proliferation. PD-1 was discovered by screening for differential expression in apoptotic cells.
  • PD-1 has two ligands, PD-L1 and PD-L2.
  • PD-L1 is mainly expressed on T cells, B cells, macrophages and dendritic cells (DC), and the expression on cells can be up-regulated after activation.
  • 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 found high PD-L1 was detected in human tumor tissues such as breast cancer, lung cancer, stomach cancer, bowel cancer, kidney cancer, melanoma, non-small cell lung cancer, colon cancer, bladder cancer, ovarian cancer, pancreatic cancer and liver cancer.
  • the expression of protein and the expression level of PD-L1 are closely related to the clinical and prognosis of patients.
  • the histone methyltransferase encoded by the EZH2 gene is the catalytic component of the polycomb inhibitory complex 2 (PRC2).
  • PRC2 polycomb inhibitory complex 2
  • Tazemetostat developed by Eisai is used for the treatment of non-Hodgkin B-cell lymphoma. It is currently in phase II clinical phase.
  • CPI developed by Constellation -1205 is used for the treatment of B-cell lymphoma and is currently in clinical phase I.
  • GSK-2816126 developed by GlaxoSmithKline is used for the treatment of diffuse large B-cell lymphoma and follicular lymphoma. It is currently in clinical phase I.
  • WO2017084494A provides an EZH2 inhibitor, the structure is as follows:
  • the anti-tumor mechanism of TKIs may be achieved through the following ways: inhibiting tumor cell damage and repair, blocking cell division in the G1 phase, inducing and maintaining cell apoptosis, and anti-angiogenesis.
  • Overexpression of EGFR often indicates poor prognosis, fast metastasis, resistance to chemotherapy drugs, hormone resistance, and shorter survival time.
  • the FDA has approved a variety of multi-target TKIs, such as: sorafenib (sorafenib), vandetanib (vandetanib) and Sunitinib (Sutent, SU-11248) and so on.
  • WO2007085188 discloses a compound similar to Sunitinib, as shown in the following formula (II), which may be better applied to the treatment of the above-mentioned tumors.
  • the chemical name of the compound is 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indole-3-ylidene-methyl)- 3-Methyl-1,5,6,7-tetrahydro-pyrrole [3,2-c]pyridin-4-one, which is known to inhibit tumor proliferation and angiogenesis, and can selectively inhibit vascular endothelial growth factor
  • the kinase activity of (VEGF) receptors can be used clinically for the treatment of renal cancer, gastrointestinal stromal tumors, colorectal cancer and pancreatic neuroendocrine tumors.
  • WO2018068691 discloses the use of a combination of an anti-PD-1 antibody and a VEGFR inhibitor in the preparation of a medicine for the treatment of cancer.
  • WO2019097369A discloses a method of administering an EZH2 inhibitor and a platinum-based anti-tumor agent to a patient to treat cancer. Further, other anti-cancer agents can be administered, and the other anti-cancer agents can be selected from anti-PD-1 antibodies and anti-PD -L1 antibody and anti-CTLA-4 antibody, etc.
  • Example 1 discloses tissue testing for patients with epithelioid sarcoma and renal medullary carcinoma and found that PD-L1 will be up-regulated after EZH2 inhibition. The data indicate that these tumors are triggered due to the presence of T cell-mediated immune responses in the tumors, but the immune response It may be inhibited by the increased expression of PD-L1 in tumors, indicating that this tumor can be treated by a combination of EZH2 inhibition and PD-1/PD-L1 inhibition.
  • Example 2 patients with soft tissue sarcoma were given the combination therapy of tazemetostat and atezolizumab, but no specific pharmacodynamic information was disclosed.
  • WO2017210395A claims a method for treating cancer in a subject in need, comprising administering to the subject a therapeutically effective amount of an EZH2 inhibitor and a therapeutically effective amount of an immune checkpoint inhibitor, the immune checkpoint
  • the inhibitor can be an anti-PD-L1 antibody.
  • the example discloses a treatment plan for the combination of tazemetostat and atezolizumab for patients with locally advanced or metastatic urothelial cancer, patients with diffuse large B-cell lymphoma, and non-Hodgkin’s lymphoma. However, no specific efficacy information was given.
  • the present disclosure provides a use of an EZH2 inhibitor, an immune checkpoint inhibitor, and a multi-target tyrosine kinase inhibitor in the preparation of a drug for treating tumors.
  • the EZH2 inhibitor described in the present disclosure may be selected from CPI-0209, CPI-1205, GSK126, valemetostat, tazemetostat, PF-06821497, DS-3201GSK-2816126, 3-deazaneplanocin A, HKMT-I -005, at least one of KM-301.
  • the EZH2 inhibitor described in the present disclosure is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • the pharmaceutically acceptable salt of the compound represented by formula (I) in the present disclosure can be hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, acetate, oxalate, malonate, Valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, methanesulfonate, isethionate, maleate Acid salt, malate, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate, succinate, gluconate, lactobionate or lauryl sulfonic acid Salt etc.
  • the immune checkpoint inhibitor described in the present disclosure may be an anti-PD-1 antibody or an antigen-binding fragment thereof.
  • the anti-PD-1 antibodies or antigen-binding fragments thereof described in the present disclosure can be selected from sintilimab, cemiplimab, JS-001, nivolumab, tislelizumab, pembrolizumab, AK-103, dostarlimab, PD1-PIK, GLS- 010, genolimzumab, BI-754091, spartalizumab, MGA-012, PF-06801591, XmAb-20717, CS-1003, Sym-021, AGEN-2034, MEDI-5752, MGD-013, AK-105, AK-104, At least one of BCD-100, PF-06753512, HLX-10, AMP-224, LZM-009.
  • the light chain variable region of the PD-1 antibody described in the present disclosure includes LCDR1, LCDR2, and LCDR2 as shown in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively.
  • LCDR3, the heavy chain variable region of the PD-1 antibody includes 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 an antibody fragment selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab') 2 fragments.
  • Immunoglobulins can be derived from any commonly known isotype, including but not limited to IgA, secreted IgA, IgG, and IgM.
  • the IgG subclass is also well known to those skilled in the art, including but not limited to IgG1, IgG2, IgG3, and IgG4.
  • Immunotype refers to the Ab class or subclass (for example, IgM or IgG1) encoded by the 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 IgG1 or IgG4 isotype The constant region of the heavy chain.
  • the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain constant region of kappa or lambda.
  • the light chain variable region sequence of the humanized antibody is preferably the sequence shown in SEQ ID NO: 10 or a variant thereof, and the variant preferably has 0-10 amino acid changes in the light chain variable region.
  • the amino acid change of A43S is 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 of G44R is more preferably the 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 0-10 amino acid changes in the light chain variable region, more preferably A43S amino acid change; the humanized antibody heavy chain sequence is the sequence shown in SEQ ID NO: 7 or a variant thereof, and the variant preferably has 0-10 amino acid changes in the heavy chain variable region, and more Preferably, it is an amino acid change of G44R.
  • 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 multi-target tyrosine kinase inhibitor may be selected from Sunitinib, Pazopanib, Lenvatinib, Regorafenib, Cabozantinib, Dovitinib, Sorafenib, Vandetanib, Crizotinib, Anlotinib, Pontatinib, Imatinib, ENMD-2076, Afatinib, At least one of Dasatinib and nintedanib.
