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WO2019072220A1 - Pd-1抗体和表观遗传调节剂联合在制备治疗肿瘤的药物中的用途 - Google Patents

Pd-1抗体和表观遗传调节剂联合在制备治疗肿瘤的药物中的用途 Download PDF

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WO2019072220A1
WO2019072220A1 PCT/CN2018/109945 CN2018109945W WO2019072220A1 WO 2019072220 A1 WO2019072220 A1 WO 2019072220A1 CN 2018109945 W CN2018109945 W CN 2018109945W WO 2019072220 A1 WO2019072220 A1 WO 2019072220A1
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tumor
antibody
cancer
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French (fr)
Inventor
韩为东
王春萌
刘洋
杨清明
聂晶
沈连军
陶维康
邹建军
曹国庆
杨昌永
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Jiangsu Hengrui Medicine Co Ltd
Chinese PLA General Hospital
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Jiangsu Hengrui Medicine Co Ltd
Chinese PLA General Hospital
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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • 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

Definitions

  • an anti-PD-1 antibody in combination with an epigenetic modulator in the manufacture of a medicament for treating tumors and/or enhancing T-cell activity.
  • PD-1 (programmed death receptor 1) antibody can specifically recognize and bind to PD-1 on the surface of lymphocytes, block PD-1/PD-L1 signaling pathway, and then activate T cell immune killing effect on tumors.
  • the immune system removes tumor cells from the body.
  • Epigenetic changes are closely related to cancer development and drug resistance. As the study progressed, it was found that there was resistance after repeated administration of PD-1 antibody to patients.
  • DNA methylation inhibitor decitabine It has been approved for hematologic treatment of malignant tumors and its clinical efficacy in solid tumors. Various animal models and cell line studies have shown that decitabine induces genes that control apoptosis, cell cycle arrest, and tumor surface antigens.
  • WO2015035112 discloses an epigenetic modulator combined with an immunomodulator for treating a tumor, wherein the epigenetic regulator is selected from the group consisting of For citrate, the immunomodulator may be selected from the group consisting of PD-1/PD-L1 antibodies.
  • the anti-PD-1 antibody provided by the present invention discloses the sequence and preparation method of the antibody, and the PD-1 antibody is currently in the clinical phase I of China, and the safety is good, and the reported clinical research results have shown that it has certain Antitumor effect ([J]. Journal of Clinical Oncology 35 (2017): e15572-e15572).
  • the invention provides the use of an immunotherapeutic agent in combination with an epigenetic modulator in the manufacture of a medicament for treating a tumor and/or enhancing T-cells, the immunotherapeutic agent being selected from the group consisting of PD-1 antibodies.
  • a PD-1 antibody is known, and preferably the light chain variable region of the PD-1 antibody comprises LCDR1, LCDR2 and 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 comprises HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively.
  • the PD-1 antibody is a humanized antibody.
  • the humanized antibody light chain variable region sequence is the sequence set forth in SEQ ID NO: 10 or a variant thereof; said variant preferably has a 0-10 amino acid change in the light chain variable region; Amino acid changes of A43S are preferred.
  • the humanized antibody heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 9 or a variant thereof; the variant preferably has an amino acid change of 0-10 in the heavy chain variable region; more preferably Amino acid changes in G44R.
  • variable region sequences of the heavy and light chains of the aforementioned humanized antibodies are as follows:
  • the humanized antibody light chain sequence is the sequence set forth in SEQ ID NO: 8 or a variant thereof; said variant preferably has a 0-10 amino acid change in the light chain variable region; more preferably A43S Amino acid changes.
  • the humanized antibody heavy chain sequence is the sequence set forth in SEQ ID NO: 7 or a variant thereof; the variant preferably has an amino acid change of 0-10 in the heavy chain variable region; more preferably an amino acid of G44R Variety.
  • the humanized antibody light chain sequence is the sequence set forth in SEQ ID NO: 8
  • the heavy chain sequence is the sequence set forth in SEQ ID NO: 7.
  • sequences of the aforementioned humanized antibody heavy and light chains are as follows:
  • the epigenetic regulator is selected from the group consisting of a demethylating agent, a DNA methyltransferase (DNMT) inhibitor, a histone deacetylase (HDAC) inhibitor, or
  • the DNMT inhibitor is selected from the group consisting of guadecitabine, RX-3117, Lenalidomide and azacitidine compound, EPI-01, decitabine and E-7727 compound, RRx-001, temozolomide, CM-272, KM -101, KRX-0402, TdCyd, UVI-5008, azacitidine prodrug, decitabine prodrug, aza-T-dCyd, XB-05, PMX-700, CP-4200; said HDAC inhibitor Selected from mocetinostat, entinostat, purinostat, largazole, largazole analog, ACY-738, resminostat, VRx-3996, gi
  • the epigenetic regulator is selected from the group consisting of azacitidine, decitabine, Fludarabine, Guadecitabine, Zebularine, NPEOC-DAC, CP-4200, Vorinostat, Romidepsin, Panobinostat, CI -994,5,6-dihydro-5-azacytidine, 5-fluoro-2'-deoxycytidine, RX-3117, epigallocatechin gallate (EGCG), genistein, curcumin Oligonucleotides, preferably from decitabine, azacitidine, Guadecitabine, Romidepsin, Fludarabine.
  • EGCG epigallocatechin gallate
  • Oligonucleotides preferably from decitabine, azacitidine, Guadecitabine, Romidepsin, Fludarabine.
  • the tumor is selected from the group consisting of a malignant tumor and a benign tumor; and the malignant tumor is selected from the group consisting of a malignant epithelial tumor, a sarcoma, a myeloma, a leukemia, a lymphoma, Melanoma, head and neck tumor, brain tumor, mixed tumor, childhood malignant tumor; the malignant epithelial tumor is selected from the group consisting of lung cancer, breast cancer, liver cancer, pancreatic cancer, colorectal cancer, stomach cancer, gastroesophageal adenocarcinoma, esophageal cancer , small bowel cancer, cardia cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, vulvar cancer, testicular cancer, prostate cancer, penile cancer, kidney cancer, bladder cancer, anal cancer, gallbladder cancer, cholangiocarcinoma, teratoma, heart Tumor
  • the lung cancer is selected from the group consisting of the lung cancer selected from the group consisting of non-small cell lung cancer and small cell lung cancer; and the breast cancer is selected from the group consisting of the hormone receptor (HR) positive.
  • Breast cancer human epidermal growth factor receptor-2 (HER2)-positive breast cancer, triple-negative breast cancer;
  • the renal cancer is selected from the group consisting of transparent renal cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, and collecting duct
  • the cancer of the neuroepithelial tissue is selected from the group consisting of: preferably astrocytoma, anaplastic astrocytoma, glioblastoma;
  • the liver cancer is selected from the group consisting of primary liver cancer, secondary liver cancer, and primary liver cancer. It is selected from the group consisting of hepatocellular carcinoma, cholangiocarcinoma, and mixed liver cancer; and the colorectal cancer is selected from the group consisting of colon cancer and rectal cancer.
  • the tumor is selected from the group consisting of a solid tumor, Hodgkin's lymphoma, non-Hodgkin's lymphoma, prostate cancer, pancreatic cancer, lung cancer, esophageal cancer, liver cancer, cholangiocarcinoma, breast. Cancer, colorectal cancer, gastric cancer, kidney cancer, acute myeloid lymphocytic leukemia, myelodysplastic syndrome, glioma.
