WO2019096233A1 - 免疫治疗剂、核苷类抗代谢物和铂类联合在制备***的药物中的用途 - Google Patents

免疫治疗剂、核苷类抗代谢物和铂类联合在制备***的药物中的用途 Download PDF

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WO2019096233A1
WO2019096233A1 PCT/CN2018/115796 CN2018115796W WO2019096233A1 WO 2019096233 A1 WO2019096233 A1 WO 2019096233A1 CN 2018115796 W CN2018115796 W CN 2018115796W WO 2019096233 A1 WO2019096233 A1 WO 2019096233A1
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antibody
use according
seq
group
sequence
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PCT/CN2018/115796
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French (fr)
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邹建军
杨清
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江苏恒瑞医药股份有限公司
苏州盛迪亚生物医药有限公司
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Priority to CN201880059097.XA priority Critical patent/CN111093703A/zh
Publication of WO2019096233A1 publication Critical patent/WO2019096233A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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

  • the present invention provides the use of an immunotherapeutic, a nucleoside antimetabolite and a platinum complex in the preparation of a medicament for the treatment of nasopharyngeal carcinoma.
  • Nasopharyngeal carcinoma is a common malignant tumor in southern China and Southeast Asia. It has a high degree of malignancy and early metastasis. About 30%-50% of patients with nasopharyngeal carcinoma have cervical lymph nodes at the time of treatment. Transfer and distant transfer. With the gradual improvement of the diagnosis and treatment of nasopharyngeal carcinoma, the local control rate of patients with nasopharyngeal carcinoma has been significantly improved, but local recurrence and distant metastasis are still the main reasons for the failure of nasopharyngeal carcinoma treatment. Radiotherapy or concurrent chemoradiotherapy is still the main treatment for early or local late nasopharyngeal carcinoma.
  • the 5-year survival rate is about 85%, but these patients will eventually have recurrence or metastasis, and 15% of patients with nasopharyngeal carcinoma will be found at the time of initial diagnosis. Distant metastasis, the treatment of patients with recurrent or metastatic nasopharyngeal carcinoma is very limited, the median survival is more than 20 months.
  • Tumor immunotherapy is a hotspot in the field. By fully utilizing and mobilizing the killer T cells in tumor patients, the tumor is killed.
  • PD-1 programmed death-1, programmed death receptor 1
  • the killing effect is to modulate the body's immune system and remove 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.
  • PD-1 monoclonal antibody disclosed by BMS, Merck, and WO2015085847 (publication date 2015.06.18) is currently a leading PD-1 antibody drug, and the FDA has approved PD-1 antibody in malignant melanoma, non-small cell lung cancer, Single-agent use in multiple tumors such as head and neck squamous cell carcinoma, kidney cancer, liver cancer, lymphoma, etc., FDA has not approved PD-1 antibody monotherapy for nasopharyngeal carcinoma, but Novartis's PDR-001 antibody is undergoing monotherapy for nasal use. Clinical study of pharyngeal cancer.
  • Gemcitabine is a difluoronucleoside anti-metabolite anticancer drug that destroys cell replication. It is a water-soluble analog of deoxycytidine and a substitute for an inhibitory enzyme of ribonucleotide reductase. This enzyme is essential for the production of deoxynucleotides during DNA synthesis and repair.
  • Cisplatin is a commonly used metal platinum complex, which has the characteristics of wide anti-tumor spectrum and effective for hypoxic cells. However, it is toxic to the kidneys, nervous system and pancreas. It can bind to DNA to form cross-links, so that the function of destroying DNA is no longer replicated; at high concentrations, it also inhibits the synthesis of RNA and proteins.
  • This product is a periodic non-specific drug.
  • Another feature of this product is that it also has a role in hypoxic cells. Upon entering the body, it can diffuse through the charged cell membrane. It is stable under the condition of high Cl- ion concentration. After entering the cell, the drug is hydrolyzed into a cationic hydrate due to the low intracellular Cl- concentration. It has the function of a bifunctional group similar to an alkylating agent, mainly with a base on the DNA chain. Base effect.
  • PD-1 monoclonal antibody combined with chemotherapy has achieved good results in non-small cell lung cancer and has been approved by the FDA.
  • studies in bladder cancer and breast cancer are also underway, but PD-1 monoclonal antibody combined with chemotherapy is rarely reported in nasopharyngeal carcinoma.
  • the technical problem to be solved by the present invention is to provide a combination of an immunotherapeutic agent, a nucleoside antimetabolite and a platinum complex in the preparation of a medicament for treating nasopharyngeal cancer, the combination therapy method showing good safety, High efficacy, low toxicity and other adverse reactions.
  • the present invention provides a use of an immunotherapeutic agent, a nucleoside antimetabolite and a platinum complex in combination for the preparation of a medicament for treating nasopharyngeal carcinoma, 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.