  • the multi-target tyrosine kinase inhibitor is a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
  • the pharmaceutically acceptable salt of the compound represented by formula (II) may be hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, acetate, oxalate, and malonic acid. Salt, valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, methanesulfonate, isethionate, Maleate, malate, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate, succinate, gluconate, lactobionate, or lauryl Sulfonate, etc. In an alternative embodiment, the pharmaceutically acceptable salt of the compound represented by formula (II) is malate.
  • the administration dose of EZH2 is selected from 1 to 1600 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, 65 mg, 70 mg, 75 mg, 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, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 10 mg, 15 mg
  • the dosage of EZH2 is selected from 1-800 mg, and the frequency of administration is 2 times a day, once a day, once every 2 days, once every 3 days, once every 4 days, and every 5 days. Once a day, once every 6 days, once a week, once every 2 weeks, once every 3 weeks or once every 4 weeks, preferably twice a day or once a day.
  • the administration dose of EZH2 is selected from 50mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, administration
  • the frequency is 2 times a day, once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, once every 2 weeks, once every 3 weeks or Once every 4 weeks, preferably twice a day or once a day.
  • the administration dose of EZH2 is selected from 50mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, administration
  • the frequency is 2 times a day or 1 time a day.
  • the dosage of EZH2 is selected from 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, and the frequency of administration is 2 times a day, once a day, once every 2 days, every 3 Once a day, once every 4 days, once every 5 days, once every 6 days, once a week, once every 2 weeks, once every 3 weeks or once every 4 weeks.
  • the dosage of EZH2 is selected from 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, and the frequency of administration is twice a day or once a day.
  • the administration dose of the immune checkpoint inhibitor may be in the following range: 0.1-10.0 mg/kg, 0.1-5 mg/kg, 1-5 mg/kg, 2-5 mg/kg, for example,
  • the dose can 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, 4.4mg/kg, 4.6mg/kg, 4.8m
  • the dose range of the immune checkpoint inhibitor is selected from 1-1000 mg, 80-800 mg, 80-700 mg, 80-600 mg, 80-500 mg, 80-400 mg, 80-300 mg, 100-300 mg or 200-300mg.
  • the dosage can be 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, 2.0 mg, 2.2 mg, 2.4 mg, 2.6 mg, 2.8 mg, 3.0 mg, 3.2 mg, 3.4 mg, 3.6 mg, 3.8 mg, 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.
  • the dose of the immune checkpoint inhibitor is 80 mg, 100 mg, 160 mg, 200 mg, 240 mg, 300 mg, 320 mg, 400 mg, 500 mg, 600 mg, 700 mg or 800 mg, and the frequency of administration is once a week, every 2 weeks It is administered once, once every 3 weeks, once every 4 weeks, once a month, once every 3-6 months or longer.
  • the amount of immune checkpoint inhibitor is 200 mg
  • the frequency of administration is once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once a month, every 3-6 It is administered frequently every month or more.
  • the frequency of administration of the immune checkpoint inhibitor is once every 2 weeks or once every 3 weeks.
  • the dose of the multi-target tyrosine kinase inhibitor is selected from 0.1-1000 mg, and the frequency of administration may be once a day, twice a day, or 3 times a day, preferably once a day.
  • the dose of the multi-target tyrosine kinase inhibitor is selected from 0.1-100 mg, specifically 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8mg, 0.9mg, 1.0mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg , 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46m
  • the multi-target tyrosine kinase inhibitor is administered according to body weight, and the dose is selected from 0.1-10.0 mg/kg.
  • the dose of the multi-target tyrosine kinase inhibitor may be 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/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, 4.4mg/kg, 4.6mg/kg, 4.8mg/kg, 5.0mg/kg, 5.2mg/kg, 5.4mg/kg, 5.6mg/kg
  • the dose of the multi-target tyrosine kinase inhibitor is selected from 1-25 mg, specifically 15 mg, 20 mg, and 25 mg can be selected.
  • the frequency of administration can be once a day, twice a day, or 3 times a day. Times, preferably once a day.
  • the multi-target tyrosine kinase inhibitor is the compound shown in (II) malate.
  • the tumor described in the present disclosure is selected from the group consisting of adrenal cortical cancer, anal cancer, anorectal cancer, anal canal cancer, appendix cancer, cerebellar astrocytoma, brain astrocytoma, basal cell carcinoma, skin cancer (non-melanoma ), biliary tract cancer, extrahepatic cholangiocarcinoma, intrahepatic cholangiocarcinoma, bladder cancer, bone and joint cancer, osteosarcoma, malignant fibrous histiocytoma, brain cancer, brain tumor, brainstem glioma, ependymoma, neuroblast Angiocytoma, 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 Myelocytic leukemia, leukemia, chronic myeloproliferative disease
  • the immune checkpoint inhibitor of the present disclosure can be constituted in a composition, for example, a pharmaceutical composition containing an antibody and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition containing an antibody and a pharmaceutically acceptable carrier.
  • “Pharmaceutically acceptable carrier” as used herein includes any and all solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic agents and absorption delaying agents that are physiologically compatible.
  • the carrier for the antibody-containing composition is suitable for intravenous, intramuscular, subcutaneous, parenteral, intraperitoneal, spinal or epidermal administration (for example, by injection or infusion),
  • 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, emulsifiers and dispersing agents.
  • the PD-1 antibody or its antigen-binding fragment is administered by injection, such as subcutaneous or intravenous injection or intraperitoneal injection.
  • the PD-1 antibody or its antigen-binding fragment must be injected before injection.
  • Formulated in an injectable form is an injection or a lyophilized powder injection, which contains the PD-1 antibody or its antigen-binding fragment, a buffer, a stabilizer, and optionally a surface Active agent.
  • the buffer can 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 , Polysorbate 20 is most preferred.
  • the most preferred injectable form of PD-1 antibody or antigen-binding fragment thereof comprises PD-1 antibody or antigen-binding fragment thereof, acetate buffer, trehalose and polysorbate 20.
  • the present disclosure provides a method for treating tumors, which includes administering to a patient a therapeutically effective amount of the above-mentioned EZH2 inhibitor, immune checkpoint inhibitor, and multi-target tyrosine kinase inhibitor.
  • Another aspect of the present disclosure provides an EZH2 inhibitor for the treatment of tumors, which is used in combination with the immune checkpoint inhibitor and the multi-target tyrosine kinase inhibitor.
  • Another aspect of the present disclosure provides an immune checkpoint inhibitor for the treatment of tumors, which is used in combination with an EZH2 inhibitor and a multi-target tyrosine kinase inhibitor.
  • Another aspect of the present disclosure provides a multi-target tyrosine kinase inhibitor, which is used in combination with an EZH2 inhibitor and an immune checkpoint inhibitor.
  • the patient in the method for treating tumors provided in the present disclosure, is a human.
  • the tyrosine kinase inhibitors described in the present disclosure refer to drugs that can block tyrosine kinases, and the multi-target tyrosine kinase inhibitors refer to drugs that can produce at least two receptor tyrosine kinases at the same time.
  • Inhibited drugs, receptor tyrosine kinases include but are not limited to PDGF-R, VEGFR, flt3, EGFR, HER2, FGFR, etc.