  • the tumor is mediated and/or expresses PD-L1 by PD-1.
  • the tumor is selected from the group consisting of a middle-stage tumor, a relapsed and refractory tumor, a chemotherapy-treated drug failure and/or a recurrent tumor, a radiotherapy failure and/or a recurrent tumor, and a targeted drug treatment. Failure and/or recurrence of the tumor, failure of immunotherapy, and/or recurrence of the tumor.
  • the tumor is either resistant or resistant to immunotherapeutics or immunotherapy
  • the immunotherapeutic agent is PD-1 and/or PD-L1 or CTLA- 4 (cytotoxic T lymphocyte-associated protein 4) as a target
  • the immunotherapy is selected from the group consisting of immunological checkpoint block (ICB) therapy, chimeric antigen receptor T cell immunotherapy (CAR-T therapy), autologous cellular immunity Therapy (CIK therapy).
  • IB immunological checkpoint block
  • CAR-T therapy chimeric antigen receptor T cell immunotherapy
  • CIK therapy autologous cellular immunity Therapy
  • the immunotherapeutic agent is selected from the group consisting of a PD-1 antibody, a PD-L1 antibody, and a CTLA-4 antibody, and the PD-1 antibody includes, but is not limited to, Pidilizumab, MEDI-0680.
  • PD-L1 Antibodies include, but are not limited to, MSB-0011359-C, CA-170, LY-3300054, BMS-936559, Durvalumab, Avelumab, Atezolizumab;
  • CTLA-4 antibodies include, but are not limited to, ipilimumab, AK-104, JHL-1155, ATOR -1015, AGEN-1884, PRS-010, tremelimumab, IBI-310, MK-1308, BMS-986218, SN-CA21, FPT-155, KN-044, CG-0161, ONC-392, AGEN-2041, PBI -5D3H5.
  • a PD-1 antibody in combination with an epigenetic modulator for the preparation of a medicament for enhancing T-cell activity, preferably a peripheral T-cell.
  • the PD-1 antibody dose is selected from the group consisting of 1-10 mg/kg, preferably from 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg. 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, more preferably 3 mg/kg, 4 mg/kg, 5 mg/kg.
  • the PD-1 antibody dose is selected from the group consisting of 50-600 mg, preferably from 50 mg, 60 mg, 70 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 375 mg, 400 mg. 425 mg, 450 mg, 475 mg, 500 mg, 600 mg, more preferably from 100 mg, 200 mg, 400 mg.
  • the epigenetic modulator dose is selected from the group consisting of 5-100 mg/m 2 , preferably from 5 mg/m 2 , 6 mg/m 2 , 7 mg/m 2 , 8 mg/m 2 , 9 mg/ m 2 , 10 mg/m 2 , 12 mg/m 2 , 15 mg/m 2 , 20 mg/m 2 , 25 mg/m 2 , 30 mg/m 2 , 35 mg/m 2 , 40 mg/m 2 , 50 mg/m 2 , 60 mg/ m 2 , 75 mg/m 2 ; more preferably 7 mg/m 2 , 10 mg/m 2 , 12 mg/m 2 , 15 mg/m 2 , 20 mg/m 2 , 25 mg/m 2 , 30 mg/m 2 , 40 mg/m 2 , 50 mg/m 2 , 75 mg/m 2 .
  • the epigenetic modulator dose is selected from the group consisting of 5 to 500 mg, preferably from 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg. 275 mg, 300 mg, 400 mg, 500 mg, more preferably 10 mg, 20 mg, 100 mg, 200 mg, 300 mg.
  • the weight ratio of the PD-1 antibody to the epigenetic regulator is selected from 0.01 to 100:1, preferably from 5:1, 4:1, 3:1, 5:2. , 2:1, 7:4, 3:2, 4:3, 5:4, 1:1, 3:4, 2:3, 3:5, 1:2, 2:5, 1:3, 3 :10, 1:4, 40:1, 25:1, 20:1, 15:1, 25:2, 12:1, 10:1, 8:1, 9:2, 25:4, 6:1 20:3, 15:4; more preferably from 5:1, 4:1, 3:1, 5:2, 2:1, 1:1, 2:3, 4:3, 40:1, 20: 1.
  • the combination further comprises a third component selected from the group consisting of an alkylating agent, a platinum complexing agent, a metabolic antagonist, a plant alkaloid, a hormone anticancer agent, and a protease.
  • a third component selected from the group consisting of an alkylating agent, a platinum complexing agent, a metabolic antagonist, a plant alkaloid, a hormone anticancer agent, and a protease.
  • a body inhibitor an aromatase inhibitor, an immunomodulator, an EGFR inhibitor, an ALK inhibitor, a PARP inhibitor VEGF antibody, a VEGFR inhibitor, and an mTOR inhibitor.
  • the chemotherapeutic agent is selected from the group consisting of an alkylating agent, a platinum complexing agent, a metabolic antagonist, a plant alkaloid (such as a vinblastine, a harringtonine), a hormone anticancer agent, a proteasome inhibitor, and a fragrance.
  • the chemotherapeutic agent includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, busulfan, and nevi Mustidine, ramustine, dacarbazine, temozolomide, hydrochloric acid mustard, dibromomannitol, cisplatin, carboplatin, oxaliplatin, nedaplatin, methotrexate, 5-fluorouracil, tega Fluoride, gemcitabine, capecitabine, fulvestrant, pemetrexed, anthracyclines, mitomycin, bleomycin, actinomycin, vinblastine, camptothecin, paclitaxel , vincristine, vinblastine, vindesine, etoposide, docetaxel, paclitaxel, albumin-bound paclitaxel, paclitaxel liposome, ir
  • the targeted drug is selected from the group consisting of an EGFR inhibitor, an ALK inhibitor, a PARP inhibitor, a VEGF antibody and a VEGFR inhibitor, an mTOR inhibitor, one or more of the treatments.
  • the EGFR inhibitor may be selected from the group consisting of gefitinib, erlotinib, ectinib, and afatinib, cetuximab, trastuzumab.
  • ALK inhibitors may be selected from the group consisting of crizotinib, ceritinib, axitinib, Brigatinib; VEGF antibodies are selected from bevacizumab, Brolucizumab, Vanucizumab, Navicixizumab, Ranibizumab, Conbercept One or more; the VEGFR inhibitor is selected from one or more of sunitinib, apatinib, and faritinib;
  • the third component is selected from the group consisting of gemcitabine, cisplatin, carboplatin, paclitaxel albumin, paclitaxel liposome, paclitaxel, docetaxel, cyclophosphamide, doxorubicin, One or more of epirubicin, vincristine, tegafur, tegafur, 5-fluorouracil, and Tetrahydrouridine.
  • the third component may be based on a patient's body surface area, body weight, or KPS functional status scoring standard or ECOG physical status scoring standard (Zubrod-ECOG-WHO) and various tumor diagnosis and treatment guidelines.
  • the dosages and dosing regimens recommended for different types of tumor chemotherapy regimens are selected.
  • the albumin-paclitaxel dose of 50-500mg / m 2, preferably 125mg / m 2; gemcitabine, gemcitabine dose of 500-2000mg / m 2, preferably 1000mg / m 2; cisplatin dose of 25-200mg / m 2 , preferably 75 mg/m 2 .