  • a preferred humanized antibody light chain variable region sequence is the sequence set forth in SEQ ID NO: 10 or a variant thereof, said variant preferably having an amino acid change of 0-10 in the light chain variable region, more preferably Is the amino acid change of A43S;
  • the humanized antibody heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 9 or a variant thereof, preferably having 0-10 in the heavy chain variable region
  • the amino acid change is more preferably an amino acid change of G44R.
  • variable region sequences of the heavy and light chains of the aforementioned humanized antibodies are as follows:
  • a preferred 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 nucleoside anti-metabolite is selected from the group consisting of gemcitabine, guanidine, nelarabine, fludarabine, cladribine, clofarabine ), azacitidine, amphetamine, tracitabine, capecitabine, decitabine, preferably gemcitabine.
  • the platinum complex is selected from the group consisting of cisplatin, carboplatin, nedaplatin, oxaliplatin or lobaplatin, preferably cisplatin.
  • the tumor is selected from the group consisting of a malignant tumor, a benign tumor; the malignant tumor is selected from the group consisting of a malignant epithelial tumor, a sarcoma, a myeloma, a leukemia, a lymphoma, a melanoma, a head and neck tumor, and a brain.
  • 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 intestine cancer, cardiac cancer, endometrium Cancer, ovarian cancer, fallopian tube cancer, vulvar cancer, testicular cancer, prostate cancer, penile cancer, kidney cancer, bladder cancer, anal cancer, gallbladder cancer, cholangiocarcinoma, teratoma, cardiac tumor; the head and neck tumor is selected from Nasopharyngeal carcinoma, laryngeal cancer, thyroid cancer, tongue cancer, oral cancer; the sarcoma is selected from the group consisting of Askin tumor, chondrosarcoma, Ewing's sarcoma, malignant hemangioendothelioma, malignant schwannomas, osteosarcoma, soft tissue sarcoma;
  • the tumor is selected from the group consisting of Ask
  • the nasopharyngeal carcinoma is selected from the group consisting of no previous chemotherapy, recurrent, metastatic, unsuitable for local treatment, recurrence or metastasis after radiotherapy, preferably no chemotherapy before. It is not suitable for local treatment of nasopharyngeal carcinoma, recurrence after radiotherapy or metastasis of nasopharyngeal carcinoma.
  • 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) is 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 immunotherapy (CIK therapy).
  • IB immunological checkpoint block
  • CAR-T therapy chimeric antigen receptor T cell immunotherapy
  • CIK therapy autologous cellular immunotherapy
  • the immunotherapeutic agent is selected from the group consisting of a PD-1 antibody, a PD-L1 antibody, and a CTLA-4 antibody, including but not limited to 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; the PD-L1 antibody Including but not limited to MSB-0011359-C, CA-170, LY-3300054, BMS-936559, Durvalumab, Avelumab, Atezolizumab; the CTLA-4 antibodies include, but are not limited to, ipilimumab, AK-104, JHL-1155, ATOR- 1015, AGEN-1884, PRS-010, tremelimumab
  • a PD-1 antibody in combination with a nucleoside antimetabolite, a platinum group, for the preparation of a medicament for enhancing T-cell activity, preferably a peripheral T-cell.
  • the immunotherapeutic agent is selected from the group consisting of 1-10 mg/kg, preferably 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 immunotherapeutic agent is selected from the group consisting of 50-600 mg, preferably 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 100 mg, 200 mg, 400 mg.
  • the nucleoside anti-metabolite dose is selected from 5-1000 mg/m 2 , preferably from 5 mg/m 2 , 6 mg/m 2 , 7 mg/m 2 , 8 mg/m 2 , 9 mg.
  • the nucleoside anti-metabolite dose is selected from the group consisting of 5 to 2000 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, 600 mg, 800 mg, 1000 mg, 1200 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 2000 mg, more preferably 10 mg, 20 mg, 100 mg, 200 mg, 300 mg, 500 mg, 1000 mg or 1500 mg.
  • the dose of platinum complex is selected from 5-200mg / m 2, preferably from 5mg / m 2, 6mg / m 2, 7mg / m 2, 8mg / m 2, 9mg / 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 , 80 mg/m 2 , 85 mg/m 2 , 90 mg/m 2 , 95 mg/m 2 , 100 mg/m 2 , 120 mg/m 2 , 125 mg/m 2 , 130 mg/m 2 , 150 mg/ m 2 , 160 mg/m 2 , 180 mg/m 2 , 180 mg/m 2 , 190 mg/m 2 , 195 mg/m 2 , 200 mg/m/m 2, a
  • the platinum complex dose is selected from the group consisting of 5 to 400 mg, preferably from 10 mg, 15 mg, 20 mg, 25 mg, 40 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 130 mg, 135 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 180 mg, 185 mg, 190 mg, 200 mg, 250 mg, 300 mg, 400 mg, more preferably 10 mg, 20 mg, 50 mg, 60 mg, 70 mg, 80mg, 100mg.