  • the "combination" described in the present disclosure is a mode of administration, which refers to the administration of at least one dose of immune checkpoint inhibitor, EZH2 inhibitor, and multi-target tyrosine kinase inhibitor within a certain period of time, wherein All three drugs show pharmacological effects.
  • the time limit may be within one administration cycle, for example, within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours.
  • Immune checkpoint inhibitors, EZH2 inhibitors and multi-target tyrosine kinase inhibitors can be administered simultaneously or in no particular order. This period includes treatments in which immune checkpoint inhibitors, EZH2 inhibitors, and multi-target tyrosine kinase inhibitors are administered through the same route of administration 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 Of human germline antibody framework sequences. It can overcome the strong variable antibody response induced by the chimeric antibody due to the 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.
  • the germline DNA sequences of the human heavy chain and light chain variable region genes 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, EA, etc. People, 1991 Sequences of Proteins of Immunological Interest, found in the 5th edition.
  • the CDR sequence of the humanized PD-1 antibody is selected from SEQ ID NO: 1, 2, 3, 4, 5, 6.
  • the "antigen-binding fragment” in the present disclosure refers to Fab fragments, Fab' fragments, F(ab')2 fragments, and Fv fragments that bind to human PD-1, sFv fragments that have antigen-binding activity;
  • the antibody is selected from one or more CDR regions in SEQ ID NO: 1 to SEQ ID NO: 6.
  • the Fv fragment contains the variable region of the heavy chain of the antibody and the variable region of the light chain, but has no constant region and is the smallest antibody fragment with all antigen binding sites.
  • an Fv antibody also contains a polypeptide linker between the VH and VL domains, and can form the structure required for antigen binding.
  • Different linkers can also be used to connect the variable regions of two antibodies into a polypeptide chain, which is called single chain antibody or single chain Fv (sFv).
  • binding to PD-1 in the present disclosure refers to the ability to interact with human PD-1.
  • antigen-binding site in the present disclosure refers to a discrete three-dimensional site on the antigen that is recognized by the antibody or antigen-binding fragment in the present disclosure.
  • Example 1 Verification of the efficacy of the test drug in the colorectal cancer cell line CT-26 female huPD-1 mouse allograft model
  • mice huPD-1BALB/c, Jiangsu Jicui Yaokang Biotechnology Co., Ltd., 6-8 weeks old, 18-20g, 48 mice plus 40% redundancy, a total of 68 mice.
  • CT-26 from the Chinese Academy of Sciences, colorectal cancer cells, F3 generation; the required cell volume is 8.2X10E7.
  • EZH2 inhibitor compound represented by formula (I); multi-target tyrosine kinase inhibitor: compound represented by formula (II) malate; anti-PD-1 antibody: PD-1 antibody disclosed in WO2017054646A, heavy and light
  • the sequence of the chain is shown in SEQID NO: 7 and SEQID NO: 8 respectively.
  • CT-26 cells were resuscitated and cultured in vitro to obtain 1X10E8 cells; 68 6-8 week old female huPD-1 were adaptively reared for 1 week, weighed, and each mouse was inoculated subcutaneously at the bilateral shoulder blades for 5* 10E5 cells, each seeding volume is 0.1mL.
  • the tumor volume and body weight were measured once a week , and mice with tumor volumes between 60-120 mm 3 on both sides were selected and randomly divided into 6 groups according to the tumor volume and body weight on the right side, with 8 mice in each group.
  • the administration was started immediately after grouping. The start date of administration is regarded as day 0, and the administration and grouping information is shown in Table 2. After the start of the administration, the mouse body weight and tumor volume were measured 3 times a week.
  • BID interval is 8 hours.
