WO2021057764A1 - Pd-1抗体联合紫杉类化合物在制备治疗三阴性乳腺癌的药物中的用途 - Google Patents

Pd-1抗体联合紫杉类化合物在制备治疗三阴性乳腺癌的药物中的用途 Download PDF

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WO2021057764A1
WO2021057764A1 PCT/CN2020/117007 CN2020117007W WO2021057764A1 WO 2021057764 A1 WO2021057764 A1 WO 2021057764A1 CN 2020117007 W CN2020117007 W CN 2020117007W WO 2021057764 A1 WO2021057764 A1 WO 2021057764A1
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antibody
antigen
binding fragment
seq
use according
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PCT/CN2020/117007
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French (fr)
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邹建军
张晓静
朱晓宇
邵志敏
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江苏恒瑞医药股份有限公司
苏州盛迪亚生物医药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants

Definitions

  • the present disclosure belongs to the field of medicine, and relates to the use of PD-1 antibody combined with taxane compounds in the preparation of drugs for treating triple-negative breast cancer.
  • Breast cancer has the highest incidence rate among Chinese female cancers and is on the rise. It is a common malignant tumor that endangers women's health. In China, according to the data collected by the National Cancer Registry in 2017, the number of new female breast cancer cases in 2014 was about 279,000, with an incidence rate of 41.82 per 100,000, ranking first among female malignant tumors; the number of deaths was about 66,000. The mortality rate is 9.9 per 100,000, and the age of onset is younger than that in Western countries.
  • Breast cancer is the sum of a group of diseases, which can be divided into at least four molecular subtypes: luminal A, luminal B, HER2 overexpression, and triple-negative.
  • TNBC Triple negative breast cancer
  • IM immunomodulatory type
  • LAR luminal androgen receptor type
  • BLIS basal-like immunosuppressive type
  • MES Mesenchymal
  • IM immunomodulatory type
  • TILs tumor infiltrating lymphocytes
  • PD-1 programmed death-1
  • PD-L1 and PD-L2 are the ligands of PD-1 and can specifically bind to PD-1.
  • PD-1 inhibitors are a new class of tumor immunotherapy drugs that are currently attracting attention. They regulate the anti-tumor activity of T lymphocytes by blocking the PD-1/PD-L1 signaling pathway and cause tumor apoptosis.
  • chemotherapeutic drugs that cause tumor cell death through cytotoxicity
  • more and more studies have proved that they can enhance the body's anti-tumor immune function.
  • Clinical practice shows that breast cancer patients (stage II/III) who have received taxane treatment have enhanced T cell and NK cell functions.
  • Chemotherapy kills tumor cells to release large amounts of tumor antigens, increases the amount of cross-presented tumor antigens, and then stimulates the body to produce an immune response.
  • T cells caused by PD-1/PD-L1 inhibitors recognize the signals of standard chemotherapy to release tumor antigens, further enhance the immune response, and kill tumor cells to benefit patients. Based on the relationship between the presence of TILs in breast cancer and the overexpression of PD-L1, combined chemotherapy and immunotherapy have become the current hot anti-tumor strategies for triple-negative breast cancer.
  • the present disclosure provides a use of a PD-1 antibody or antigen-binding fragment combined with a taxane compound in the preparation of a medicine for treating tumor diseases such as triple-negative breast cancer, and shows a good synergistic effect and anti-tumor effect.
  • the disclosure provides a use of a PD-1 antibody or an antigen-binding fragment thereof combined with a taxane compound in the preparation of a medicine for treating tumor diseases such as triple-negative breast cancer.
  • the PD-1 antibody or antigen-binding fragment thereof is selected from: AMP-224, GLS-010, IBI-308, REGN-2810, PDR-001, BGB-A317, Pidilizumab, PF-06801591, Genolimzumab, CA-170, MEDI-0680, JS-001, TSR-042, Camrelizumab, Pembrolizumab, LZM-009, AK-103 and Nivolumab.
  • the light chain variable region of the anti-PD-1 antibody or antigen-binding fragment thereof comprises LCDR1 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively.
  • the CDR sequences in the light/heavy chain of the PD-1 antibody or antigen-binding fragment are shown in the following table:
  • the PD-1 antibody is selected from humanized antibodies or antigen-binding fragments thereof.
  • the PD-1 antibody or antigen-binding fragment thereof is an antibody fragment selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab') 2 fragments.
  • Immunoglobulins can be derived from any commonly known isotype, including but not limited to IgA, secreted IgA, IgG, and IgM.
  • the IgG subclass is also well known to those skilled in the art, including but not limited to IgG1, IgG2, IgG3, and IgG4.
  • "Isotype" refers to the Ab class or subclass (for example, IgM or IgG1) encoded by the heavy chain constant region gene.
  • the PD-1 antibody or antigen-binding fragment thereof in the present disclosure comprises a heavy chain constant region of human IgG1, IgG2, IgG3 or IgG4 isotype, preferably comprising IgG1 or IgG4 isotype. Constant region of the heavy chain.