  • the treatment period may be 1 day, 3 days, 1 week, 2 weeks, 3 weeks, 3-4 weeks, 4 weeks, preferably 3 weeks or 3-4 weeks or 4 weeks.
  • the treatment cycle includes, but is not limited to, a chemotherapy cycle or a radiation therapy cycle or other related targeted drug therapy cycle or immunotherapy cycle.
  • a PD-1 antibody is used in combination with an epigenetic modulator for a tumor, and the order of administration of the two is administered by an epigenetic modulator before administration of the PD-1 antibody, or both.
  • an epigenetic modulator is administered after administration of the PD-1 antibody; preferably, the epigenetic modulator is administered prior to administration of the PD-1 antibody.
  • the epigenetic agent and the PD-1 antibody can be used in combination for treating tumors in the same or different treatment cycles, and the epigenetic agent is administered in combination with the PD-1 antibody during the treatment of the tumor.
  • the tumor may be treated in combination according to different tumor preferred chemotherapy regimens or radiotherapy treatment regimens or targeted small molecule drug treatment regimens or immunotherapy regimens, including but not limited to cellular immunotherapy (eg CAR- T therapy, tumor vaccine, CIK therapy, etc.); in addition, the combination of an epigenetic agent with a PD-1 antibody may also be administered alone in combination with other treatment regimens.
  • the PD-1 antibody and the epigenetic regulator can be combined with different pathological types and progression stages of tumors according to various tumor diagnosis norms or guidelines, the tumors.
  • Medical treatment norms or guidelines include, but are not limited to, NCCN (National Comprehensive Cancer Network publishes guidelines for clinical practice of various malignancies) or the guidelines for the diagnosis and treatment of malignant tumors issued by the Chinese Ministry of Health.
  • the epigenetic regulator can be used in 1-2 treatment cycles prior to conventional tumor treatment protocols including, but not limited to, chemotherapy, radiotherapy, small molecule targeted therapy, surgical resection, endoscopic treatment.
  • Continuous administration in any one of the 1-7 day period, preferably in a period of 1-5 days, during which the PD-1 antibody is administered concurrently with the epigenetic modulator or
  • the PD-1 antibody can be administered on the first day, the second day, the third day, the fourth day after the end of the administration of the decitabine, before the epigenetic modulator or after the epigenetic modulator.
  • Dosing on days, 5th, 6th, and 7th, preferably on days 3, 4, and 5; preferably, PD-1 antibodies can be administered before the start of decitabine administration. Dosing on the 1st day, the first 2 days, the first 3 days, the first 4 days, the first 5 days, the first 6 days, the first 7 days, preferably the first 3 days, the first 4 days, the first 5 days; the epigenetic regulation
  • the agent is selected from the group consisting of decitabine and azacitidine; the dose of decitabine is preferably 10 mg or 7 mg/m 2 .
  • the present invention relates to "combination" as a mode of administration, which means administering at least one dose of PD-1 antibody and at least one dose of an epigenetic modulator over a certain period of time, both of which exhibit pharmacology. effect.
  • the time period may be within one administration period, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours, within 12 hours.
  • the PD-1 antibody and epigenetic modulator can be administered simultaneously or sequentially.
  • Such a term includes a treatment in which a PD-1 antibody and an epigenetic modulator are administered by the same route of administration or by different routes of administration.
  • the combined modes of administration of the present invention are selected from the group consisting of simultaneous administration, independent formulation and co-administration or independently formulated and administered sequentially.
  • the invention further relates to the use of the medicament, wherein the frequency of administration of the PD-1 antibody is once a day, twice a day, three times a day, once a week, once every two weeks, once every three weeks, one time Once a month, the frequency of administration of epigenetic regulators is once a day, twice a day, three times a day, once a week, once every two weeks, once every three weeks, once a month.
  • decitabine is administered at a dose of 10 mg/day for 5 days per day for a period of 21 days, and a PD-1 antibody of 4 mg/kg is administered once per week; wherein the PD-1 antibody is also A fixed dose of 200 mg or 400 mg per patient (weight greater than 80 kg); 8 dosing cycles can be administered according to this method of administration.
  • 21 days is a dosing cycle, 10th day / 5th day of the first dosing cycle is given 10 mg / day of decitabine; on day 8 is administered PD-1 antibody 4 mg / kg;
  • the PD-1 antibody can also be administered in a fixed dose of 200 mg or 400 mg per patient (weight greater than 80 kg).
  • the PD-1 antibody is administered by injection, for example subcutaneously or intravenously, and the PD-1 antibody is formulated in an injectable form prior to injection.
  • a particularly preferred injectable form of the PD-1 antibody is an injection or lyophilized powder comprising a PD-1 antibody, a buffer, a stabilizer, and optionally a surfactant.
  • the buffering agent may be selected from one or more of the group consisting 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 the group consisting of 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 preferred is polysorbate 20. Injectable forms of the most preferred PD-1 antibodies comprise PD-1 antibody, acetate buffer, trehalose and polysorbate 20.
  • the combined administration routes of the present invention are selected from the group consisting of oral administration, parenteral administration, and transdermal administration, and include, but are not limited to, intravenous injection, subcutaneous injection, and intramuscular injection.
  • the present invention provides the above immunotherapeutic agent in combination with the above epigenetic modulator as a therapeutic preparation for treating tumors and/or enhancing T-cell activity.
  • a method of treating tumors and/or enhancing T-cell activity comprising administering to a patient an immunotherapeutic agent as described above and the above epigenetic modulator.
  • the present invention also provides a pharmaceutical kit, or a pharmaceutical pack comprising the aforementioned epigenetic modulator and PD-1 antibody.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the aforementioned effective amount of a PD-1 antibody and an epigenetic modulator, and one or more pharmaceutically acceptable excipients, diluents or carriers.
  • immunotherapy refers to the use of the immune system to treat diseases, and in the present invention mainly refers to stimulating and enhancing the body's anti-tumor immune response by increasing the immunogenicity of tumor cells and sensitivity to effector cell killing, and applying The immune cells and effector molecules are infused into the host to cooperate with the body's immune system to kill tumors and inhibit tumor growth.
  • Example 1 Decitabine combined with PD-1 antibody in the treatment of relapsed and refractory Hodgkin's lymphoma
  • the PD-1 antibody was prepared according to the method disclosed in WO2015085847, corresponding to the code number H005-1, and the sequences of the heavy and light chains thereof are SEQ ID NO: 7 and SEQ ID NO: 8 in the present invention.
  • diazepam lyophilized powder injection 50mg/bottle, reconstituted with sterile water for injection, formulated into a solution of about 5mg/mL, and then formulated with physiological saline, 0.5% glucose solution or lactic acid green solution according to clinical requirements. A 0.1-1 mg/mL solution was used.
  • Lymphoma subjects define at least one 1 cm measurable lesion by lymphoma response criteria
  • the enrolled subjects were given 10 mg/d of decitabine 10 mg/d on the 1st to 5th day of the first administration cycle (21 days); the PD-1 antibody was administered 200 mg on the 8th day (if the body weight exceeded 80 kg, 400 mg) was administered, and 8 administration cycles were cycled according to this administration method.
  • Example 2 Decitabine combined with PD-1 antibody in the treatment of relapsed and refractory malignant tumors
  • the subjects were given 10 mg/d of decitabine 10 mg/d on the 1st to 5th day of the first administration period (21 days), and the PD-1 antibody was administered 4 mg/kg on the 8th day.
  • the drug method is cycled for 8 dosing cycles.