  • the weight of the experimental animals was measured once a week. After grouping, measure the weight of experimental animals 3 times a week or change the frequency of measuring the weight of mice according to customer requirements. After inoculation to before grouping, when tumors are visible, the tumor volume of experimental animals is measured once a week. After inoculation and grouping, the tumor volume of experimental animals is measured once a week.
  • % ⁇ T/C (mean(T)-mean(T0))/(mean(C)-mean(C0))*100%; T-administration group Tumor volume, T0-initial tumor volume of the administration group, C-tumor volume of the control group, C0-initial tumor volume of the control group.
  • Mean% ⁇ Inhibition(TGI%) ((mean(C)-mean(C0))-(mean(T)-mean(T0)))/(mean(C)-mean(C0))*100%; T -Tumor volume of the administration group, T0-initial tumor volume of the administration group, C-tumor volume of the control group, C0-initial tumor volume of the control group.
  • the tumor growth curves on the left and right sides of each group are shown in Figure 2.
  • the left tumor volume of 34 and 35# mice was analyzed as an abnormal value by Prism abnormal value, which was excluded in the drawing.
  • group 2 tumor volume on day 14 is 2020.2 ⁇ 177.82mm 3

Abstract

EZH2抑制剂与免疫检查点抑制剂、酪氨酸激酶抑制剂联合在制备治疗肿瘤药物中的用途。具体而言，所述的EZH2抑制剂为式(I)所示化合物或其可药用盐，所述的免疫检查点抑制剂为抗PD-1抗体或者其抗原结合片段，所述酪氨酸激酶抑制剂为式(II)所示化合物或其可药用盐。

Description

EZH2抑制剂与免疫检查点抑制剂、酪氨酸激酶抑制剂联合在制备治疗肿瘤药物中的用途 技术领域
本公开涉及EZH2抑制剂与免疫检查点抑制剂、多靶点酪氨酸激酶抑制联合在制备治疗肿瘤的药物中的用途。
背景技术
蛋白质程序性死亡1(PD-1)是CD28受体家族的抑制性成员，该家族还包括CD28、CTLA-4、ICOS和BTLA。PD-1在活化的B细胞、T细胞和髓样细胞上表达。根据加入单克隆抗体后对提升T细胞增殖的功能性影响发现了家族最初的成员，CD28和ICOS。通过在凋亡细胞中筛选差异表达发现了PD-1。目前，已有小野公司的Nivolumab及Merck公司的Pembrolizumab成功获批上市，用于治疗不可切除或转移性黑色素瘤、非小细胞肺癌、晚期肾细胞癌、霍奇金淋巴瘤、复发性或转移性鳞状细胞癌等。PD-1有两个配体，分别为PD-L1和PD-L2。PD-L1主要表达于T细胞、B细胞、巨噬细胞和树突状细胞(dendritic cell,DC)上，在活化后细胞上的表达能够进行上调。PD-L1通过和PD-1及B7-1的结合抑制免疫系统，很多肿瘤细胞及肿瘤组织微环境的免疫细胞表达PD-L1。新的研究发现乳腺癌、肺癌、胃癌、肠癌、肾癌、黑素瘤、非小细胞肺癌、结肠癌、膀胱癌、卵巢癌、胰腺癌及肝癌等人类肿瘤组织中检测到高PD-L1蛋白的表达，且PD-L1的表达水平和患者的临床及预后紧密相关。
EZH2基因编码的组蛋白甲基转移酶是多梳蛋白抑制性复合体2(PRC2)的催化组分。与正常组织相比，EZH2水平在癌组织异常升高，而在癌症晚期或不良预后中，EZH2的表达水平最高。在一些癌症类型中，EZH2表达过剩与EZH2基因的扩增同时发生。大量si/shRNA实验研究发现在肿瘤细胞系中减少EZH2表达，可抑制肿瘤细胞的增殖，迁移和侵袭或血管生成，并导致细胞凋亡。
目前已有进入临床开发阶段的EZH2抑制剂，以下简要列举，卫材开发的Tazemetostat(EPZ-6438)用于治疗非霍奇金B细胞淋巴瘤，目前处于临床Ⅱ期阶段，Constellation公司开发的CPI-1205用于治疗B细胞淋巴瘤，目前处于临床Ⅰ期阶段，葛兰素史克公司开发的GSK-2816126用于治疗弥漫大B细胞淋巴瘤、滤泡性淋巴瘤，目前处于临床Ⅰ期阶段。
WO2017084494A中提供了一种EZH2抑制剂，结构如下所示：
Figure PCTCN2020118710-appb-000001
Lu Gan等的综述中提到了EZH2在肿瘤免疫中的新兴作用(Biomarker Research，December 2018,6:10)。
氨酸激酶抑制剂(TKIs)的抗肿瘤作用机制可能通过以下途径实现：抑制肿瘤细胞的损伤修复、使细胞分裂阻滞在G1期、诱导和维持细胞凋亡、抗新生血管形成等。EGFR过度表达常预示病人预后差、转移快、对化疗药物抗拒、激素耐药、生存期较短等。FDA已批准多种多靶点TKIs上市，如：索拉非尼(sorafenib)、凡德他尼(vandetanib)和Sunitinib(Sutent，SU-11248)等。WO2007085188公开了一种与Sunitinib类似的化合物，如下式(II)所示，其可能更好地应用于上述肿瘤的治疗。该化合物化学名为5-(2-二乙胺基-乙基)-2-(5-氟-2-氧代-1,2-二氢-吲哚-3-亚基-甲基)-3-甲基-1,5,6,7-四氢-吡咯[3,2-c]吡啶-4-酮，已知其具有抑制参与肿瘤增殖和血管生成，能够选择性抑制血管内皮生长因子(VEGF)受体的激酶活性，临床上可用于肾癌、胃肠间质瘤、结直肠癌和胰腺神经内分泌瘤等多种肿瘤的治疗，
Figure PCTCN2020118710-appb-000002
WO2018068691公开了一种抗PD-1抗体和VEGFR抑制剂联合在制备治疗癌症的药物中的用途。
WO2019097369A公开了一种向患者施用EZH2抑制剂和铂基抗肿瘤剂联用治疗癌症的方法，进一步还可以施用其他抗癌剂，所述其他抗癌剂可选自抗PD-1抗体，抗PD-L1抗体和抗CTLA-4的抗体等。
WO2018223030A实施例1公开针对上皮样肉瘤和肾髓样癌患者的组织检测发现EZH2抑制后PD-L1会发生上调，数据表明这些肿瘤被引发由于肿瘤中存在T细胞介导的免疫应答，但是免疫应答可能受到肿瘤中PD-L1表达增加的抑制，这表明这种肿瘤可通过EZH2抑制和PD-1/PD-L1抑制的组合来治疗。实施例2中针对软组织肉瘤的患者给与tazemetostat和atezolizumab的组合治疗，但未公开具体药效信息。
WO2017210395A要求保护一种在有需要的受试者中治疗癌症的方法，包括 向所述受试者施用治疗有效量的EZH2抑制剂和治疗有效量的免疫检查点抑制剂，所述的免疫检查点抑制剂可选抗PD-L1抗体，实施例公开了tazemetostat和atezolizumab联用针对局部晚期或转移性尿路上皮癌患者、弥漫性大B细胞淋巴瘤患者及非霍奇金淋巴瘤的治疗方案，但是未给出具体的药效信息。
发明内容
本公开中提供一种EZH2抑制剂与免疫检查点抑制剂、多靶点酪氨酸激酶抑制剂联合在制备治疗肿瘤的药物中的用途。
某些实施方案中，本公开中所述的EZH2抑制剂可选自CPI-0209、CPI-1205、GSK126、valemetostat、tazemetostat、PF-06821497、DS-3201GSK-2816126、3-deazaneplanocin A、HKMT-I-005、KM-301中的至少一种。
某些实施方案中，本公开中所述EZH2抑制剂为式(I)所示化合物或其可药用盐，
Figure PCTCN2020118710-appb-000003
本公开中式(I)所示化合物可药用盐可以是盐酸盐、磷酸盐、磷酸氢盐、硫酸盐、硫酸氢盐、亚硫酸盐、乙酸盐、草酸盐、丙二酸盐、戊酸盐、谷氨酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、对甲苯磺酸盐、甲磺酸盐、羟乙基磺酸盐、马来酸盐、苹果酸盐、酒石酸盐、苯甲酸盐、双羟萘酸盐、水杨酸盐、香草酸盐、扁桃酸盐、琥珀酸盐、葡萄糖酸盐、乳糖酸盐或月桂基磺酸盐等。
某些实施方案中，本公开中所述的免疫检查点抑制剂可以为抗PD-1抗体或者其抗原结合片段。
某些实施方案中，本公开中所述的抗PD-1抗体或者其抗原结合片段可选sintilimab、cemiplimab、JS-001、nivolumab、tislelizumab、pembrolizumab、AK-103、dostarlimab、PD1-PIK、GLS-010、genolimzumab、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中的至少一种。
在某些实施方式中，本公开中所述的PD-1抗体的轻链可变区包含分别如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示的LCDR1、LCDR2和LCDR3，所述的PD-1抗体的重链可变区包含分别如SEQ ID NO:1、SEQ ID NO:2和SEQ  ID NO:3所示的HCDR1、HCDR2和HCDR3。
其中，前面所述的各CDR序列如下表1所示：
表1.