  • the PD-1 antibody or antigen-binding fragment thereof comprises a light chain constant region of kappa or lambda.
  • the PD-1 antibody or antigen-binding fragment thereof comprises the light chain variable region shown in SEQ ID NO: 10 or a variant thereof, and the variant is preferably the light chain variable region shown in SEQ ID NO: 10 There are 0-10 amino acid changes in the variable region sequence, more preferably the amino acid change of A43S; and the heavy chain variable region shown in SEQ ID NO: 9 or a variant thereof, the variant is preferably in SEQ ID NO: There are 0-10 amino acid changes in the heavy chain variable region sequence shown in 9, more preferably G44R amino acid changes.
  • variable region sequences of the heavy and light chains of the aforementioned PD-1 antibody or its antigen-binding fragment are as follows:
  • the PD-1 antibody or antigen-binding fragment thereof comprises the light chain variable region shown in SEQ ID NO: 8 or a variant thereof, and the variant is preferably shown in SEQ ID NO: 8 There are 0-10 amino acid changes in the light chain variable region sequence, more preferably A43S amino acid changes; the PD-1 antibody or antigen-binding fragment thereof includes the heavy chain variable region shown in SEQ ID NO: 7 or The variants, the variants preferably have 0-10 amino acid changes in the heavy chain variable region sequence shown in SEQ ID NO: 7, more preferably G44R amino acid changes.
  • the PD-1 antibody or antigen-binding fragment thereof comprises a light chain shown in SEQ ID NO: 8 and a heavy chain shown in SEQ ID NO: 7.
  • sequences of the heavy and light chains of the PD-1 antibody or its antigen-binding fragment are as follows:
  • the taxane compound described in the present disclosure is selected from but not limited to paclitaxel or docetaxel.
  • Paclitaxel albumin is a paclitaxel nanoparticle freeze-dried agent that uses human serum albumin as a carrier. It uses nanotechnology to combine paclitaxel and human serum albumin to make a new formulation of nanoparticle. Compared with paclitaxel, paclitaxel albumin has better pharmacokinetic properties, faster and higher tissue distribution, and its distribution speed is 40 times faster than the discharge rate. It binds to the albumin receptors in the tumor stroma. Paclitaxel in tumor tissues The concentration is 26% higher than traditional paclitaxel. In some embodiments, the paclitaxel is selected from paclitaxel albumin.
  • the use of the present disclosure further includes administering famitinib or a pharmaceutically acceptable salt thereof to tumor patients such as triple-negative breast cancer patients.
  • the three-drug combination treatment program shows the synergy of drugs effect.
  • tumors described in the use of the present disclosure are selected from but not limited to breast cancer (such as triple-negative breast cancer), lung cancer, gastric cancer, colorectal cancer (such as rectal cancer, colorectal cancer), kidney cancer (such as renal cell carcinoma), Liver cancer (e.g. hepatocellular carcinoma), melanoma (e.g. metastatic melanoma), non-small cell lung cancer, pancreatic cancer, solid tumors, lymphoma (e.g.
  • lymphoma such as Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, lymphoma Blastic T-cell lymphoma, Burkitt’s lymphoma, follicular lymphoma
  • kidney cancer such as Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, lymphoma Blastic T-cell lymphoma, Burkitt
  • the breast cancer is selected from triple negative breast cancer. Journal literature (J. Cancer Cell, 2019, 35:1-13) According to the different characteristics of subtype surface proteins, triple-negative breast cancer is divided into 4 subtypes: immunomodulatory (IM), luminal androgen receptor Type (LAR), Basal-like Immunosuppressive Type (BLIS), Interstitial Type (MES).
  • IM immunomodulatory
  • LAR luminal androgen receptor Type
  • BLIS Basal-like Immunosuppressive Type
  • MES Interstitial Type
  • the immunomodulatory (IM) type is characterized by the increased signal transduction of immune cells observed in the gene expression data, and H&E staining confirmed the increase of stromal cells and tumor infiltrating lymphocytes (TILs).
  • TILs tumor infiltrating lymphocytes
  • the tumor in the use of the present disclosure is selected from immunomodulatory type.
  • the triple-negative breast cancer patient is a patient who has not used paclitaxel before or has used paclitaxel in the adjuvant/neo-adjuvant treatment phase, but the interval from the end of treatment to relapse is greater than 6 months, preferably Particularly, the triple-negative breast cancer patient has not received systemic anti-tumor therapy at an advanced stage.
  • the triple-negative breast cancer patient is treatment failure (refractory triple-negative breast).
  • treatment failure The commonly used chemotherapy drugs available in China include anthracyclines, taxanes, platinum, capecitabine, gemcitabine and vinorelbine. The above-mentioned commonly used chemotherapy drugs failed, and the patient's condition before enrollment was not Patients who are under effective control and whose condition is progressing.