  • Example 3 Decitabine combined with PD-1 antibody in the treatment of relapsed and refractory malignant tumors
  • a total of 24 subjects were enrolled, including 18 Hodgkin's lymphoma, 2 B-cell non-Hodgkin's lymphoma, and 4 solid tumors (2 colorectal cancer, 1 kidney cancer, 1 breast cancer); the final evaluable target was 23 people.
  • Eight of the 18 Hodgkin's lymphoma subjects had previously received 3-13 Nivolumab or Pembrolizumab treatments, 5 had previously received CAR-T treatment, and 2 had B-cell non-Hodgkin's lymphoma subjects. He had previously received 13 treatments for Nivolumab, and one had previously received CAR-T treatment; 2 of the 4 solid tumor subjects had previously received 2 or 10 Nivolumab treatments, and 1 had previously received 4 CIK treatments.
  • the subjects were given 10 mg/d of decitabine 10 mg/d on the 1st to 5th day of the first administration period (21 days), and the PD-1 antibody was administered 4 mg/kg on the 8th day.
  • the drug method is cycled for 8 dosing cycles.
  • the control rate (DCR) of relapsed and refractory malignant tumors treated with decitabine + PD-1 antibody is as high as 21/23 (91 %).
  • the treatment of relapsed and refractory malignant tumor with decitabine + PD-1 antibody is undoubtedly prolonging the patient who is tolerated or relapsed by PD-1 antibody treatment and tolerated or relapsed by CAR-T treatment or CIK treatment. Survival provides an important treatment path.

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Abstract

本发明提供了PD-1抗体和表观遗传调节剂联合在制备治疗肿瘤的药物中的用途。具体而言，本发明提供了PD-1抗体和表观遗传调节剂联合在制备治疗肿瘤和/或增强T-细胞活性的药物中的用途。

Description

PD-1抗体和表观遗传调节剂联合在制备治疗肿瘤的药物中的用途 技术领域
抗PD-1抗体和表观遗传调节剂联合在制备治疗肿瘤和/或增强T-细胞活性的药物中的用途。
背景技术
PD-1(程序性死亡受体1)抗体可以特异性识别并结合淋巴细胞表面PD-1，阻断PD-1/PD-L1信号通路，进而激活T细胞对肿瘤的免疫杀伤作用，调动机体免疫系统而清除体内肿瘤细胞。表观遗传改变与癌症发展和耐药性密切相关。随着研究的深入，发现向患者重复施用PD-1抗体后存在耐药情况。DNA甲基化抑制剂地西他滨
Figure PCTCN2018109945-appb-000001
已被批准用于血液学治疗恶性肿瘤及其对实体瘤的临床疗效受到关注，各种动物模型和细胞系研究表明，地西他滨诱导控制细胞凋亡、细胞周期停滞以及肿瘤表面抗原的基因表达；通过DNA去甲基化效应诱导主要组织相容性复合体(MHC)和共刺激分子，其结果导致地西他滨提高了抗肿瘤免疫治疗的响应率、抑制肿瘤生长。研究发现甲基化修饰以及特定基因的沉默可能对T-细胞的成熟和定型过程中发挥关键作用，已有报道5-阿扎胞苷可增加以PD-1/PD-L1(程序性死亡配体1)为靶点的免疫检查点治疗的敏感度，因此表观遗传学治疗联合免疫治疗可提高肿瘤临床治疗的有效性(Cancer letters 354.1(2014):12-20)。Riccadonna等人的研究表明去甲基化剂具有提高免疫疗法对各种神经胶质瘤细胞识别和随后的破坏，其细胞和动物试验表明地西他宾联合多种免疫疗法对恶性胶质瘤模型具有良好抑瘤效果([J].PloS one,2016,11(8):e0162105)；Tamas A等人的研究发现地西他滨联合免疫检查点抑制剂(Anti-PD-1H)，尤其是在在KBC胰腺癌模型小鼠中可显著提高抑瘤效率，在地西他滨给药后发现显著升高T细胞PD-1H的表达，地西他滨接续抗PD-1H治疗可显著延长小鼠生存期([J].Gastroenterology,2017,152(5):S42-S43)；WO2015035112公开了一种表观遗传调节剂联合免疫调节剂用于治疗肿瘤，其中表观遗传调节剂选自地西他滨，免疫调节剂可选自PD-1/PD-L1抗体。
目前临床研究已逐步开展地西他滨联合抗PD-1抗体的治疗，PD-1抗体 Nivolumab联合阿扎胞苷治疗复发难治性AML(急性髓性淋巴细胞白血病)的临床研究中有18％的患者疗效评价为CR([J].Blood 2016 128:763)；Chunmeng Wang报道的PD-1抗体联合地西他滨治疗晚期和未治疗的恶性肿瘤的I期临床研究显示入组的11名患者中有1名患者疗效评价为CR([J].Journal of Clinical Oncology 35(2017):e14555-e14555)。PD-L1抑制剂Durvalumab联合口服阿扎胞苷治疗既往对地西他滨或阿扎胞苷不敏感的骨髓增生异常综合征的II期临床研究正在进行中(NCT02281084)；PD-1抑制剂Pembrolizumab联合地西他滨治疗复发难治性AML也正在开展中(NCT02996474)，但目前已有报道的临床结果仍不甚理想，对于难治性肿瘤总生存期的延长并不令人满意，而正在进行临床研究的结果尚未可知，如何筛选最佳的PD-1/PD-L1抑制剂与DNA去甲基化抑制剂获得最佳抑瘤效果并同时兼顾安全性仍然是临床亟待解决的问题。
本发明提供的抗PD-1抗体，WO2015085847公开了该抗体的序列和制备方法，目前PD-1抗体正处于国内临床I期，安全性良好，已报到的临床研究结果已经显示出其具有一定的抗肿瘤作用([J].Journal of Clinical Oncology 35(2017):e15572-e15572)。