名称 序列 编号
HCDR1 SYMMS SEQID NO：1
HCDR2 TISGGGANTYYPDSVKG SEQID NO：2
HCDR3 QLYYFDY SEQID NO：3
LCDR1 LASQTIGTWLT SEQID NO：4
LCDR2 TATSLAD SEQID NO：5
LCDR3 QQVYSIPWT SEQID NO：6
优选的，所述的PD-1抗体为人源化抗体或其片段。
在可选实施方案中，本公开中所述抗PD-1抗体或其抗原结合片段选自由Fab，Fab’-SH，Fv，scFv，和(Fab’)2片段组成的组的抗体片段。
免疫球蛋白可以来源于任何通常已知的同种型，包括但不限于IgA、分泌型IgA、IgG和IgM。IgG亚类也是本领域技术人员众所周知的，包括但不限于IgG1、IgG2、IgG3和IgG4。“同种型”是指由重链恒定区基因编码的Ab种类或亚类(例如，IgM或IgG1)。在一些可选实施方案中，本公开中所述抗PD-1抗体或其抗原结合片段包含人源IgG1、IgG2、IgG3或IgG4同种型的重链恒定区，优选包含IgG1或IgG4同种型的重链恒定区。
在另一些可选实施方案中，所述抗PD-1抗体或其抗原结合片段包含κ或λ的轻链恒定区的轻链恒定区。
进一步地，优选人源化抗体轻链可变区序列为如SEQ ID NO:10所示的序列或其变体，所述变体优选在轻链可变区有0-10的氨基酸变化，更优选为A43S的氨基酸变化；所述人源化抗体重链可变区序列为如SEQ ID NO:9所示的序列或其变体，所述变体优选在重链可变区有0-10的氨基酸变化，更优选为G44R的氨基酸变化。
前述的人源化抗体重、轻链的序列如下所示：
重链可变区
Figure PCTCN2020118710-appb-000004
轻链可变区
Figure PCTCN2020118710-appb-000005
Figure PCTCN2020118710-appb-000006
优选的，所述人源化抗体轻链序列为如SEQ ID NO:8所示的序列或其变体；所述变体优选在轻链可变区有0-10的氨基酸变化，更优选为A43S的氨基酸变化；所述人源化抗体重链序列为如SEQ ID NO:7所示的序列或其变体，所述变体优选在重链可变区有0-10的氨基酸变化，更优选为G44R的氨基酸变化。
在某些实施方式中，所述人源化抗体的轻链序列为如SEQ ID NO:8所示的序列，重链序列为如SEQ ID NO:7所示的序列。
所述人源化抗体重、轻链的序列如下所示：
重链
Figure PCTCN2020118710-appb-000007
轻链
Figure PCTCN2020118710-appb-000008
在某些实施方式中，所述多靶点酪氨酸激酶抑制可选自Sunitinib、Pazopanib、Lenvatinib、Regorafenib、Cabozantinib、Dovitinib、Sorafenib、Vandetanib、Crizotinib、Anlotinib、Ponatinib、Imatinib、ENMD-2076、Afatinib、Dasatinib、nintedanib中的至少一种。
在某些实施方案中，所述多靶点酪氨酸激酶抑制剂为式(II)所示化合物或其可药用盐，
Figure PCTCN2020118710-appb-000009
本公开中，式(II)所示化合物可药用盐可以是盐酸盐、磷酸盐、磷酸氢盐、硫酸盐、硫酸氢盐、亚硫酸盐、乙酸盐、草酸盐、丙二酸盐、戊酸盐、谷氨酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、对甲苯磺酸盐、甲磺酸盐、羟乙基磺酸盐、马来酸盐、苹果酸盐、酒石酸盐、苯甲酸盐、双羟萘酸盐、水杨酸盐、香草酸盐、扁桃酸盐、琥珀酸盐、葡萄糖酸盐、乳糖酸盐或月桂基磺酸盐等，可选的实施方案中式(II)所示化合物可药用盐为苹果酸盐。
在某些实施方案中，所述EZH2的给药剂量选自1-1600mg，例如：10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、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、280mg、290mg、300mg、310mg、320mg、330mg、340mg、350mg、360mg、370mg、380mg、390mg、400mg、410mg、420mg、430mg、440mg、450mg、460mg、470mg、480mg、490mg、500mg、510mg、520mg、530mg、540mg、550mg、560mg、570mg、580mg、590mg、600mg、625mg、650mg、675mg、700mg、725mg、750mg、775mg、800mg、825mg、850mg、875mg、900mg、925mg、950mg、975mg、1000mg、1025mg、1050mg、1075mg、1100mg、1125mg、1150mg、1175mg、1200mg、1225mg、1250mg、1275mg、1300mg、1325mg、1350mg、1375mg、1400mg、1425mg、1450mg、1475mg、1500mg、1525mg、1550mg、1575mg、1600mg，给药频次为每天2次，每天1次，每2天1次，每3天一次，每4天一次，每5天一次，每6天一次，每周一次，每2周一次，每3周一次或每4周一次，优选每天2次或每天1次。
在某些实施方案中，所述EZH2的给药剂量选自1-800mg，给药频次为每天2次，每天1次，每2天1次，每3天一次，每4天一次，每5天一次，每6天一次，每周一次，每2周一次，每3周一次或每4周一次，优选每天2次或每天1次。
在某些实施方案中，所述EZH2的给药剂量选自50mg、100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg，给药频次为每天2次，每天1次，每2天1次，每3天一次，每4天一次，每5天一次，每6天一次，每周一次，每2周一次，每3周一次或每4周一次，优选每天2次或每天1次。
在某些实施方案中，所述EZH2的给药剂量选自50mg、100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg，给药频次为每天2次或每天1次。
在某些实施方案中，所述EZH2的给药剂量选自150mg、200mg、250mg、 300mg、350mg、400mg、450mg，给药频次为每天2次，每天1次，每2天1次，每3天一次，每4天一次，每5天一次，每6天一次，每周一次，每2周一次，每3周一次或每4周一次。
在某些实施方案中，所述EZH2的给药剂量选自150mg、200mg、250mg、300mg、350mg、400mg、450mg，给药频次为每天2次或每天1次。
在一些实施方案中，所述免疫检查点抑制剂的给药剂量可以在以下范围内：0.1-10.0mg/kg、0.1-5mg/kg、1-5mg/kg、2-5mg/kg，例如，剂量可以是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、4.4mg/kg、4.6mg/kg、4.8mg/kg、5.0mg/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、10.0mg/kg，给药频次为每周一次、每2周一次、每3周一次、每4周一次、1个月一次、每3-6个月或更长一次的给药频次施用。