  • the administration dose of the anti-PD-1 antibody or antigen-binding fragment thereof in a human subject is selected from 0.1 to 10.0 mg/kg, preferably 0.1 mg/kg, 0.2 mg/kg, 0.3mg/kg, 0.4mg/kg, 0.5mg/kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg, 1.0mg/kg, 1.2mg/kg, 1.4 mg/kg, 1.6mg/kg, 1.8mg/kg, 2.0mg/kg, 2.2mg/kg, 2.4mg/kg, 2.6mg/kg, 2.8mg/kg, 3.0mg/kg, 3.2mg/kg, 3.4 mg/kg, 3.6mg/kg, 3.8mg/kg, 4.0mg/kg, 4.2mg/kg, 4.4mg/kg, 4.6mg/kg, 4.8mg/kg,
  • the dose of the PD-1 antibody or antigen-binding fragment thereof in a human subject is 1-600 mg, preferably 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, 2.0 mg, 2.2mg, 2.4mg, 2.6mg, 2.8mg, 3.0mg, 3.2mg, 3.4mg, 3.6mg, 3.8mg, 4.0mg, 4.2mg, 4.4mg, 4.6mg, 4.8mg, 5.0mg, 5.2mg, 5.4mg, 5.6mg, 5.8mg, 6.0mg, 6.2mg, 6.4mg, 6.6mg, 6.8mg, 7.0mg, 7.2mg, 7.4mg, 7.6mg, 7.8mg, 8.0mg, 8.2mg, 8.4mg, 8.6mg , 8.8mg, 9.0mg, 9.2mg, 9.4mg, 9.6mg, 9.8mg, 10.0m
  • the administration dose of the taxane compound in a human subject is selected from 50-400 mg/m 2 , preferably 50 mg/m 2 , 55 mg/m 2 , 60 mg/m 2 , 65 mg/m 2 , 70mg/m 2 , 75mg/m 2 , 80mg/m 2 , 85mg/m 2 , 90mg/m 2 , 95mg/m 2 , 100mg/m 2 , 105mg/m 2 , 110mg/m 2 , 115mg/m 2 , 120mg/m 2 , 125mg/m 2 , 130mg/m 2 , 135mg/m 2 , 140mg/m 2 , 145mg/m 2 , 150mg/m 2 , 155mg/m 2 , 160mg/m 2 , 165mg/m 2 , 170mg/m 2 , 175mg/m 2 , 180mg/m 2 ,
  • the administering dose of famitinib or its pharmaceutically acceptable salt in a human subject is selected from 1-250 mg, and may be 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg , 2.0mg, 2.2mg, 2.4mg, 2.6mg, 2.8mg, 3.0mg, 3.2mg, 3.4mg, 3.6mg, 3.8mg, 4.0mg, 4.2mg, 4.4mg, 4.6mg, 4.8mg, 5.0mg, 5.2 mg, 5.4mg, 5.6mg, 5.8mg, 6.0mg, 6.2mg, 6.4mg, 6.6mg, 6.8mg, 7.0mg, 7.2mg, 7.4mg, 7.6mg, 7.8mg, 8.0mg, 8.2mg, 8.4mg, 8.6mg, 8.8mg, 9.0mg, 9.2mg, 9.4mg, 9.6mg, 9.8m
  • the frequency of administration of the anti-PD-1 antibody or antigen-binding fragment thereof of the present disclosure is once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, Once every two weeks, once every three weeks, once every four weeks, or once a month, preferably once every two weeks or once every three weeks.
  • the frequency of administration of the taxane compound is once a day, once every two days, once every three days, once a week, once every two weeks, once a week, and stop for one week after three consecutive weeks.
  • the frequency of administration of famitinib or its pharmaceutically acceptable salt is once a day, once every two days, once every three days, once every four days, once every five days, once every six days, and once a week, It is administered three days a week, once a day, four days a week, once a day, and five days a week, once a day.
  • the administration dose of the PD-1 antibody or antigen-binding fragment thereof in a human subject is 0.1-10.0 mg/kg; the taxane compound such as paclitaxel albumin
  • the dose administered in a human subject is selected from 50 to 400 mg/m 2 .
  • the PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dose of 1 to 600 mg, preferably 200 mg; the taxane compound such as paclitaxel albumin is effective in human subjects.
  • the administered dose is selected from 50 to 400 mg/m 2 .
  • the dose of the PD-1 antibody or antigen-binding fragment thereof in a human subject is 200 mg; the dose of the taxane compound such as paclitaxel albumin in a human subject is selected from 100 mg /m 2 .
  • the dose of the PD-1 antibody or antigen-binding fragment thereof in a human subject is 0.1 to 10.0 mg/kg, once every two weeks; the taxanes
  • the dosage of the compound such as paclitaxel albumin in human subjects is selected from 50-400 mg/m 2 , once a week.
  • the administration dose of the paclitaxel albumin in human subjects is selected from 50-400 mg/m 2 , once a week, and the drug is stopped once every three weeks in combination.
  • the PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dose of 200 mg, once every two weeks; the taxane compound such as paclitaxel albumin is effective in human subjects.
