WO2019072220A1 - Utilisation d'un anticorps pd-1 combiné à un régulateur épigénétique dans la préparation d'un médicament pour le traitement de tumeurs - Google Patents

Utilisation d'un anticorps pd-1 combiné à un régulateur épigénétique dans la préparation d'un médicament pour le traitement de tumeurs 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
use according
group
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PCT/CN2018/109945
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Chinese (zh)
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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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江苏恒瑞医药股份有限公司
中国人民解放军总医院
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Priority to CN201880059360.5A priority Critical patent/CN111132696B/zh
Publication of WO2019072220A1 publication Critical patent/WO2019072220A1/fr

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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.

Abstract

L'invention concerne l'utilisation d'un anticorps PD-1 combiné à un régulateur épigénétique dans la préparation d'un médicament pour le traitement de tumeurs. En particulier, l'invention concerne une utilisation de l'anticorps PD-1 combiné au régulateur épigénétique dans la préparation d'un médicament pour le traitement de tumeurs et/ou le renforcement de l'activité des lymphocytes T.
PCT/CN2018/109945 2017-10-13 2018-10-12 Utilisation d'un anticorps pd-1 combiné à un régulateur épigénétique dans la préparation d'un médicament pour le traitement de tumeurs WO2019072220A1 (fr)

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WO2021057764A1 (fr) * 2019-09-24 2021-04-01 江苏恒瑞医药股份有限公司 Utilisation d'un anticorps pd-1 en combinaison avec un composé taxoïde dans la préparation de médicaments pour le traitement du cancer du sein triple-négatif
WO2021058974A1 (fr) * 2019-09-27 2021-04-01 Celleron Therapeutics Limited Nouveau traitement
CN113116879A (zh) * 2020-01-15 2021-07-16 江苏恒瑞医药股份有限公司 法米替尼联合紫杉类和铂类药物在制备***疾病的药物中的用途
EP3737405A4 (fr) * 2018-01-12 2021-10-06 Viracta Therapeutics, Inc. Modificateurs épigénétiques destinés à être utilisés en immunothérapie cellulaire

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CN113413389B (zh) * 2021-07-19 2024-03-15 成都赜灵生物医药科技有限公司 一种组蛋白去乙酰化酶抑制剂的制剂及其制备方法和用途
CN116196415B (zh) * 2022-12-07 2023-08-01 浙江省肿瘤医院 用于增敏pd-1抗体的混合制剂及其使用方法

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