在一些实施方案中，所述免疫检查点抑制剂的剂量范围选自1-1000mg、80-800mg、80-700mg、80-600mg、80-500mg、80-400mg、80-300mg、100-300mg或200-300mg。例如，剂量可以是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、35mg、40mg、45mg、50mg、55mg、60mg、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、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、390mg、395mg、400mg、405mg、410mg、415mg、420mg、425mg、430mg、435mg、440mg、445mg、450mg、455mg、460mg、465mg、470mg、475mg、480mg、485mg、490mg、495mg、500mg、505mg、510mg、515mg、520mg、525mg、530mg、535mg、540mg、545mg、550mg、555mg、560mg、565mg、570mg、575mg、580mg、585mg、590mg、595mg、600mg，给药频次 为每周一次、每2周一次、每3周一次、每4周一次、1个月一次、每3-6个月或更长一次的给药频次施用。
可选的实施方案中，免疫检查点抑制剂的剂量为80mg、100mg、160mg、200mg、240mg、300mg、320mg、400mg、500mg、600mg、700mg或800mg，给药频次为每周一次、每2周一次、每3周一次、每4周一次、1个月一次、每3-6个月或更长一次的给药频次施用。
可选的实施方案中，免疫检查点抑制剂的量为200mg，给药频次为每周一次、每2周一次、每3周一次、每4周一次、1个月一次、每3-6个月或更长一次的给药频次施用。
可选的实施方案中，所述免疫检查点抑制剂的给药频次为每2周一次或每3周一次。
可选的实施方案中，所述多靶点酪氨酸激酶抑制剂的剂量选自0.1-1000mg，给药频次可以是每天1次、一日二次、每天3次，优选每天1次。
可选的实施方案中，所述多靶点酪氨酸激酶抑制剂的剂量选自0.1-100mg，具体可选0.1mg、0.2mg、0.3mg、0.4mg、0.5mg、0.6mg、0.7mg、0.8mg、0.9mg、1.0mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、11mg、12mg、13mg、14mg、15mg、16mg、17mg、18mg、19mg、20mg、21mg、22mg、23mg、24mg、25mg、26mg、27mg、28mg、29mg、30mg、31mg、32mg、33mg、34mg、35mg、36mg、37mg、38mg、39mg、40mg、41mg、42mg、43mg、44mg、45mg、46mg、47mg、48mg、49mg、50mg、51mg、52mg、53mg、54mg、55mg、56mg、57mg、58mg、59mg、60mg、61mg、62mg、63mg、64mg、65mg、66mg、67mg、68mg、69mg、70mg、71mg、72mg、73mg、74mg、75mg、76mg、77mg、78mg、79mg、80mg、81mg、82mg、83mg、84mg、85mg、86mg、87mg、88mg、89mg、90mg、91mg、92mg、93mg、94mg、95mg、96mg、97mg、98mg、99mg、100mg，给药频次可以是每天1次、一日二次、每天3次，优选每天1次。
可选的实施方案中，所述多靶点酪氨酸激酶抑制剂按体重给药，所述的剂量选自0.1-10.0mg/kg。
在上述按照体重给药的方案中，所述多靶点酪氨酸激酶抑制剂的剂量可以为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、4.4mg/kg、4.6mg/kg、4.8mg/kg、5.0mg/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、10.0mg/kg， 给药频次可以是每天1次、一日二次、每天3次，优选每天1次。
在可选的实施方案中，多靶点酪氨酸激酶抑制剂的剂量选自1-25mg，具体可选15mg、20mg、25mg，给药频次可以是每天1次、一日二次、每天3次，优选每天1次。
可选的实施方案中，所述多靶点酪氨酸激酶抑制剂为(II)所示化合物苹果酸盐。
本公开中所述肿瘤是选自上腺皮质癌、肛门癌、肛门直肠癌、肛管癌、阑尾癌、小脑星形细胞瘤、脑星形细胞瘤、基底细胞癌、皮肤癌(非黑色素瘤)、胆道癌、肝外胆管癌、肝内胆管癌、膀胱癌、骨关节癌、骨肉瘤、恶性纤维组织细胞瘤、脑癌、脑肿瘤、脑干胶质瘤、室管膜瘤、成神经管细胞瘤、视觉通路和下丘脑神经胶质瘤、乳腺癌、支气管腺瘤、神经系统癌、神经系统淋巴瘤、中枢神经系统癌、中枢神经系统淋巴瘤、宫颈癌、慢性淋巴细胞白血病、慢性粒细胞白血病白血病、慢性骨髓增生性疾病、结肠癌、结直肠癌、皮肤T细胞淋巴瘤、淋巴肿瘤、蕈样真菌病、Sezary综合征、子宫内膜癌、食管癌、颅外生殖细胞肿瘤、性腺外生殖细胞肿瘤、眼癌、眼内黑色素瘤、视网膜母细胞瘤、胆囊癌、胃癌、胃肠道类癌、胃肠道间质瘤(GIST)、生殖细胞肿瘤、卵巢生殖细胞瘤、头颈癌、肝细胞癌、霍奇金淋巴瘤、胰岛细胞瘤、卡波西肉瘤、肾癌、喉癌、急性淋巴细胞白血病、急性髓性白血病、毛细胞白血病、唇和口腔腔癌、肝癌、肺癌、非小细胞肺癌、小细胞肺癌、非霍奇金淋巴瘤、原发性中枢神经系统淋巴瘤、Waldenstroem巨球蛋白血症、黑色素瘤、间皮瘤、转移性鳞癌、舌癌、多发性内分泌肿瘤综合征、骨髓增生异常综合征、多发性骨髓瘤、鼻咽癌、神经母细胞瘤、口咽癌、卵巢癌、卵巢上皮癌、卵巢低恶性潜能肿瘤、胰腺癌、胰岛细胞胰腺癌、鼻窦和鼻腔癌、甲状旁腺癌、阴茎癌、咽癌、嗜铬细胞瘤、松果体瘤、垂体瘤、浆细胞肿瘤、胸膜肺母细胞瘤、前列腺癌、直肠癌、肾盂和输尿管移行细胞癌、视网膜母细胞瘤、横纹肌肉瘤、唾液腺癌、尤文家族肉瘤、卡波西肉瘤、滑膜肉瘤、子宫癌、子宫肉瘤、小肠癌、软组织肉瘤、鳞状细胞癌、幕上原始神经外胚层肿瘤、睾丸癌、咽喉癌、胸腺瘤、尿道癌、子宫内膜异位症、阴道癌、外阴癌或威尔姆氏肿瘤，优选结直肠癌或结肠癌。
可以将本公开的免疫检查点抑制剂构成在组合物中，例如，含有抗体和药学上可接受的载体的药物组合物。本文中使用的“药学上可接受的载体”包括生理学上相容的任意的和所有的溶剂、分散介质、包衣剂、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂等。在一个实施方案中，用于含有抗体的组合物的载体适合静脉、肌肉、皮下、胃肠外、腹腔、脊柱或表皮施用(例如，通过注射或输注)，本公开的药物组合物可以包括一种或多种药学上可接受的盐、抗氧化剂、水性和非水性载体，和/或佐剂，诸如防腐剂、润湿剂、乳化剂和分散剂。