发明内容
本发明提供免疫治疗剂和表观遗传调节剂联合在制备治疗肿瘤和/或增强T-细胞的药物中的用途，所述免疫治疗剂选自PD-1抗体。
PD-1抗体是已知的，优选所述的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序列如下表所示：
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。
优选的，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；所述的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、轻链的可变区序列如下所示：
重链可变区
Figure PCTCN2018109945-appb-000002
轻链可变区
Figure PCTCN2018109945-appb-000003
优选的，人源化抗体轻链序列为如SEQ ID NO:8所示的序列或其变体；所述的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。
特别优选的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。
前述的人源化抗体重、轻链的序列如下所示：
重链
Figure PCTCN2018109945-appb-000004
轻链
Figure PCTCN2018109945-appb-000005
本发明优选的实施例方案中，所述表观遗传调节剂选自去甲基化剂、DNA甲基转移酶(DNMT)抑制剂、组蛋白去乙酰化酶(HDAC)抑制剂的一种或多种，其中所述DNMT抑制剂选自guadecitabine、RX-3117、Lenalidomide和阿扎胞苷复方、EPI-01、地西他滨和E-7727复方、RRx-001、替莫唑胺、CM-272、KM-101、KRX-0402、TdCyd、UVI-5008、阿扎胞苷前药、地西他滨前药、aza-T-dCyd、XB-05、PMX-700、CP-4200；所述HDAC抑制剂选自mocetinostat、entinostat、purinostat、largazole、largazole类似物、ACY-738、resminostat、VRx-3996、givinostat、MPT-0E028、tucidinostat、TMB-ADC、romidepsin、panobinostat、4SC-202、abexinostat、CUDC-907、vorinostat、pracinostat、HLY-0019、DWP-0016、remetinostat、苯丁酸钠、丙戊酸、CKD-509、CKD-504、CKD-506、CKD-581、ricolinostat、CG-200745、AR-42、SP-2-59、citarinostat、vorinostat、AP-001、quisinostat、SP-1-161、RCY-1497、belinostat、trichostatin A、TMP-195、RND-001、GSK-3117391、ACY-1083、tefinostat、tinostamustine、SF-2558HA、CXD-101、JW-1521、CG-1255、LB-205、LB-201、OCID-4681、QTX-153、APH-0812、CX-1026、OBP-801、CS-3158、RG-2833、TL-112、HG-3001、KDAC-001、thailandepsin B、QTX-125、RGFP-966、SP-1003、BEBT-908、BRD-3308、BEBT-201、BEBT-906、ACY-257、NMB-T-BMX-OS01、NBM-HD-1、zebularine。
本发明另外优选的实施例方案中，所述表观遗传调节剂选自阿扎胞苷、地西他滨、Fludarabine、Guadecitabine、Zebularine、NPEOC-DAC、CP-4200、Vorinostat、Romidepsin、Panobinostat、CI-994、5,6-二氢-5-氮杂胞苷、5-氟-2’-脱氧胞苷、RX-3117、表没食子儿茶素没食子酸酯(EGCG)、染料木黄酮、姜黄素、寡核苷酸类，优选自地西他滨、阿扎胞苷、Guadecitabine、Romidepsin、Fludarabine。
本发明优选的实施例方案中，在本发明优选的实施例方案中，所述肿瘤选自恶性肿瘤、良性肿瘤；所述恶性肿瘤选自恶性上皮肿瘤、肉瘤、骨髓瘤、白血病、淋巴瘤、黑色素瘤、头颈部肿瘤、脑部肿瘤、混合型肿瘤、儿童恶性肿瘤；所述 恶性上皮肿瘤选自肺癌、乳腺癌、肝癌、胰腺癌、结直肠癌、胃癌、胃食管腺癌、食管癌、小肠癌、贲门癌、子宫内膜癌、卵巢癌、输卵管癌、外阴癌、睾丸癌、前列腺癌、阴茎癌、肾癌、膀胱癌、肛门癌、胆囊癌、胆管癌、畸胎瘤、心脏肿瘤；所述头颈部肿瘤选自鼻咽癌、喉癌、甲状腺癌、舌癌、口腔癌；所述肉瘤选自Askin瘤、软骨肉瘤、尤文氏肉瘤、恶性血管内皮瘤、恶性神经鞘瘤、骨肉瘤、软组织肉瘤；所述骨髓瘤选自孤立型骨髓瘤、多发型骨髓瘤、弥漫型骨髓瘤、白血病型骨髓瘤、髓外型骨髓瘤；所述白血病选自急性淋巴性白血病、慢性淋巴性白血病、急性骨髓性白血病、慢性骨髓性白血病、多毛细胞性白血病、T细胞淋巴细胞白血病、大颗粒淋巴细胞性白血病、成人T细胞白血病；所述淋巴瘤选自非霍奇金淋巴瘤、霍奇金淋巴瘤；所述脑部肿瘤选自神经上皮组织肿瘤、颅神经和脊髓神经肿瘤、脑膜组织肿瘤；所述儿童恶性肿瘤选自肾母细胞瘤、神经母细胞瘤、视网膜母细胞瘤、儿童生殖细胞肿瘤。
在本发明另外一个优选的实施例方案中，所述肺癌选自所述肺癌选自非小细胞肺癌、小细胞肺癌；所述乳腺癌选自所述乳腺癌选自激素受体(HR)阳性乳腺癌、人表皮生长因子受体-2(HER2)阳性乳腺癌、三阴乳腺癌；所述肾癌选自透明肾细胞癌、乳头状肾细胞癌、嫌色细胞性肾细胞癌、集合管癌；所述神经上皮组织肿瘤选自优选星形细胞瘤、间变性星形细胞瘤、胶质母细胞瘤；所述肝癌选自原发性肝癌、继发性肝癌，所述原发性肝癌选自肝细胞癌、胆管细胞癌、混合性肝癌；所述结直肠癌选自结肠癌、直肠癌。
在本发明另外一个优选的实施例方案中，所述肿瘤选自实体瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、前列腺癌、胰腺癌、肺癌、食管癌、肝癌、胆管癌、乳腺癌、结直肠癌、胃癌、肾癌、急性髓性淋巴细胞白血病、骨髓增生异常综合征、胶质瘤。
在本发明优选的实施例方案中，所述肿瘤由PD-1介导和/或表达PD-L1。
在本发明优选的实施例方案中，所述肿瘤选自中晚期肿瘤、复发难治性肿瘤、经化疗药物治疗失败和/或复发肿瘤、经放疗失败和/或复发肿瘤、经靶向药物治疗失败和/或复发肿瘤、经免疫治疗失败和/或复发肿瘤。
在本发明优选的实施例方案中，所述肿瘤对免疫治疗剂或免疫疗法或表现为抵抗或耐药，优选的，所述免疫治疗剂是以PD-1和/或PD-L1或CTLA-4(细胞毒性T淋巴细胞相关蛋白4)为靶点；所述免疫疗法选自免疫检查点阻断(ICB)疗 法、嵌合抗原受体T细胞免疫疗法(CAR-T疗法)、自体细胞免疫疗法(CIK疗法)。