  • the combination further comprises a fourth component selected from the group consisting of an alkylating agent, a platinum complex, a nucleoside anticancer agent, a metabolic antagonist, a plant alkaloid
  • a fourth component selected from the group consisting of an alkylating agent, a platinum complex, a nucleoside anticancer agent, a metabolic antagonist, a plant alkaloid
  • a hormone anticancer agent a proteasome inhibitor, an aromatase inhibitor, an immunomodulator, an EGFR inhibitor, an ALK inhibitor, a PARP inhibitor, a 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, nimo Statin, ramustine, dacarbazine, temozolomide, hydrochloric acid mustard, dibromomannitol, cisplatin, carboplatin, oxaliplatin, nedaplatin, methotrexate, 5-fluorouracil, tegafur , decitabine, capecitabine, fulvestrant, pemetrexed, anthracyclines, mitomycin, bleomycin, actinomycin, vinblastine, camptothecin , paclitaxel, vincristine, vinblastine, vindesine, etoposide, docetaxel, paclitaxel, albumin-bound paclitaxel, paclitaxel liposomes, ir
  • the targeted drug is selected from one or more of the EGFR inhibitors, ALK inhibitors, PARP inhibitors, VEGF antibodies and VEGFR inhibitors, mTOR inhibitors.
  • EGFR inhibitors are selected from the group consisting of gefitinib, erlotinib, ectinib, and afatinib, cetuximab, trastuzumab One or more;
  • the ALK inhibitor is selected from one or more of crizotinib, ceratinib, axitinib, Brigatinib;
  • the VEGF antibody is selected from bevacizumab, Brolucizumab, Vanucizumab, Navicixizumab One or more of Ranibizumab, Conbercept;
  • the VEGFR inhibitor is selected from one or more of sunitinib, apatinib, and faritinib.
  • the fourth component is selected from the group consisting of decitabine, carboplatin, paclitaxel albumin, paclitaxel liposome, paclitaxel, docetaxel, cyclophosphamide, doxorubicin, Tetrahydrouridine.
  • the fourth component may be based on the patient's body surface area, body weight, or KPS functional status score standard or ECOG physical condition score standard (Zubrod-ECOG-WHO) and various tumor treatment guidelines.
  • the recommended dosages and dosing schedules for different types of tumor chemotherapy regimens are selected.
  • paclitaxel albumin is administered at a dose of 50-500 mg/m 2 , preferably 125 mg/m 2
  • decitabine is administered at a dose of 5-500 mg/m 2 , preferably 5-100 mg/m 2 ;
  • the treatment period may be 1 day, 3 days, 1 week, 2 weeks, 3 weeks, preferably 3 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.
  • the immunotherapeutic agent, the nucleoside antimetabolite and the platinum complex can be used in combination for treating tumors in the same or different treatment cycles, and in the process of treating tumors, immunotherapeutics, nucleosides Simultaneously with or before or after administration of an antimetabolite in combination with a platinum complex, the tumor may be treated in combination with a preferred chemotherapy regimen or a radiotherapy treatment regimen or a targeted small molecule drug treatment regimen or immunotherapeutic regimen.
  • Treatment options include, but are not limited to, cellular immunotherapy (such as CAR-T therapy, tumor vaccine, CIK therapy, etc.); in addition, the combination of immunotherapy agents, nucleoside antimetabolites and platinum complexes may not be combined Other treatment options are performed separately.
  • the immunotherapeutic agent, the nucleoside antimetabolite and the platinum complex can be used in combination with different pathological types and progression stages of tumors according to various tumor diagnosis norms or guidelines.
  • the protocol or guidelines for cancer diagnosis 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 Ministry of Health of China.
  • the immunotherapeutic agent, the nucleoside antimetabolite is administered simultaneously with the platinum complex in a treatment cycle or before the nucleoside antimetabolite or after the nucleoside antimetabolite
  • gemcitabine can be administered on the first day, the second day, the third day, the fourth day, the fifth day, the sixth day, the seventh day after the end of administration of the PD-1 antibody, preferably the first day
  • cisplatin can be administered on the first day, the second day, the third day, the fourth day, the fifth day, the sixth day, and the seventh day after the administration of the PD-1 antibody. It is preferred to administer on day 1; one treatment cycle every 3 weeks, and up to 6 cycles of combination therapy, after which treatment can be maintained with PD-1 antibody alone until the end.