在本公开中优选的实施方案中，所述的PD-1抗体或其抗原结合片段以注射 的方式给药，例如皮下或静脉注射或腹腔，注射前需将PD-1抗体或其抗原结合片段配制成可注射的形式。本公开特别优选的实施方案中抗PD-1抗体的可注射形式是注射液或冻干粉针，其包含PD-1抗体或其抗原结合片段、缓冲剂、稳定剂，任选地还含有表面活性剂。缓冲剂可选自醋酸盐、柠檬酸盐、琥珀酸盐、以及磷酸盐中的一种或几种。稳定剂可选自糖或氨基酸，优选二糖，例如蔗糖、乳糖、海藻糖、麦芽糖。表面活性剂选自聚氧乙烯氢化蓖麻油、甘油脂肪酸酯、聚氧乙烯山梨醇酐脂肪酸酯，优选所述聚氧乙烯山梨醇酐脂肪酸酯为聚山梨酯20、40、60或80，最优选聚山梨酯20。最为优选的PD-1抗体或其抗原结合片段的可注射形式包含PD-1抗体或其抗原结合片段、醋酸盐缓冲剂、海藻糖和聚山梨酯20。
本公开提供一种治疗肿瘤的方法，包括给与患者治疗有效量的上述EZH2抑制剂、免疫检查点抑制剂和多靶点酪氨酸激酶抑制剂。
本公开另一方面提供一种用于治疗肿瘤的EZH2抑制剂，所述EZH2抑制剂与所述免疫检查点抑制剂、多靶点酪氨酸激酶抑制剂联合使用。
本公开另一方面提供一种用于治疗肿瘤的免疫检查点抑制剂，所述免疫检查点抑制剂与EZH2抑制剂、多靶点酪氨酸激酶抑制剂联合使用。
本公开另一方面提供一种多靶点酪氨酸激酶抑制剂，所述多靶点酪氨酸激酶抑制剂与EZH2抑制剂、免疫检查点抑制剂联合使用。
可选的实施方案中，本公开提供的治疗肿瘤的方法，所述患者为人类。
本公开中所述的酪氨酸激酶抑制剂是指能阻断酪氨酸激酶的药物，所述多靶点酪氨酸激酶抑制剂是指能同时对于至少两个受体酪氨酸激酶产生抑制的药物，受体酪氨酸激酶包括但不限于PDGF-R、VEGFR、flt3、EGFR、HER2、FGFR等。
本公开中所述的“联合”是一种给药方式，是指在一定时间期限内给予至少一种剂量的免疫检查点抑制剂、EZH2抑制剂和多靶点酪氨酸激酶抑制剂，其中三种药物都显示药理学作用。所述的时间期限可以是一个给药周期内，例如4周内，3周内，2周内，1周内，或24小时以内。可以同时或不分先后顺序给予免疫检查点抑制剂、EZH2抑制剂和多靶点酪氨酸激酶抑制剂。这种期限包括这样的治疗，其中通过相同给药途径或不同给药途径给予免疫检查点抑制剂、EZH2抑制剂和多靶点酪氨酸激酶抑制剂。
本公开中所述“人源化抗体(humanized antibody)”，也称为CDR移植抗体(CDR-grafted antibody)，是指将小鼠的CDR序列移植到人的抗体可变区框架，即不同类型的人种系抗体构架序列中产生的抗体。可以克服嵌合抗体由于携带大量小鼠蛋白成分，从而诱导的强烈的抗体可变抗体反应。此类构架序列可以从包括种系抗体基因序列的公共DNA数据库或公开的参考文献获得。如人重链和轻链可变区基因的种系DNA序列可以在“VBase”人种系序列数据库(在因特网www.mrccpe.com.ac.uk/vbase可获得)，以及在Kabat，E.A.等人，1991Sequences  of Proteins of Immunological Interest，第5版中找到。在本公开中一个优选的实施方案中，所述的PD-1人源化抗体的CDR序列选自SEQ ID NO:1，2，3，4，5，6。
本公开中所述“抗原结合片段”，指具有抗原结合活性的Fab片段，Fab‘片段，F(ab’)2片段，以及与人PD-1结合的Fv片段sFv片段；包含本公开中所述抗体的选自SEQ ID NO:1至SEQ ID NO:6中的一个或多个CDR区。Fv片段含有抗体重链可变区和轻链可变区，但没有恒定区，并具有全部抗原结合位点的最小抗体片段。一般地，Fv抗体还包含在VH和VL结构域之间的多肽接头，且能够形成抗原结合所需的结构。也可以用不同的连接物将两个抗体可变区连接成一条多肽链，称为单链抗体(single chain antibody)或单链Fv(sFv)。本公开中的术语“与PD-1结合”，指能与人PD-1相互作用。本公开中的术语“抗原结合位点”指抗原上不连续的，由本公开中抗体或抗原结合片段识别的三维空间位点。
附图说明
图1.各组小鼠体重变化曲线图；
图2.CT-26小鼠同种移植模型肿瘤体积变化曲线。
具体实施方式
以下结合实施例用于进一步描述本公开，但这些实施例并非限制本公开的范围。
实施例1、验证受试药在结直肠癌细胞系CT-26雌性huPD-1小鼠同种移植模型中的药效
1、实验材料
1)实验动物
小鼠，huPD-1BALB/c，江苏集萃药康生物科技有限公司，6-8周龄，18-20g，48只加40％冗余共68只。
2)实验细胞
CT-26，来自于中科院，结直肠癌细胞，F3代次；所需细胞量8.2X10E7。
3)实验药物
EZH2抑制剂：式(I)所示化合物；多靶点酪氨酸激酶抑制剂：式(II)所示化合物苹果酸盐；抗PD-1抗体：WO2017054646A公开的PD-1抗体，重、轻链的序列分别如SEQID NO：7、SEQID NO：8所示。
2、实验方法及步骤
1)CT-26细胞复苏，体外培养，获得1X10E8细胞；68只6-8周龄雌性huPD-1 经1周适应性饲养，称重，后每只小鼠于双侧肩胛处皮下接种5*10E5个细胞，每只接种体积为0.1mL。每周1次测量肿瘤体积及体重，选择两侧肿瘤体积均在60-120mm 3之间的小鼠，依据其右侧肿瘤体积和体重随机分为6组，每组8只。分组后随即开始给药。给药开始日期视为第0天，给药及分组信息见表2。给药开始后，小鼠每周3次测量体重及肿瘤体积。
表2.CT26细胞接种小鼠分组及给药信息
Figure PCTCN2020118710-appb-000010
注：a：BID间隔8小时。
2)实验药物配置见表3。
表3.实验药物配置信息
Figure PCTCN2020118710-appb-000011
Figure PCTCN2020118710-appb-000012
3)实验观察及数据收集及统计分析
接种后，每工作日观察动物发病及死亡情况。日常观察包括，肿瘤生长及药物对实验动物造成的影响，如活动变化、摄食饮水变化、消瘦情况、毛发、眼的外观变化、死亡及其他临床症状。接种后至分组前，每周一次测量实验动物体重。分组后每周3次测量实验动物体重或根据客户要求变更测量小鼠体重频率。接种后至分组前，当肿瘤可见时，每周一次测量实验动物肿瘤体积，接种分组后，实验中的动物肿瘤体积每周测量一次。
肿瘤体积测量采用双向测量法，首先利用游标卡尺测量肿瘤长短径，再使用公式TV＝0.5×a×b 2计算肿瘤体积。其中a是肿瘤的长径，b是肿瘤的短径。实验终点时，将采用以下分析方法进行数据分析：％ΔT/C＝(mean(T)-mean(T0))/(mean(C)-mean(C0))*100％；T–给药组肿瘤体积，T0–给药组初始肿瘤体积，C–对照组肿瘤体积，C0–对照组初始肿瘤体积。Mean％ΔInhibition(TGI％)＝((mean(C)-mean(C0))-(mean(T)-mean(T0)))/(mean(C)-mean(C0))*100％；T–给药组肿瘤体积，T0–给药组初始肿瘤体积，C–对照组肿瘤体积，C0–对照组初始肿瘤体积。
3、实验结果
1)小鼠体重
各组体重在不同时间点的平均体重如表4所示。
表4.各组体重变化
Figure PCTCN2020118710-appb-000013
注：a平均值±标准误
各组体重变化百分比见表5。
表5.各组体重变化百分比
Figure PCTCN2020118710-appb-000014
Figure PCTCN2020118710-appb-000015
注：a平均值±标准误
各组小鼠体重变化曲线如图1所示。