在本发明优选的实施例方案中，优选的，所述免疫治疗剂选自PD-1抗体、PD-L1抗体、CTLA-4抗体，所述PD-1抗体包括但不限于Pidilizumab、MEDI-0680、AMP-224、PF-06801591、TSR-042、JS-001、GLS-010、PDR-001、Genolimzumab、Camrelizumab、BGB-A317、IBI-308、REGN-2810、Pembrolizumab、Nivolumab；所述PD-L1抗体包括但不限于MSB-0011359-C、CA-170、LY-3300054、BMS-936559、Durvalumab、Avelumab、Atezolizumab；所述CTLA-4抗体包括但不限于ipilimumab、AK-104、JHL-1155、ATOR-1015、AGEN-1884、PRS-010、tremelimumab、IBI-310、MK-1308、BMS-986218、SN-CA21、FPT-155、KN-044、CG-0161、ONC-392、AGEN-2041、PBI-5D3H5。
在本发明优选的实施例方案中，提供PD-1抗体与表观遗传调节剂联合在制备增强T-细胞活性药物中的用途，所述T细胞优选外周T-细胞。
本发明优选的实施例方案中，所述的PD-1抗体剂量选自1-10mg/kg，优选自1mg/kg、2mg/kg、3mg/kg、4mg/kg、5mg/kg、6mg/kg、7mg/kg、8mg/kg、9mg/kg、10mg/kg，更优选3mg/kg、4mg/kg、5mg/kg。
本发明优选的实施例方案中，所述的PD-1抗体剂量选自50-600mg，优选自50mg、60mg、70mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、375mg、400mg、425mg、450mg、475mg、500mg、600mg，更优选自100mg、200mg、400mg。
本发明优选的实施例方案中，所述表观遗传调节剂剂量选自5-100mg/m 2，优选自5mg/m 2、6mg/m 2、7mg/m 2、8mg/m 2、9mg/m 2、10mg/m 2、12mg/m 2、15mg/m 2、20mg/m 2、25mg/m 2、30mg/m 2、35mg/m 2、40mg/m 2、50mg/m 2、60mg/m 2、75mg/m 2；更优选7mg/m 2、10mg/m 2、12mg/m 2、15mg/m 2、20mg/m 2、25mg/m 2、30mg/m 2、40mg/m 2、50mg/m 2、75mg/m 2。
本发明优选的实施例方案中，所述表观遗传调节剂剂量选自5-500mg，优选自10mg、15mg、20mg、25mg、50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、400mg、500mg，更优选10mg、20mg、100mg、200mg、300mg。
本发明优选的实施例方案中，所述的PD-1抗体与表观遗传调节剂的重量比选自0.01-100:1，优选自5:1、4:1、3:1、5:2、2:1、7:4、3:2、4:3、5:4、1:1、3:4、2:3、 3:5、1:2、2:5、1:3、3:10、1:4、40:1、25:1、20:1、15:1、25:2、12:1、10:1、8:1、9:2、25:4、6:1、20:3、15:4；更优选自5:1、4:1、3:1、5:2、2:1、1:1、2:3、4:3、40:1、20:1。
本发明优选的实施例方案中，所述联合还包含第三组分，所述第三组分选自烷化剂、铂络合剂、代谢拮抗剂、植物生物碱、激素抗癌剂、蛋白酶体抑制剂、芳香化酶抑制剂、免疫调节剂、EGFR抑制剂、ALK抑制剂、PARP抑制剂VEGF抗体、VEGFR抑制剂、mTOR抑制剂的一种或多种。
优选的，所述化疗药物选自烷化剂、铂络合剂、代谢拮抗剂、植物生物碱(如长春碱类、三尖杉酯碱类)、激素抗癌剂、蛋白酶体抑制剂、芳香化酶抑制剂、免疫调节剂的一种或多种；在另外优选的实施例方案中，所述化疗药物包括但不限于环磷酰胺、异环磷酰胺、美法仑、白消安、尼莫司丁、雷莫司汀、达卡巴嗪、替莫唑胺、盐酸氮芥、二溴甘露醇、顺铂、卡铂、奥沙利铂、奈达铂、甲氨蝶呤、5-氟尿嘧啶、替加氟、吉西他滨、卡培他滨、氟维司群、培美曲塞、蒽环类抗生素、丝裂霉素、博莱霉素类、放线菌素、长春碱类、喜树碱类、紫杉醇类、长春新碱、长春碱、长春地辛、依托泊苷、多西他赛、紫杉醇、白蛋白结合型紫杉醇、紫杉醇脂质体、伊立替康、长春瑞滨、米托蒽醌、长春氟宁、拓扑替康、亮丙瑞林、戈舍瑞林、度他雄胺、氟维司群、地塞米松、他莫昔芬、硼替佐米、来那度胺等、依西美坦、来曲唑、阿那曲唑。
优选的，所述靶向药物选自EGFR抑制剂、ALK抑制剂、PARP抑制剂、VEGF抗体和VEGFR抑制剂、mTOR抑制剂、中的一种或多种治疗。这些靶向药物是本领域熟知的，例如EGFR抑制剂可以选自吉非替尼、厄洛替尼、埃克替尼、和阿法替尼、西妥昔单抗、曲妥珠单抗中的一种或几种；ALK抑制剂可以选自克唑替尼、色瑞替尼、阿西替尼、Brigatinib；VEGF抗体选自贝伐珠单抗、Brolucizumab、Vanucizumab、Navicixizumab、Ranibizumab、Conbercept的一种或多种；VEGFR抑制剂选自舒尼替尼、阿帕替尼、法米替尼中的一种或几种；
本发明优选的实施例方案中，所述第三组分选自吉西他滨、顺铂、卡铂、紫杉醇白蛋白、紫杉醇脂质体、紫杉醇、多西他赛、环磷酰胺、多柔比星、表柔比星、长春新碱、替吉奥、替加氟、5-氟尿嘧啶、Tetrahydrouridine的一种或多种。
在本发明上述优选的实施例方案中，上述第三组分可根据患者的体表面积、体重，或KPS功能状态评分标准或ECOG体力状况评分标准(Zubrod-ECOG-WHO) 和各种肿瘤诊疗指南中对不同类型肿瘤化疗方案推荐的剂量和给药方案进行选择。如紫杉醇白蛋白给药剂量为50-500mg/m 2，优选125mg/m 2；吉西他滨给药剂量为500-2000mg/m 2，优选1000mg/m 2；顺铂给药剂量为25-200mg/m 2，优选75mg/m 2。
在本发明中，所述治疗周期可为1天、3天、1周、2周、3周、3-4周、4周，优选3周或3-4周或4周。
在本发明中，所述治疗周期包括但不限于化疗周期或放疗周期或其他相关靶向药物治疗周期或免疫治疗周期。
在本发明中，PD-1抗体与表观遗传调节剂联合用于肿瘤，二者的给药次序为表观遗传调节剂给药在PD-1抗体给药之前，或二者同时给药，或表观遗传调节剂给药在PD-1抗体给药之后；优选的，表观遗传调节剂给药在PD-1抗体给药之前。
在本发明中，表观遗传剂与PD-1抗体可在在相同或不同的治疗周期内联合用于治疗肿瘤，在治疗肿瘤的过程中，表观遗传剂与PD-1抗体联合给药的同时或之前或之后还可联合依据不同肿瘤优选的化疗方案或放疗治疗方案或靶向小分子药物治疗方案或免疫治疗方案治疗肿瘤，所述免疫治疗方案包括但不限于细胞免疫疗法(如CAR-T疗法，肿瘤疫苗、CIK疗法等)；此外，表观遗传剂与PD-1抗体的联合给药也可不联合其他治疗方案单独进行。
在本发明中，PD-1抗体与表观遗传调节剂在联用的同时可进行按照各种肿瘤诊疗规范或指导原则所规定的不同病理分型和进展阶段肿瘤的治疗方案，所述的肿瘤诊疗规范或指导原则包括但不限于NCCN(美国国立综合癌症网络发布各种恶性肿瘤临床实践指南)或中国卫生部颁布的恶性肿瘤诊疗规范。