  • the present invention further provides the use of the medicament, wherein the frequency of administration of the immunotherapeutic agent is once a day, twice a day, three times a day, once a week, once every two weeks, once every three weeks, a nucleus
  • the frequency of administration of glycosidic antimetabolites 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, once every two months, the administration of platinum complexes
  • the frequency 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.
  • 3 weeks is a cycle, wherein the amount of the PD-1 antibody is 60 to 600 mg, intravenous infusion, administration on the first day of each cycle; nucleoside The amount of anti-metabolites is 200mg to 2000mg/m 2 , intravenous infusion, on the first day and the 8th day of each cycle; the amount of platinum complex is 5 to 200 mg / m 2 , intravenous infusion, per Dosing on day 1 of the cycle; use up to 2-12 cycles, then maintain treatment with PD-1 antibody alone until disease progression, toxicity is intolerable, subject requirements or the investigator judges that the subject is unsuitable for continued treatment .
  • 3 weeks is a cycle, wherein the amount of the PD-1 antibody is 80 to 300 mg, intravenous infusion, administration on the first day of each cycle; nucleoside The amount of anti-metabolites is 500 to 1500 mg/m 2 , intravenous infusion, on the first day and the 8th day of each cycle; the amount of platinum complex is 10 to 100 mg/m 2 , intravenous infusion, per Dosing on day 1 of the cycle; use up to 3-10 cycles, then maintain treatment with PD-1 antibody alone until disease progression, toxicity is intolerable, subject requirements or the investigator judges that the subject is unsuitable for continued treatment .
  • 3 weeks is a cycle, wherein the amount of the PD-1 antibody is 200 mg, intravenous infusion, administration on the first day of each cycle; nucleoside resistance
  • the amount of metabolite used was 1000 mg/m 2 , intravenous infusion, on the first day and the eighth day of each cycle; the amount of platinum complex was 80 mg/m 2 , intravenous infusion, administered on the first day of each cycle.
  • Up to 6 cycles are used, after which the PD-1 antibody is used alone to maintain treatment until disease progression, toxicity is intolerable, subject requirements or the investigator judges that the subject is unsuitable for continued treatment.
  • the immunotherapeutic agent is administered by injection, for example subcutaneously or intravenously, and the immunotherapeutic agent is formulated in an injectable form prior to injection.
  • a particularly preferred injectable form of the immunotherapeutic agent is an injectable solution or a lyophilized powder comprising an immunotherapeutic agent, 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 immunotherapeutic agents 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-mentioned immunotherapeutic agent, nucleoside antimetabolite and platinum complex 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, a nucleoside antimetabolite and a platinum complex.
  • the invention also provides a drug kit, or a pharmaceutical package containing the aforementioned immunotherapeutic agent, nucleoside antimetabolite and platinum complex.
  • humanized antibody also known as CDR-grafted antibody, refers to the transplantation of mouse CDR sequences into human antibody variable region frameworks, ie different types of human germline An antibody produced in an antibody framework sequence. It is possible to overcome the strong antibody variable antibody response induced by chimeric antibodies by carrying a large amount of mouse protein components.
  • framework sequences can be obtained from public DNA databases including germline antibody gene sequences or published references.
  • the germline DNA sequences of human heavy and light chain variable region genes can be found in the "VBase" human germline sequence database (available on the Internet at www.mrccpe.com.ac.uk/vbase), as well as in Kabat, EA, etc.
  • the CDR sequence of the PD-1 humanized antibody is selected from the group consisting of SEQ ID NOs: 1, 2, 3, 4, 5, 6.
  • antigen-binding fragment refers to a Fab fragment having antigen-binding activity, a Fab' fragment, an F(ab')2 fragment, and an Fv fragment sFv fragment that binds to human PD-1; and an antibody comprising the antibody of the present invention is selected from the group consisting of One or more CDR regions of SEQ ID NO: 1 to SEQ ID NO: 6.
  • the Fv fragment contains the antibody heavy chain variable region and the light chain variable region, but has no constant region and has the smallest antibody fragment of the entire antigen binding site.
  • Fv antibodies also comprise a polypeptide linker between the VH and VL domains and are capable of forming the desired structure for antigen binding.
  • the two antibody variable regions can also be joined by a different linker into a single polypeptide chain, referred to as a single chain antibody or a single chain Fv (sFv).
  • binding to PD-1 refers to the ability to interact with human PD-1.
  • antigen binding site refers to a three-dimensional spatial site that is discrete on an antigen and is recognized by an antibody or antigen-binding fragment of the present invention.
  • 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 PD-1 antibody combined with gemcitabine and cisplatin in the treatment of recurrent or metastatic nasopharyngeal carcinoma
  • the sequence of the heavy and light chain of the PD-1 antibody is SEQ ID NO: 7 and SEQ ID NO: 8 in the present invention. 200 mg / support, and is formulated into 40 mg / ml for use.