  • the administration dose is selected from 100 mg/m 2 , once a week, and once a three-week combination is stopped.
  • the dose of the PD-1 antibody or antigen-binding fragment thereof in a human subject is 0.1 to 10.0 mg/kg; the famitinib or its medicament
  • the dosage of salt in a human subject is selected from 1-850 mg; the dosage of the taxane compound such as paclitaxel albumin in a human subject is selected from 50 to 400 mg/m 2 .
  • the PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dose of 1 to 600 mg, preferably 200 mg; the famitinib or a pharmaceutically acceptable salt thereof is administered in a human subject
  • the dosage of the taxaneous compound is selected from 1 to 850 mg; the dosage of the taxane compound such as paclitaxel albumin in a human subject is selected from 50 to 400 mg/m 2 .
  • the dosage of the PD-1 antibody or its antigen-binding fragment in a human subject is 200 mg; the dosage of the famitinib or its pharmaceutically acceptable salt in a human subject is selected From 20 mg; the dose of the taxane compound such as paclitaxel albumin in a human subject is selected from 100 mg/m 2 .
  • the dose of the PD-1 antibody or antigen-binding fragment thereof in a human subject is 0.1-10.0 mg/kg, once every two weeks;
  • the famitide The administration dose of Nitraria or its pharmaceutically acceptable salt in a human subject is selected from 1-850 mg, once a day;
  • the administration dose of the taxane compound such as paclitaxel albumin in a human subject is selected from 50-400 mg /m 2 , once a week.
  • the administration dose of the paclitaxel albumin in a human subject is selected from 50-400 mg/m 2 , once a week and once every three weeks.
  • the PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dose of 200 mg, once every two weeks; the famitinib or a pharmaceutically acceptable salt thereof is administered in a human subject
  • the administration dose in is selected from 20 mg, once a day; the administration dose of the taxane compound such as paclitaxel albumin in human subjects is selected from 100 mg/m 2 , once a week, and the drug is stopped once every three weeks in combination.
  • the pharmaceutically acceptable salts of famitinib described in the present disclosure are obtained by forming famitinib and acid salts, including but not limited to methanesulfonate, maleate, tartrate, succinate, acetate, and difluoro Acetate, fumarate, citrate, citrate, benzenesulfonate, benzoate, naphthalenesulfonate, lactate, malate, hydrochloride, hydrobromide, Sulfate and phosphate are preferably methanesulfonate, maleate, and malate.
  • the pharmaceutically acceptable salt of famitinib is famitinib malate.
  • the present disclosure also provides a method for treating tumor diseases, including administering an effective therapeutic amount of PD-1 antibody or antigen-binding fragment, famitinib or a pharmaceutically acceptable salt thereof to tumor patients, such as triple-negative breast cancer patients.
  • the method includes administering to the tumor patient an effective therapeutic amount of a PD-1 antibody or antigen-binding fragment thereof and a taxane compound.
  • the aforementioned method for treating tumor diseases also includes administering an effective therapeutic amount of famitinib or a pharmaceutically acceptable salt thereof to tumor patients, such as triple-negative breast cancer patients.
  • the method includes administering to the tumor patient an effective therapeutic amount of PD-1 antibody or antigen-binding fragment thereof, famitinib or a pharmaceutically acceptable salt thereof, and a taxane compound such as paclitaxel albumin.
  • the present disclosure also provides a PD-1 antibody or antigen-binding fragment thereof for treating tumor diseases such as triple-negative breast cancer, wherein the PD-1 antibody or antigen-binding fragment thereof is administered in combination with a taxane compound. Further, in some embodiments, the PD-1 antibody or antigen-binding fragment thereof for the aforementioned use is also administered in combination with famitinib or a pharmaceutically acceptable salt thereof.
  • the present disclosure also provides famitinib or a pharmaceutically acceptable salt thereof for the treatment of tumor diseases such as triple-negative breast cancer, wherein the famitinib or a pharmaceutically acceptable salt thereof is combined with a PD-1 antibody or an antigen-binding fragment thereof , Taxus compound used in combination.
  • the present disclosure also provides a taxane compound for the treatment of tumor diseases such as triple-negative breast cancer, wherein the taxane compound is combined with a PD-1 antibody or an antigen-binding fragment thereof, famitinib or a pharmaceutically acceptable salt thereof Apply.
  • Another aspect of the present disclosure also provides a pharmaceutical combination comprising an effective therapeutic amount of a PD-1 antibody or antigen-binding fragment and a taxane compound such as paclitaxel albumin.
  • the pharmaceutical combination also contains famitinib or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination includes an effective therapeutic amount of a PD-1 antibody or antigen-binding fragment thereof, famitinib or a pharmaceutically acceptable salt thereof, and a taxane compound such as paclitaxel albumin.
  • the combination optionally further includes other components, and the other components include but are not limited to other anti-tumor drugs and the like.
  • the PD-1 antibody or antigen-binding fragment thereof described in the present disclosure is combined with famitinib and/or a taxane compound such as paclitaxel albumin to reduce adverse drug reactions.