在本发明中，表观遗传调节剂可在传统肿瘤治疗方案(包括但不限于化疗、放疗、小分子靶向治疗、手术切除、内窥镜治疗)之前先行在1-2个治疗周期内的任意一个1-7天的时间段里进行连续给药，优选在1-5天的时间段里进行连续给药，在此治疗周期内，PD-1抗体与表观遗传调节剂同步给药或在表观遗传调节剂之前或在表观遗传调节剂之后给药，优选的，PD-1抗体可在地西他滨给药结束后的第1天、第2天、第3天、第4天、第5天、第6天、第7天给药，优选第3天、第4天、第5天给药；优选的，PD-1抗体可在地西他滨给药开始前的前1天、前2天、前3天、前4天、前5天、前6天、前7天给药，优选前3天、前4天、前5天给药；所述表观遗传调节剂选自地西他滨、阿扎胞苷；所述地西他滨剂量优选为10mg或7mg/m 2。
本发明关于“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PD-1抗体和至少一种剂量的表观遗传调节剂，其中两种物质都显示药理学作用。所述的时间期限可以是一个给药周期内，优选4周内，3周内，2周内，1周内，或24小时以内，12小时以内。可以同时或依次给予PD-1抗体和表观遗传调节剂。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PD-1抗体和表观遗传调节剂。本发明所述联合的给药方式选自同时给药、独立地配制并共给药或独立地配制并相继给药。在本发明中，本发明进一步涉及的药物中的用途，其中PD-1抗体的给药频次为一日一次、一日二次、一日三次、一周一次、二周一次、三周一次、一月一次，表观遗传调节剂的给药频次为一日一次、一日二次、一日三次、一周一次、二周一次、三周一次、一月一次。
在优选的实施方案中，以21天为一个给药周期，每周期内5天给予地西他滨10mg/天，每周期内给予一次PD-1抗体4mg/kg；其中PD-1抗体也可固定剂量给药，每名患者200mg或400mg(体重大于80kg者)；可按此给药方法循环8个给药周期。
在最优选的实施方案中，21天为一个给药周期，第1个给药周期的第1-第5天给予地西他滨10mg/天；第8天给予PD-1抗体4mg/kg；其中PD-1抗体也可固定剂量给药，每名患者200mg或400mg(体重大于80kg者)。在本发明优选的实施方案中，所述的PD-1抗体以注射的方式给药，例如皮下或静脉注射，注射前需将PD-1抗体配制成可注射的形式。特别优选的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、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抗体的可注射形式包含PD-1抗体、醋酸盐缓冲剂、海藻糖和聚山梨酯20。
本发明所述联合的给药途径选自经口给药、胃肠外给药、经皮给药，所述胃肠外给药包括但不限于静脉注射、皮下注射、肌肉注射。
本发明提供上述免疫治疗剂联合上述表观遗传调节剂作为治疗制备治疗肿瘤和/或增强T-细胞活性的药物。
在本发明中，提供了一种治疗肿瘤和/或增强T-细胞活性的办法，包括向患者施用上述免疫治疗剂和上述表观遗传调节剂。
本发明还提供了一种药物套组，或者一种药物包装盒，其中含有前述的表观遗传调节剂和PD-1抗体。
本发明还提供了一种药物组合物，包含前述的有效量的PD-1抗体和表观遗传调节剂，以及一种或多种可药用的赋型剂、稀释剂或载体。
附图说明
图1.PD-1抗体联合地西他滨与PD-1抗体给药后耐药疗效对比
图2.PD-1抗体联合地西他滨4周后肿瘤消退情况
图3.PD-1抗体联合地西他滨治疗恶性实体瘤肿瘤负荷减轻情况
图4.PD-1抗体联合地西他滨治疗恶性实体瘤肿瘤负荷随治疗时间变化情况
具体实施方式
发明详述
一、术语
为了更容易理解本发明，以下具体定义了某些技术和科学术语。除显而易见在本文件中的它处另有明确定义，否则本文使用的所有其它技术和科学术语都具有本发明所属领域的一般技术人员通常理解的含义。
术语“免疫疗法”指免疫疗法是利用免疫系统来治疗疾病，在本发明中主要指通过提高肿瘤细胞的免疫原性和对效应细胞杀伤的敏感性，激发和增强机体抗肿瘤免疫应答，并应用免疫细胞和效应分子输注宿主体内，协同机体免疫系统杀伤肿瘤、抑制肿瘤生长。
以下结合实施例用于进一步描述本发明，但这些实施例并非限制本发明的范围。
实施例1：地西他滨联合PD-1抗体治疗复发难治性霍奇金淋巴瘤
1、受试抗体和化合物
PD-1抗体按WO2015085847公开的方法制备，对应其代号为H005-1，其重、轻链的序列如本发明中SEQID NO：7和SEQID NO：8。批号：P1512，200mg/每瓶，配成20mg/ml备用。
市售地西他滨冻干粉针剂，50mg/瓶，采用无菌注射用水重溶，配成约5mg/mL溶液，再按临床需求采用生理盐水、0.5％葡萄糖溶液或乳酸格林式液配制成0.1-1mg/mL的溶液使用。
2、入组受试者
(1)霍奇金淋巴瘤病理学确诊；
(2)年龄12-80岁；
(3)ECOG评分小于2分；
(4)预期寿命至少3个月；
(5)淋巴瘤受试者由淋巴瘤反应标准定义至少一个1cm的可测病灶；
(6)必须至少接受两次化疗、且已经历至少4周的洗脱期；自体造血干细胞移植的受试者符合条件超3个月；
(7)必须具有足够的骨髓、肝、肾、肺和心脏功能。
3、分组
截止至2017年9月27日，共入组受试者共19人，其中10人经PD-1抗体治疗耐药，分组为经PD-1抗体治疗耐药组；9人未经PD-1抗体治疗，分组为未经PD-1抗体治疗组；最终有效评价对象：PD-1抗体治疗耐药组为9人，未经PD-1抗体治疗组9人。经PD-1抗体耐药组受试者中，其中有8名受试者既往接受过3-8次Nivolumab的治疗，1名受试者既往同时接受过Nivolumab和Pembrolizumab治疗；未经PD-1抗体治疗组有3名受试者既往接受过CAR-T治疗；在最终进行疗效评价的18名患者中，有2名既往既接受Nivolumab治疗同时也接受过CAR-T治疗。
4、给药方法
入组受试者第1个给药周期(21天)的第1-第5天给予地西他滨10mg/d，静脉滴注；第8天给予PD-1抗体200mg(若体重超过80kg，给予400mg),按此给药方法循环8个给药周期。
5、试验结果
临床研究结果显示(见表1)，在临床研究过程中，无严重不良反应发生，最常见不良反应为樱桃状血管瘤、发热、恶心，皮疹，均为1-2级不良反应；地西他 滨+PD-1抗体治疗复发难治性霍奇金淋巴瘤总缓解率高达78％，且在经PD-1抗体治疗耐药组中仍有高达56％的客观缓解率，无疑为经以PD-1/PD-L1为靶点治疗耐药的患者提供了一种新的治疗途径。
表1.PD-1抗体联合地西他滨治疗复发难治性肿瘤疗效
Figure PCTCN2018109945-appb-000006
备注：经PD-1抗体治疗耐药组指接受PD-1抗体治疗≥四周，且无客观反应(CR+PR)；经PD-1抗体治疗后疾病复发
实验结束时共入组71名病人，其中一组单独使用PD-1抗体治疗，具体结果如下：
Figure PCTCN2018109945-appb-000007
实施例2：地西他滨联合PD-1抗体治疗复发难治性恶性肿瘤
1、受试抗体和化合物
见实施例1
2、入组受试者
(1)恶性肿瘤病理学确诊；
(2)年龄12-80岁；
(3)ECOG评分小于2分；
(4)预期寿命至少3个月；
(5)由淋巴瘤反应标准定义至少一个1cm的可测病灶；
(6)必须经一线化疗失败、且已经历至少4周的洗脱期；
(7)必须具有足够的骨髓、肝、肾、肺和心脏功能。
3、分组
截止至2016年10月30日，共入组受试者共11人，包括6名弥漫性大B细胞淋巴瘤，1名B细胞淋巴瘤，1名霍奇金淋巴瘤，4名实体瘤(2名胃癌、1名食管癌)；最终可评价对象为9人。其中两名漫性大B细胞淋巴瘤受试者接受过CAR-T治疗，一名胃癌受试者既往接受CIK治疗。