  • nasopharyngeal carcinoma diagnosed by pathology (primary metastatic nasopharyngeal carcinoma or recurrent nasopharyngeal carcinoma not suitable for local treatment), systemic chemotherapy patients who have not received recurrent or metastatic nasopharyngeal carcinoma for the first time Except for neoadjuvant chemotherapy, concurrent chemotherapy or adjuvant chemotherapy received 6 months ago; with measurable lesions; ECOG score 0-1;
  • PD-1 antibody 200mg/time, on the first day of each cycle, at least 30min before administration of chemotherapy, intravenous infusion>30min
  • gemcitabine 1000mg/m 2 , day 1 and 8 per cycle, intravenous infusion for 30min
  • cisplatin 80 mg/m 2 , on the first day of each cycle, intravenous infusion for 4 h.
  • Each 3 weeks is a treatment period, and each treatment cycle is administered for more than 3 days, which will be considered as delayed administration, and the subsequent administration time is calculated on the actual date of the previous administration.
  • the combination was administered for up to 6 cycles, after which the treatment was continued with PD-1 antibody alone until disease progression, toxicity was intolerable, subject requirements or the investigator judged that the subject was unsuitable for continued treatment.
  • 2017.10.27 23 patients were enrolled, and 22 were used for evaluation.
  • the three-component combination of PD-1 antibody, gemcitabine, and cisplatin has a remission rate of 90.9% and a control rate of 100%, indicating good safety and efficacy.

Abstract

本发明提供了免疫治疗剂、核苷类抗代谢物和铂类联合在制备***的药物中的用途。具体而言，本发明提供了PD-1抗体、吉西他滨和和顺铂在制备治疗鼻咽癌的药物中的用途。

Description

免疫治疗剂、核苷类抗代谢物和铂类联合在制备***的药物中的用途 技术领域
本发明提供了免疫治疗剂、核苷类抗代谢物和铂类络合物联合在制备治疗鼻咽癌的药物中的用途。
背景技术
鼻咽癌(Nasopharyngeal carcinoma,NPC)是我国南方及东南亚地区常见的一种恶性肿瘤，其恶性程度较高，转移较早，约30％-50％的鼻咽癌患者就诊时已发生颈部***转移和远处转移。随着鼻咽癌诊断和治疗方法的逐步提高，鼻咽癌患者的局部控制率得到显著改善，但局部复发和远处转移仍是鼻咽癌治疗失败的主要原因。放疗或同期放化疗仍是早期或局部晚鼻咽癌的主要治方法，5年生存率在85％左右，但是这些患者终将出现复发或转移，并且15％的鼻咽癌患者初诊时就发现远处转移，对于复发或原转移性鼻咽癌患者的治疗很有限，中位生存多在20个月左右。
肿瘤免疫治疗是领域的热点，通过充分利用、调动肿瘤患者体内的杀伤性T细胞，对肿瘤进行杀伤作用。PD-1(programmed death-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***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。目前有多家跨国制药公司在研发针对PD-1的单克隆抗体，它通过阻断PD-L1/PD-1之间结合，最大限度的提高患者自身对肿瘤免疫***反应，从而达到对肿瘤细胞进行杀伤的目。BMS公司、Merck公司、WO2015085847(公开日2015.06.18)公开的PD-1单克隆抗体，目前是前沿的PD-1抗体药物，FDA已经批准PD-1抗体在恶性黑色素瘤、非小细胞肺癌、头颈部鳞癌、肾癌、肝癌、淋巴瘤等多个肿瘤中的单药使用，FDA尚未批准PD-1抗体单药治疗鼻咽癌，但诺华的 PDR-001抗体正在开展单药治疗鼻咽癌的临床研究。
吉西他滨(gemcitabine)是一种破坏细胞复制的二氟核苷类抗代谢物抗癌药，是去氧胞苷的水溶性类似物，是核糖核苷酸还原酶的一种抑制性酶的替代物，这种酶在DNA合成和修复过程中，对脱氧核苷酸的生成是至关重要的。顺铂(Cisplatin)为目前常用的金属铂类络合物，具有抗瘤谱广、对乏氧细胞有效的特点。但对肾、神经***及胰腺有毒性。能与DNA结合形成交叉键，从而破坏DNA的功能不再复制；高浓度时也抑制RNA及蛋白质的合成。为一种周期非特异性药物。本品作用的另一特点是对乏氧细胞也有作用。进入人体后可扩散通过带电的细胞膜。在Cl-离子浓度高的条件下较稳定，进入细胞后由于细胞内Cl-浓度较低，药物水解为阳离子水化物，具有类似烷化剂的双功能基团的作用，主要与DNA链上碱基作用。