  • the adverse drug reactions are selected from PD-1 antibody or antigen-binding fragment, famitinib, or taxane compounds such as paclitaxel albumin.
  • the PD-1 antibody or its antigen-binding fragment of the present disclosure is combined with famitinib and/or a taxane compound such as paclitaxel albumin as an anti-PD-1 antibody or antigen-binding fragment, and famitinib or its pharmacologically used Salt, or a taxane compound such as paclitaxel albumin is administered alone in a dose of the drug.
  • the dose of famitinib or a taxane compound such as paclitaxel albumin is 10% to 100% of the dose administered alone, preferably 10% to 75%, more preferably 75%, 50%, 25%, 12.5%.
  • the dose of the PD-1 antibody or antigen-binding fragment is 10% to 100% of the dose administered alone, preferably 10%. % To 75%, more preferably 75%, 50%, 25%, 12.5%.
  • the anti-PD-1 antibody or antigen-binding fragment thereof is administered by injection, such as subcutaneous or intravenous injection, and the anti-PD-1 antibody or antigen-binding fragment thereof needs to be formulated to be injectable before injection. form.
  • injectable forms of anti-PD-1 antibodies or antigen-binding fragments thereof are injections or freeze-dried powder injections, such as injectable forms of anti-PD-1 antibodies, which contain anti-PD-1 antibodies, buffers, and stabilizers , Optionally also contains a surfactant.
  • the buffer can be selected from one or more of acetate, citrate, succinate, and phosphate.
  • the stabilizer may be selected from sugars or amino acids, preferably disaccharides, such as sucrose, lactose, trehalose, maltose.
  • the surfactant is selected from polyoxyethylene hydrogenated castor oil, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, preferably the polyoxyethylene sorbitan fatty acid ester is polysorbate 20, 40, 60 or 80 , Polysorbate 20 is most preferred.
  • “combination” or “combination” is a mode of administration, which means that at least one dose of PD-1 antibody or antigen-binding fragment thereof, taxane compounds such as paclitaxel albumin, is administered within a certain period of time, And/or famitinib, two or three of which show pharmacological effects.
  • the time limit may be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours, more preferably within 12 hours.
  • PD-1 antibodies or antigen-binding fragments thereof, taxane compounds such as paclitaxel albumin, and/or famitinib can be administered simultaneously or sequentially.
  • This period includes treatment in which the PD-1 antibody or antigen-binding fragment thereof, a taxane compound such as paclitaxel albumin, and/or famitinib are administered through the same route of administration or different routes of administration.
  • the method of administration of the combination described in this application is selected from simultaneous administration, independent formulation and co-administration, or independent formulation and sequential administration.
  • the "effective amount” or “effective therapeutic amount” includes an amount sufficient to improve or prevent the symptoms or conditions of a medical disorder.
  • An effective amount also means an amount sufficient to allow or facilitate diagnosis.
  • the effective amount for a particular patient or veterinary subject can vary depending on factors such as the condition to be treated, the patient's general health, the method of administration and dosage, and the severity of side effects.
  • the effective amount can be the maximum dose or dosing schedule that avoids significant side effects or toxic effects.
  • humanized antibody also known as CDR-grafted antibody, refers to the transplantation of mouse CDR sequences into the human antibody variable region framework, that is, different types of human germlines The antibody produced in the antibody framework sequence. It can overcome the strong variable antibody response induced by the chimeric antibody due to the large amount of mouse protein components.
  • framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences.
  • the germline DNA sequences of the human heavy chain and light chain variable region genes can be found in the "VBase" human germline sequence database (available on the Internet www.mrccpe.com.ac.uk/vbase), as well as in Kabat, EA, etc.
  • human antibody variable region framework sequence can be subjected to minimal reverse mutations or back mutations to maintain activity.
  • the humanized antibodies of the present disclosure also include humanized antibodies that have been further subjected to affinity maturation for CDR by phage display.
  • the "antigen-binding fragments" described in the present disclosure refer to Fab fragments, Fab' fragments, F(ab')2 fragments, and Fv fragments that bind to human PD-L1, ScFv fragments that have antigen-binding activity; it includes the present disclosure
  • the antibody is selected from one or more CDR regions in SEQ ID NO: 1 to SEQ ID NO: 12.
  • the Fv fragment contains the variable region of the heavy chain of the antibody and the variable region of the light chain, but does not have the constant region, and has the smallest antibody fragment with all antigen binding sites.
  • an Fv antibody also contains a polypeptide linker between the VH and VL domains, and can form the structure required for antigen binding.
  • Different linkers can also be used to connect the variable regions of two antibodies into a polypeptide chain, which is called single chain antibody or single chain Fv (sFv).
  • binding to PD-L1 in the present disclosure refers to the ability to interact with human PD-L1.
  • antigen-binding site in the present disclosure refers to a discrete three-dimensional site on an antigen that is recognized by the antibody or antigen-binding fragment of the present disclosure.