2)肿瘤体积数据
在本实验中，1，2，3，4组无瘤内给药，因此左侧和右侧肿瘤视为同样处理方式，数据合并进行分析。第4组34，35#小鼠左侧肿瘤体积用Prism异常值分析为异常值，在统计中予以排除，各个处理组肿瘤各时间点的体积如表6所示。
表6.实验中的各组平均肿瘤体积数据
Figure PCTCN2020118710-appb-000016
注：a平均值±标准误
3)肿瘤生长抑制情况
各组肿瘤生长抑制情况见表7。
表7.受试药CT26模型肿瘤中的抑瘤效果
Figure PCTCN2020118710-appb-000017
注：a平均值±标准误
4)肿瘤各单药组与对应联合用药组两两比较结果见表8。
表8.肿瘤单药组与联合用药组比较
联合用药组 单药组 p值
第4组 第2组 <0.0001
第4组 第3组 0.0486
5)肿瘤生长曲线
各组左右侧肿瘤生长曲线如图2所示。第4组34，35#小鼠左侧肿瘤体积用Prism异常值分析为异常值，在制图中予以排除。
讨论：
EZH2抑制剂(第2组)在p.o.给药后第14天平均肿瘤体积为1871.8±263.53mm 3，与对照组(第1组，第14天肿瘤体积为2020.2±177.82mm 3)相比无显著差异(TGI％＝8％，p＝0.6439)。
抗PD-1抗体与多靶点酪氨酸激酶抑制剂联合给药组(第3组)在给药后第14天平均肿瘤体积为918.4±206.16mm 3，与对照组相比有显著性差异(第1组，第14天肿瘤体积为2020.2±177.82mm 3，TGI％＝57％，p＝0.0003)。
EZH2抑制剂、抗PD-1抗体与多靶点酪氨酸激酶抑制剂联合用药组(第4组)在给药后第14天平均肿瘤体积为425.5±110.32mm 3，与对照组相比有显著性差异(第1组，第14天肿瘤体积为2020.2±177.82mm 3，TGI％＝82％，p<0.0001)。与EZH2抑制剂单独用药组(第2组，p<0.0001)和抗PD-1抗体&多靶点酪氨酸激酶抑制剂给药组(第3组)相比，三药联合用药抑瘤作用更显著(p<0.0001和p＝0.0486)。

Claims (17)

  1. 一种EZH2抑制剂与免疫检查点抑制剂、多靶点酪氨酸激酶抑制剂联合在制备治疗肿瘤的药物中的用途。
  2. 根据权利要求1所述的用途，所述的EZH2抑制剂为式(I)所示化合物或其可药用盐，
    Figure PCTCN2020118710-appb-100001
  3. 根据权利要求1所述的用途，所述的免疫检查点抑制剂为抗PD-1抗体或者其抗原结合片段。
  4. 根据权利要求3所述的用途，所述抗PD-1抗体的轻链可变区包含分别如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示的LCDR1、LCDR2和LCDR3，所述的PD-1抗体的重链可变区包含分别如SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3所示的HCDR1、HCDR2和HCDR3。
  5. 根据权利要求3所述的用途，所述抗PD-1抗体或其抗原结合片段选自人源化抗体或其片段。
  6. 根据权利要求4或5所述的用途，所述抗PD-1抗体或其抗原结合片段包含人源IgG1、IgG2、IgG3或IgG4同种型的重链恒定区，优选包含IgG1或IgG4同种型的重链恒定区。
  7. 根据权利要求5所述的用途，其中所述人源化抗体的轻链可变区序列为如SEQ ID NO:10所示的序列或其变体，所述人源化抗体的重链可变区序列为如SEQ ID NO:9所示的序列或其变体。
  8. 根据权利要求5所述的用途，其中所述人源化抗体的轻链序列为如SEQ  ID NO:8所示的序列或其变体；所述人源化抗体的重链序列为如SEQ ID NO:7所示的序列或其变体。
  9. 根据权利要求5所述的用途，其中所述的人源化抗体轻链序列为如SEQ ID NO:8所示的序列，重链序列为如SEQ ID NO:7所示的序列。
  10. 根据权利要求1所述的用途，所述多靶点酪氨酸激酶抑制剂为式(II)所示化合物或其可药用盐，
    Figure PCTCN2020118710-appb-100002
  11. 根据权利要求10所述的用途，所述多靶点酪氨酸激酶抑制剂为(II)所示化合物苹果酸盐。
  12. 根据权利要求2-11任一项所述的用途，所述EZH2抑制剂为式(I)所示化合物。
  13. 根据权利要求1-12任一项所述的用途，所述肿瘤选自上腺皮质癌、肛门癌、肛门直肠癌、肛管癌、阑尾癌、小脑星形细胞瘤、脑星形细胞瘤、基底细胞癌、皮肤癌(非黑色素瘤)、胆道癌、肝外胆管癌、肝内胆管癌、膀胱癌、骨关节癌、骨肉瘤、恶性纤维组织细胞瘤、脑癌、脑肿瘤、脑干胶质瘤、室管膜瘤、成神经管细胞瘤、视觉通路和下丘脑神经胶质瘤、乳腺癌、支气管腺瘤、神经系统癌、神经系统淋巴瘤、中枢神经系统癌、中枢神经系统淋巴瘤、宫颈癌、慢性淋巴细胞白血病、慢性粒细胞白血病白血病、慢性骨髓增生性疾病、结肠癌、结直肠癌、皮肤T细胞淋巴瘤、淋巴肿瘤、蕈样真菌病、Sezary综合征、子宫内膜癌、食管癌、颅外生殖细胞肿瘤、性腺外生殖细胞肿瘤、眼癌、眼内黑色素瘤、视网膜母细胞瘤、胆囊癌、胃癌、胃肠道类癌、胃肠道间质瘤(GIST)、生殖细胞肿瘤、卵巢生殖细胞瘤、头颈癌、肝细胞癌、霍奇金淋巴瘤、胰岛细胞瘤、卡波西肉瘤、肾癌、喉癌、急性淋巴细胞白血病、急性髓性白血病、毛细胞白血病、唇和口腔腔癌、肝癌、肺癌、非小细胞肺癌、小细胞肺癌、非霍奇金淋巴瘤、原 发性中枢神经系统淋巴瘤、Waldenstroem巨球蛋白血症、黑色素瘤、间皮瘤、转移性鳞癌、舌癌、多发性内分泌肿瘤综合征、骨髓增生异常综合征、多发性骨髓瘤、鼻咽癌、神经母细胞瘤、口咽癌、卵巢癌、卵巢上皮癌、卵巢低恶性潜能肿瘤、胰腺癌、胰岛细胞胰腺癌、鼻窦和鼻腔癌、甲状旁腺癌、阴茎癌、咽癌、嗜铬细胞瘤、松果体瘤、垂体瘤、浆细胞肿瘤、胸膜肺母细胞瘤、前列腺癌、直肠癌、肾盂和输尿管移行细胞癌、视网膜母细胞瘤、横纹肌肉瘤、唾液腺癌、尤文家族肉瘤、卡波西肉瘤、滑膜肉瘤、子宫癌、子宫肉瘤、小肠癌、软组织肉瘤、鳞状细胞癌、幕上原始神经外胚层肿瘤、睾丸癌、咽喉癌、胸腺瘤、尿道癌、子宫内膜异位症、阴道癌、外阴癌或威尔姆氏肿瘤，优选结直肠癌、结肠癌。
  14. 根据权利要求1-13任一项所述的用途，所述EZH2抑制剂的剂量选自1-1600mg，给药频次为每天2次、每天1次、每2天1次、每3天一次、每4天一次、每5天一次、每6天一次、每周一次、每2周一次、每3周一次、每4周一次，优选每天2次或每天1次。
  15. 根据权利要求14所述的用途，所述免疫检查点抑制剂的剂量选自0.1-10.0mg/kg或1-1000mg，给药频次为每周一次、每2周一次、每3周一次、每4周一次、1个月一次、每3-6个月一次，优选每2周一次或每3周一次。
  16. 根据权利要求15所述的用途，所述多靶点酪氨酸激酶抑制剂的剂量为0.1-1000mg或0.1-10mg/kg，给药频次为每天1次、每天2次或每天3次，优选每天1次。
  17. 根据权利要求16所述的用途，所述多靶点酪氨酸激酶抑制剂的剂量为给药剂量选自15mg、20mg、25mg，给药频次为每天1次、每天2次或每天3次，优选每天1次。
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