PD-1单克隆抗体联合化疗在非小细胞肺癌中获得了较好的效果，已经获得FDA的批准。此外膀胱癌、乳腺癌中的研究也正在进行，但是PD-1单克隆抗体联合化疗在鼻咽癌中少见报道，我们希望通过PD-1联合化疗进一步有效治疗鼻咽癌。
发明内容
本发明要解决的技术问题是提供一种免疫治疗剂、核苷类抗代谢物和铂类络合物联合在制备治疗鼻咽癌的药物中的用途，该联合治疗方法显示良好的安全性、疗效高、毒性等不良反应低的优点。
本发明的技术方案如下：
本发明提供一种免疫治疗剂、核苷类抗代谢物和铂类络合物联合在制备治疗鼻咽癌的药物中的用途，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 PCTCN2018115796-appb-000001
轻链可变区
Figure PCTCN2018115796-appb-000002
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 PCTCN2018115796-appb-000003
轻链
Figure PCTCN2018115796-appb-000004
本发明优选的实施方案中，所述核苷类抗代谢物选自吉西他滨、巯嘌呤、奈拉滨(nelarabine)、氟达拉滨(fludarabine)、克拉屈滨(cladribine)、氯法拉滨(clofarabine)、阿扎胞苷、安西他滨、曲沙他滨、卡培他滨、地西他滨，优选吉西他滨。
在一些实施方案中，所述铂类络合物选自顺铂、卡铂、奈达铂、奥沙利铂或洛铂，优选顺铂。
在本发明优选的实施方案中，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、***癌、***癌、肾癌、膀胱癌、***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方案中，所述鼻咽癌选自之前没有接受过任何化疗、复发性、转移性、不适合局部治疗、放疗后复发或转移肿瘤，优选之前没有接受过任何化疗、不适合局部治疗鼻咽癌、放疗后复发或转移鼻咽癌。
在本发明优选的实施方案中，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方案中，提供PD-1抗体与核苷类抗代谢物、铂类联合在制备增强T-细胞活性药物中的用途，所述T细胞优选外周T-细胞。
在本发明优选的实施方案中，所述的免疫治疗剂剂量选自1-10mg/kg，优选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。
在本发明优选的实施方案中，所述的免疫治疗剂剂量选自50-600mg，优选50mg、60mg、70mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、375mg、400mg、425mg、450mg、475mg、500mg、600mg，更优选100mg、200mg、400mg。
在本发明优选的实施方案中，所述核苷类抗代谢物剂量选自5-1000mg/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、80mg/m 2、85mg/m 2、90mg/m 2、100mg/m 2、110mg/m 2、150mg/m 2、180mg/m 2、200mg/m 2、250mg/m 2、300mg/m 2、350mg/m 2、400mg/m 2、450mg/m 2、500mg/m 2、550mg/m 2、600mg/m 2、650mg/m 2、700mg/m 2、800mg/m 2、900mg/m 2、1000mg/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、100mg/m 2、150mg/m 2、180mg/m 2、200mg/m 2、300mg/m 2、400mg/m 2、500mg/m 2、600mg/m 2、700mg/m 2、800mg/m 2、900mg/m 2或1000mg/m 2。
在本发明优选的实施方案中，所述核苷类抗代谢物剂量选自5-2000mg，优选自10mg、15mg、20mg、25mg、50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、400mg、500mg、600mg、800mg、1000mg、1200mg、1500mg、1600mg、1700mg、1800mg、2000mg，更优选10mg、20mg、100mg、200mg、300mg、500mg、1000mg或1500mg。
在本发明优选的实施方案中，所述铂类络合物剂量选自5-200mg/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、80mg/m 2、85mg/m 2、90mg/m 2、95mg/m 2、100mg/m 2、120mg/m 2、125mg/m 2、130mg/m 2、150mg/m 2、160mg/m 2、180mg/m 2、180mg/m 2、190mg/m 2、195mg/m 2、200mg/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、80mg/m 2。
在本发明优选的实施方案中，所述铂类络合物剂量选自5-400mg，优选自10mg、15mg、20mg、25mg、、40mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、125mg、130mg、135mg、150mg、155mg、160mg、165mg、170mg、180mg、185mg、190mg、200mg、250mg、300mg、400mg，更优选10mg、20mg、50mg、60mg、70mg、80mg、100mg。
本发明优选的实施方案中，所述联合还包含第四组分，所述第四组分选自烷化剂、铂类络合物、核苷类抗癌剂、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、地西他滨、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、***、他莫昔芬、硼替佐米、来那度胺等、依西美坦、来曲唑、阿那曲唑。