  • the "toxicity intolerance” mentioned in this disclosure refers to the inability to continue receiving treatment due to adverse reactions caused by drugs.
  • PFS Progression-free survival
  • OS Overall survival
  • Objective response rate refers to the proportion of patients whose tumors have shrunk to a certain level and maintained for a certain period of time, including CR and PR cases.
  • the solid tumor remission assessment standard (RECIST 1.1 standard) was used to assess the objective tumor remission. Subjects must be accompanied by measurable tumor lesions at baseline.
  • the efficacy evaluation criteria are divided into complete remission (CR), partial remission (PR), stable (SD), and progress (PD) according to the RECIST 1.1 standard.
  • Duration of remission The time from the first PR or CR to the first PD or death.
  • Disease Control Rate refers to the percentage of confirmed cases of complete remission, partial remission and stable disease ( ⁇ 8 weeks) among patients with evaluable efficacy.
  • CR Complete remission
  • Partial remission The sum of the diameters of the target lesions is reduced by at least 30% from the baseline level.
  • PD Disease progression: Take the minimum value of the sum of the diameters of all target lesions measured during the entire experimental study as the reference, and the relative increase in diameter and relative increase of at least 20% (if the baseline measurement value is the smallest, the baseline value is used as the reference); In addition, the absolute value of the diameter sum must be increased by at least 5mm (the appearance of one or more new lesions is also regarded as disease progression).
  • Stable disease The degree of reduction of the target lesion did not reach the PR, and the degree of increase did not reach the PD level, between the two. The minimum sum of the diameters can be used as a reference during the study.
  • CR Complete remission
  • Incomplete remission/non-disease progression the presence of one or more non-target lesions and/or the persistence of tumor marker levels above normal levels.
  • Disease progression There is a clear progression of existing non-target lesions. Note: The appearance of one or more new lesions is also considered disease progression.
  • Non-hematological toxicity Grade III/IV non-hematological toxicity (gastrointestinal toxicity (such as nausea and vomiting) and electrolyte disturbances must be treated as best and continue to be Grade III/IV, but not including: alopecia; with Definite cause of fever, such as tumor or infection; pain caused by tumor bone metastasis; elevation of alkaline phosphatase, creatine kinase, lactate dehydrogenase or lipase but not associated with significant clinical symptoms, etc.); degree II and above Cardiac insufficiency, kidney damage, neurotoxicity;
  • Hematological toxicity IV degree of hematological toxicity, such as IV degree of neutropenia, anemia, thrombocytopenia, etc., or III degree neutropenia with ⁇ 38°C fever, III degree thrombocytopenia with obvious Clinical bleeding tendency.
  • Figure 1 follow-up PFS in patients with different subtypes of triple-negative breast cancer after treatment (abscissa is survival time, ordinate is progression-free survival (PFS); BLIS, basal-like immunosuppressive patients; IM, immunomodulatory patients; LAR, patients with luminal androgen receptor type; MES, patients with interstitial type)
  • Invasive triple-negative breast cancer confirmed by histology (specific definition: immunohistochemical detection of ER ⁇ 1% tumor cells is defined as ER negative, PR ⁇ 1% tumor cells is defined as PR negative, HER2 0-1+ Or if HER2 is ++ but it is negative by FISH or CISH without amplification, it is defined as HER2 negative);
  • Refractory triple-negative breast cancer existing treatment has failed
  • the above-mentioned commonly used chemical medicine treatment fails, the patient's condition has not been effectively controlled before enrollment, and the condition is in progress.
  • TNBC IHC classification and molecular tumor biomarker evaluation were performed on each patient during the earlier treatment period or during the disease progression after standard treatment, and they were divided into immunomodulatory type (IM) and cavity surface androgen receptor type (LAR), basal immunosuppressive type (BLIS), interstitial type (MES) patients. According to the patient's subtype and genetic characteristics, they are assigned to different treatment groups.
  • IM immunomodulatory type
  • LAR cavity surface androgen receptor type
  • BLIS basal immunosuppressive type
  • MES interstitial type
  • Immunomodulation (IM) group 18 cases were enrolled. Among the 14 evaluable patients, the objective response rate (ORR) was 64.3%, and the disease control rate (Disease Control Rate, DCR) was 85.7%. Compared with baseline, the tumor burden of 9 patients was significantly reduced (ie, partial remission [PR]), and the reduction in tumor burden and treatment efficacy was maintained over a relatively long period of time. The median duration of response was 21 weeks (from 19 It doesn't wait until 32 weeks). Of the 11 remissions (whose best response was not disease progression [PD]), 8 discontinued treatment after disease progression (characterized by the growth of target lesions and/or the appearance of new lesions). The remaining 3 responders are still receiving treatment and have so far received nab-paclitaxel anti-PD-1 treatment for 2 to 7.3 months.
  • ORR objective response rate
  • DCR Disease Control Rate
  • the median PFS was 66 days (95% CI 39 to 93 days).
  • the IM subtype has the best prognosis, while the MES subtype has the worst prognosis (see Figure 1).