4、给药方法
入组受试者第1个给药周期(21天)的第1-第5天给予地西他滨10mg/d，静脉滴注；第8天给予PD-1抗体4mg/kg，按此给药方法循环8个给药周期。
5、试验结果
临床研究结果显示(见表2)，地西他滨+PD-1抗体治疗复发难治性恶性肿瘤总缓解率为7/9(78％)，其中4名受试者经PD-1抗体单药治疗进展后采用PD-1抗体联合地西他滨治疗取得了彻底缓解或部分缓解的疗效评价，无疑为延续该类患者生存期提供了新的选择。
表2 PD-1抗体联合地西他滨治疗复发难治性恶性肿瘤疗效评价
Figure PCTCN2018109945-appb-000008
Figure PCTCN2018109945-appb-000009
实施例3：地西他滨联合PD-1抗体治疗复发难治性恶性肿瘤
1、受试抗体和化合物
见实施例1
2、入组受试者
(1)恶性肿瘤病理学确诊；
(2)年龄12-80岁；
(3)ECOG评分小于2分；
(4)预期寿命至少3个月；
(5)由淋巴瘤反应标准定义至少一个1cm的可测病灶；
(6)必须经一线化疗失败、且已经历至少4周的洗脱期；
(7)必须具有足够的骨髓、肝、肾、肺和心脏功能。
3、分组
截止至2017年9月26日，共入组受试者共24人，包括18名霍奇金淋巴瘤，2名B细胞非霍奇金淋巴瘤；4名实体瘤(2名结直肠癌、1名肾癌、1名乳腺癌)；最终可评价对象为23人。18名霍奇金淋巴瘤受试者中有8名既往接受3-13次Nivolumab或Pembrolizumab的治疗，5名既往接受CAR-T治疗；2名B细胞非霍奇金淋巴瘤受试者中一名既往接受13次Nivolumab治疗，1名既往接受CAR-T治疗；4名实体瘤受试者中有2名既往分别接受2次或10次Nivolumab治疗，1名既往接受4次CIK治疗。
4、给药方法
入组受试者第1个给药周期(21天)的第1-第5天给予地西他滨10mg/d，静脉滴注；第8天给予PD-1抗体4mg/kg，按此给药方法循环8个给药周期。
5、试验结果
临床研究结果显示(见图3、图4)，按照抗肿瘤细胞免疫治疗疗效评价标准 (immune-related response criteria，irRC标准)地西他滨+PD-1抗体治疗复发难治性恶性肿瘤总缓解率为10/23(44％)，其中5名受试者彻底缓解(CR，与基线水平相比肿瘤负荷下降大于100％)，5名患者受试者部分缓解(PR，与基线水平相比肿瘤负荷下降大于50％)，10名受试者疾病稳定(SD，与基线水平相比肿瘤负荷下降小于25％，但增加不超过25％)，2名受试者疾病进展(PD，与基线水平相比肿瘤负荷增加超过25％)。按照irRC标准，即使患者疗效评价为SD,实际上认为同样属于临床获益人群,因此地西他滨+PD-1抗体治疗复发难治性恶性肿瘤疾病控制率(DCR)高达21/23(91％)。通过本发明实施例，地西他滨+PD-1抗体治疗复发难治性恶性肿瘤无疑为延长经PD-1抗体治疗耐受或复发以及经CAR-T治疗或CIK治疗耐受或复发的患者生存期提供了重要治疗路径。

Claims (17)

  1. 免疫治疗剂和表观遗传调节剂联合在制备治疗肿瘤和/或增强T-细胞活性的药物中的用途，其特征在于，所述免疫治疗剂选自PD-1抗体，所述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。
  2. 根据权利要求1所述的用途，其特征在于，所述PD-1抗体为人源化抗体。
  3. 根据权利要求2所述的用途，其中所述抗PD-1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，所述的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；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。
  4. 根据权利要求1-3任一项所述的用途，其特征在于，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。
  5. 根据权利要求1-4任一项所述的用途，其特征在于，所述表观遗传调节剂选自去甲基化剂、DNA甲基转移酶(DNMT)抑制剂、组蛋白去乙酰化酶(HDAC)抑制剂的一种或多种。
  6. 根据权利要求1-5任一项所述的用途，其特征在于，所述表观遗传调节剂选自阿扎胞苷、地西他滨、Fludarabine、Guadecitabine、Zebularine、NPEOC-DAC、CP-4200、Vorinostat、Romidepsin、Panobinostat、CI-994、5,6-二氢-5-氮杂胞苷、5-氟-2’-脱氧胞苷、RX-3117、表没食子儿茶素没食子酸酯(EGCG)、染料木黄酮、姜黄素、寡核苷酸类，优选自地西他滨、阿扎胞苷、Guadecitabine、Romidepsin、Fludarabine。
  7. 根据权利要求1-6任一项所述的用途，其特征在于，所述肿瘤选自恶性肿 瘤、良性肿瘤；所述恶性肿瘤选自恶性上皮肿瘤、肉瘤、骨髓瘤、白血病、淋巴瘤、黑色素瘤、头颈部肿瘤、脑部肿瘤、混合型肿瘤、儿童恶性肿瘤。
  8. 根据权利要求1-7任一项所述的用途，其特征在于，所述肿瘤选自实体瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、前列腺癌、胰腺癌、肺癌、食管癌、肝癌、胆管癌、乳腺癌、结直肠癌、胃癌、肾癌、急性髓性淋巴细胞白血病、骨髓增生异常综合征、胶质瘤。
  9. 根据权利要求1-8任一项所述的用途，其特征在于，所述肿瘤由PD-1介导和/或表达PD-L1。
  10. 根据权利要求1-9任一项所述的用途，其特征在于，所述肿瘤选自中晚期肿瘤、复发难治性肿瘤、经化疗药物治疗失败和/或复发肿瘤、经放疗失败和/或复发肿瘤、经靶向药物治疗失败和/或复发肿瘤、经免疫治疗失败和/或复发肿瘤。
  11. 根据权利要求1-10任一项所述的用途，其特征在于，所述肿瘤对免疫治疗剂或免疫疗法表现为抵抗或耐药。
  12. 根据权利要求1-11任一项所述的用途，其特征在于，所述肿瘤对以PD-1或PD-L1或CTLA-4为靶点的免疫治疗剂表现为抵抗或耐药。
  13. 根据权利要求1-12任一项所述的用途，其特征在于，所述的PD-1抗体剂量选自1-10mg/kg，优选3mg/kg、4mg/kg、5mg/kg。
  14. 根据权利要求1-13任一项所述的用途，其特征在于，所述的PD-1抗体剂量选自50-600mg，优选200mg、400mg每次，其中每三周给药一次。
  15. 根据权利要求1-14任一项所述的用途，其特征在于，所述表观遗传调节剂的给药剂量为10mg/天，其中每21天内给予5天。
  16. 一种药物包装盒，其特征在于，包含有权利要求1-15任意一项所述的表观遗传调节剂和PD-1抗体。
  17. 一种药物组合物，其特征在于，包含有权利要求1-15任意一项所述的有效量的PD-1抗体和表观遗传调节剂，以及一种或多种可药用的赋型剂、稀释剂或载体。
PCT/CN2018/109945 2017-10-13 2018-10-12 Pd-1抗体和表观遗传调节剂联合在制备治疗肿瘤的药物中的用途 Ceased WO2019072220A1 (zh)

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