优选地，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剂。这些靶向药物是本领域熟知的，例如EGFR抑制剂选自吉非 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抑制剂选自克唑替尼、色瑞替尼、阿西替尼、Brigatinib中的一种或多种；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。
在一些实施方案中，所述第四组分选自地西他滨、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、Tetrahydrouridine。
在本发明上述优选的实施方案中，第四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；地西他滨给药剂量为5-500mg/m 2，优选5-100mg/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，优选3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，免疫治疗剂、核苷类抗代谢物与铂类络合物可在相同或不同的治疗周期内联合用于***，在***的过程中，免疫治疗剂、核苷类抗代谢物与铂类络合物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***，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，表免疫治疗剂、核苷类抗代谢物与铂类络合物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，免疫治疗剂、核苷类抗代谢物与铂类络合物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***颁布的恶性肿瘤诊疗规范。
在本发明中，在一个治疗周期内，免疫治疗剂、核苷类抗代谢物与铂类络合物同步给药或在核苷类抗代谢物之前或在核苷类抗代谢物之后给药，优选地，吉西他滨可在PD-1抗体给药结束后的第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1天、第8天给药，顺铂可在PD-1抗体给药结束后的第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1天给药；每3周为一治疗周期，联合用药最多使用6个周期，之后可单独使用PD-1抗体维持治疗、直到结束。
在本发明中，本发明进一步提供了的药物中的用途，其中免疫治疗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，核苷类抗代谢物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、两月一次，铂类络合物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。
在本发明一个优选的实施方案中，在给药时，3周为一个周期，其中所述的PD-1抗体的用量是60至600mg，静脉输注，每周期第1天给药；核苷类抗代谢物的用量是200mg至2000mg/m 2，静脉输注，每周期第1天、第8天给药；铂类络合物的用量是5至200mg/m 2，静脉输注，每周期第1天给药；最多使用2-12个周期，之后单独使用PD-1抗体维持治疗，直到疾病进展、毒性不可耐受、受试者要求或研究者判断受试者不适合继续接受治疗。
在本发明一个优选的实施方案中，在给药时，3周为一个周期，其中所述的PD-1抗体的用量是80至300mg，静脉输注，每周期第1天给药；核苷类抗代谢物的用量是500至1500mg/m 2，静脉输注，每周期第1天、第8天给药；铂类络合物的用量是10至100mg/m 2，静脉输注，每周期第1天给药；最多使用3-10个周期，之后单独使用PD-1抗体维持治疗，直到疾病进展、毒性不可耐受、受试者要求或研究者判断受试者不适合继续接受治疗。
在本发明一个优选的实施方案中，在给药时，3周为一个周期，其中所述的PD-1抗体的用量是200mg，静脉输注，每周期第1天给药；核苷类抗代谢物的用量是1000mg/m 2，静脉输注，每周期第1天、第 8天给药；铂类络合物的用量是80mg/m 2，静脉输注，每周期第1天给药；最多使用6个周期，之后单独使用PD-1抗体维持治疗，直到疾病进展、毒性不可耐受、受试者要求或研究者判断受试者不适合继续接受治疗。
在本发明优选的实施方案中，所述的免疫治疗剂以注射的方式给药，例如皮下或静脉注射，注射前需将免疫治疗剂配制成可注射的形式。特别优选的免疫治疗剂的可注射形式是注射液或冻干粉针，其包含免疫治疗剂、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。最为优选的免疫治疗剂的可注射形式包含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、核苷类抗代谢物与铂类络合物联合作为治疗制备***和/或增强T-细胞活性的药物。
在本发明中，提供了一种***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、核苷类抗代谢物与铂类络合物。
本发明还提供了一种药物套组，或者一种药物包装盒，其中含有前述的免疫治疗剂、核苷类抗代谢物与铂类络合物。
具体实施方式
发明详述
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“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。在本发明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。
术语“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；包含本发明所述抗体的选自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)。本发明的术语“与PD-1结合”，指能与人PD-1相互作用。本发明的术语“抗原结合位点”指抗原上不连续的，由本发明抗体或抗原结合片段识别的三维空间位点。