  • the basal-like immunosuppressive (BLIS) group 24 cases were enrolled.
  • the objective response rate (ORR) was 37.5%
  • the disease control rate (Disease Control Rate, DCR) is 50%.
  • 6 patients experienced initial PR the median duration of response was 27 weeks (from 12 weeks to 49 weeks), of 8 patients, 5 patients stopped treatment after the disease progressed, and 2 patients stopped due to serious adverse events (SAEs)
  • SAEs serious adverse events
  • Triple-negative breast cancer is defined as estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2( HER-2) were all breast cancer patients who were judged to be negative by pathological examination. Specifically: ER negative: IHC ⁇ 1%, PR negative: IHC ⁇ 1%, HER2 negative: IHC-/+ or IHC++ but FISH/CISH is negative. All specimens need to be verified by the pathology department of the participating center of this study, and those with recurrence and metastasis need to review their molecular classification again.
  • Compound A PD-1 antibody (Carrelizumab, the light chain sequence is shown in SEQ ID NO: 8, and the heavy chain sequence is shown in SEQ ID NO: 7), 200 mg, once every two weeks, intravenous injection , Jiangsu Hengrui Pharmaceutical Co., Ltd.;
  • Compound B paclitaxel albumin, 100mg/m 2 , administered once a week for three consecutive weeks and stop for one week (day 1, 8, 15), intravenous injection, Jiangsu Hengrui Pharmaceutical Co., Ltd.;
  • Compound C famitinib malate, 20 mg, orally administered on an empty stomach, once a day, can be prepared according to the method in patent application ZL200610122000.4.

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Abstract

提供了PD-1抗体联合分子化疗剂如紫杉醇在制备治疗三阴性乳腺癌的药物中的用途，该联合治疗方案具有协同效应。

Description

PD-1抗体联合紫杉类化合物在制备治疗三阴性乳腺癌的药物中的用途 技术领域
本公开属于医药领域，涉及PD-1抗体联合紫杉类化合物在制备治疗三阴性乳腺癌药物中的用途。
背景技术
乳腺癌在中国女性癌症中发病率高居首位且呈上升趋势，是危害女性健康的常见恶性肿瘤。在中国，根据2017年全国肿瘤登记中心收集的资料，2014年新发女性乳腺癌病例约为27.9万，发病率为41.82/10万，位居女性恶性肿瘤发病首位；死亡病例约为6.6万，死亡率为9.9/10万，且发病年龄较西方国家年轻。乳腺癌是一类疾病的总和，至少分为luminal A、luminal B、HER2过表达及三阴型四种分子亚型。其中三阴乳腺癌(Triple negative breast cancer，TNBC)为缺乏雌激素受体、孕酮受体和人类表皮生长因子的表达受体2的一种分子类型，其约占总乳腺癌病例的15％～20％，具有早期复发率高、远处转移率高、预后差等特点。
近来，复旦大学附属肿瘤医院等对465例三阴性乳腺癌标本通过高通量基因芯片和测序技术，绘制出全球最大三阴性乳腺癌队列多组学图谱(J.Cancer Cell,2019,35:1-13)。根据亚型表面蛋白的不同特征，命名了三阴性“家族”中的4个亚型：免疫调节型(IM)、腔面雄激素受体型(LAR)、基底样免疫抑制型(BLIS)、间质型(MES)。免疫调节型(IM)型的特征是在基因表达数据中观察到免疫细胞的信号转导升高，H&E染色证实了基质细胞和肿瘤浸润性淋巴细胞(TILs)增多。结合CIBERSORT(单细胞类型分析方法)和差异表达谱分析表明，虽然免疫抑制细胞的数量在IM亚型中没有升高，但表达谱分析显示多种免疫抑制分子，在该亚型中明显过表达。