术语“免疫疗法”指免疫疗法是利用免疫***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***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：PD-1抗体联合吉西他滨和顺铂治疗复发或转移性鼻咽癌
1、受试抗体和化合物
PD-1抗体其重、轻链的序列如本发明中SEQ ID NO:7和SEQ ID  NO:8。200mg/支，配成40mg/ml备用。
市售吉西他滨冻干粉针剂，规格为1.0g/瓶，配制方法可参考上市说明书。
市售顺铂注射液，规格为20ml:20mg，配制方法可参考上市说明书。
2、入组受试者
(1)病理学确诊的鼻咽癌患者(原发转移性鼻咽癌或不适合局部治疗的复发性鼻咽癌)，既往没有接受过复发或转移性鼻咽癌的***化疗患者，首次用药6个月之前接受的新辅助化疗、同步化疗或辅助化疗除外；具有可测量的病灶；ECOG评分0-1分；
(2)年龄18-70岁；
3、给药方法
PD-1抗体(200mg/次，每周期第1天，至少在给予化疗药前30min给予，静脉滴注>30min)、吉西他滨(1000mg/m 2，每周期第1、8天，静脉滴注30min)和顺铂(80mg/m 2，每周期第1天，静脉滴注4h)。每3周为一个治疗期，每个治疗周期给药日期超过3天，将被认为是延迟给药，后续给药时间以前次给药实际日期计算。联合用药最多使用6个周期，之后单独使用PD-1抗体维持治疗，直到疾病进展、毒性不可耐受、受试者要求或研究者判断受试者不适合继续接受治疗。截止到2017.10.27日入组病例23人，用于评价的为22人。
表1、本发明PD-1抗体联合吉西他滨和顺铂治疗原发鼻咽癌或不适合局部治疗的复发性鼻咽癌的疗效
Figure PCTCN2018115796-appb-000005
实验结论：
由表1可知，PD-1抗体、吉西他滨、顺铂的三组分联合治疗复发或转移性鼻咽癌的缓解率达到90.9％、控制率为100％，显示良好的安全性和有效性。

Claims (17)

  1. 免疫治疗剂、核苷类抗代谢物和铂类络合物联合在制备治疗鼻咽癌的药物中的用途。
  2. 如权利要求1所述的用途，其特征在于，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抗体优选自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抗体优选自MSB-0011359-C、CA-170、LY-3300054、BMS-936559、Durvalumab、Avelumab、Atezolizumab；所述CTLA-4抗体优选自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。
  3. 如权利要求2所述的用途，其特征在于，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。
  4. 如权利要求3所述的用途，其特征在于，所述PD-1抗体为人源化抗体。
  5. 如权利要求4所述的用途，其特征在于，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。
  6. 如权利要求5所述的用途，其中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。
  7. 如权利要求6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。
  8. 如权利要求1-7任一项所述的用途，其特征在于，所述核苷类抗代谢物选自吉西他滨、巯嘌呤、奈拉滨(nelarabine)、氟达拉滨(fludarabine)、克拉屈滨(cladribine)、氯法拉滨(clofarabine)、阿扎胞苷、安西他滨、曲沙他滨、卡培他滨、地西他滨，优选吉西他滨。
  9. 如权利要求1-8任一项所述的用途，其特征在于，所述铂类络合物选自顺铂、卡铂、奈达铂、奥沙利铂或洛铂，优选顺铂。
  10. 如权利要求9所述的用途，其特征在于，所述鼻咽癌选自之前没有接受过任何化疗、复发性、转移性、不适合局部治疗、放疗后复发或转移的肿瘤，优选之前没有接受过任何化疗、不适合局部治疗鼻咽癌、放疗后复发或转移鼻咽癌。
  11. 如权利要求10所述的用途，其特征在于，所述免疫治疗剂剂量选自1-10mg/kg，优选1mg/kg、3mg/kg、5mg/kg、8mg/kg、10mg/kg，更优选1mg/kg、3mg/kg、10mg/kg。
  12. 如权利要求11所述的用途，其特征在于，所述免疫治疗剂剂量选自50-600mg，优选50mg、60mg、70mg、100mg、150mg、200mg、300mg、400mg、500mg、600mg，更优选60mg、200mg、400mg。
  13. 如权利要求10所述的用途，其特征在于，所述核苷类抗代谢物剂量选自5-2000mg/m 2，优选自5mg/m 2、10mg/m 2、20mg/m 2、40mg/m 2、 80mg/m 2、100mg/m 2、300mg/m 2、500mg/m 2、800mg/m 2、1000mg/m 2、2000mg/m 2，更优选100mg/m 2、500mg/m 2、800mg/m 2或1000mg/m 2。
  14. 如权利要求13所述的用途，其特征在于，所述核苷类抗代谢物剂量选自5-2000mg，优选自10mg、100mg、200mg、500mg、800mg、1000mg、1500mg、2000mg，更优选100mg、500mg、1000mg或1500mg。
  15. 如权利要求10所述的用途，其特征在于，所述铂类络合物剂量选自5-200mg/m 2，优选自5mg/m 210mg/m 2、20mg/m 2、50mg/m 2、80mg/m 2、100mg/m 2、150mg/m 2、200mg/m 2，更优选10mg/m 2、50mg/m 2、80mg/m 2。
  16. 如权利要求15所述的用途，其特征在于，所述铂类络合物剂量选自5-400mg，优选自10mg、20mg、40mg、100mg、160mg、200mg、300mg、400mg，更优选20mg、100mg、160mg。
  17. 一种药物包装盒，其特征在于，包含有权利要求1-16任一项所述免疫治疗剂、核苷类抗代谢物和铂类络合物。
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