随着对机体免疫系统认识的不断深入以及生物技术的迅速发展，肿瘤免疫治疗取得了突破性进展，免疫疗法已成为肿瘤治疗的重要手段，并且在肿瘤综合治疗体系中占据着越来越重要的位置。如PD-1全名是程序性死亡分子-1(Programmed death-1)，是近年来发现的一种负性共刺激分子。PD-L1和PD-L2是PD-1的配体，可与PD-1特异性结合。肿瘤细胞通过高表达PD-L1分子，与T淋巴细胞上的PD-1分子结合，传递负性调控信号，导致肿瘤抗原特异性T细胞的诱导凋亡和免疫无能，使肿瘤细胞逃避机体的免疫监控和杀伤。PD-1抑制剂是当前备受瞩目的新一类肿瘤免疫治疗药物，通过阻断PD-1/PD-L1信号通路调节T淋巴细胞抗肿瘤活性，使肿瘤凋亡。
虽然近年来肿瘤免疫治疗取得了突破性进展。但是，许多三阴(性)乳腺癌患者单用抗PD-1/PD-L1抗体并未获得良好的疗效。
化疗药物除了通过细胞毒性引起肿瘤细胞死亡，近年来，越来越多的研究证明其有增强机体抗肿瘤免疫功能的作用。临床实践表明接受杉烷治疗较未接受过紫杉烷治疗的乳腺癌患者(Ⅱ/Ⅲ期)，T细胞和NK细胞的功能增强。化疗杀伤肿瘤细胞使其释放大量 肿瘤抗原，增加交叉提呈的肿瘤抗原量，进而刺激机体产生免疫应答。
联合阻断PD-1/PD-L1抑制剂引起的T细胞活化，识别标准化疗释放肿瘤抗原的信号，进一步增强免疫应答，杀伤肿瘤细胞使患者获益。基于乳腺癌中TILs的存在和PD-L1过表达的关联，联合化疗和免疫治疗成了三阴性乳腺癌目前热点的抗肿瘤策略。
2019年3月8日，FDA优先通过了对Atezolizumab联合联合白蛋白紫杉醇治疗无法切除的局部晚期或转移性PD-L1阳性的三阴性乳腺癌，但这一研究中亚洲人仅占18％，中国患者使用此治疗方案的数据有限，同时考虑药物可及性，为满足国内的TNBC临床需求，仍需探讨如何进一步提高PD-1抗体与白蛋白紫杉醇联合治疗方案的疗效以及筛选其优势获益人群。
本公开提供了一种PD-1抗体或抗原结合片段联合紫杉类化合物在制备治疗肿瘤疾病如三阴性乳腺癌的药物中的用途，并显示了良好的协同作用和抑瘤效果。
发明内容
本公开(The disclosure)提供了一种PD-1抗体或其抗原结合片段联合紫杉类化合物在制备治疗肿瘤疾病如三阴性乳腺癌的药物中的用途。
在一些实施方案中，所述PD-1抗体或其抗原结合片段选自：AMP-224、GLS-010、IBI-308、REGN-2810、PDR-001、BGB-A317、Pidilizumab、PF-06801591、Genolimzumab、CA-170、MEDI-0680、JS-001、TSR-042、Camrelizumab、Pembrolizumab、LZM-009、AK-103和Nivolumab。
在另一些实施方案中，所述抗PD-1抗体或其抗原结合片段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；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。
在一些实施方案中，所述PD-1抗体或抗原结合片段轻/重链中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
在一些实施方案中，所述PD-1抗体选自人源化抗体或其抗原结合片段。
在一些实施方案中，所述PD-1抗体或其抗原结合片段选自由Fab，Fab’-SH，Fv，scFv，和(Fab’)2片段组成的组的抗体片段。
免疫球蛋白可以来源于任何通常已知的同种型，包括但不限于IgA、分泌型IgA、IgG和IgM。IgG亚类也是本领域技术人员众所周知的，包括但不限于IgG1、IgG2、IgG3和 IgG4。“同种型”是指由重链恒定区基因编码的Ab种类或亚类(例如，IgM或IgG1)。在一些可选实施方案中，本披露中所述PD-1抗体或其抗原结合片段包含人源IgG1、IgG2、IgG3或IgG4同种型的重链恒定区，优选包含IgG1或IgG4同种型的重链恒定区。
在另一些可选实施方案中，所述PD-1抗体或其抗原结合片段包含κ或λ的轻链恒定区的轻链恒定区。
进一步地，优选PD-1抗体或其抗原结合片段包含如SEQ ID NO:10所示的轻链可变区或其变体，所述变体优选在SEQ ID NO:10所示的轻链可变区序列上有0-10的氨基酸变化，更优选为A43S的氨基酸变化；和如SEQ ID NO:9所示的重链可变区或其变体，所述变体优选在SEQ ID NO:9所示的重链可变区序列上有0-10的氨基酸变化，更优选为G44R的氨基酸变化。
前述PD-1抗体或其抗原结合片段重、轻链的可变区序列如下所示：
重链可变区
Figure PCTCN2020117007-appb-000001
轻链可变区
Figure PCTCN2020117007-appb-000002
在另一些实施方案中，所述PD-1抗体或其抗原结合片段包含SEQ ID NO:8所示的轻链可变区或其变体，所述变体优选在SEQ ID NO:8所示的轻链可变区序列上有0-10的氨基酸变化，更优选为A43S的氨基酸变化；所述PD-1抗体或其抗原结合片段包含SEQ ID NO:7所示的重链可变区或其变体，所述变体优选在SEQ ID NO:7所示的重链可变区序列上有0-10的氨基酸变化，更优选为G44R的氨基酸变化。
在优选实施方案中，所述PD-1抗体或其抗原结合片段包含SEQ ID NO:8所示轻链，和如SEQ ID NO:7所示重链。
所述PD-1抗体或其抗原结合片段的重、轻链的序列如下所示：
重链
Figure PCTCN2020117007-appb-000003
轻链
Figure PCTCN2020117007-appb-000004
在一些实施方案中，本公开所述紫杉类化合物选自但不限于紫杉醇或多西他赛。
紫杉醇白蛋白是用人血清白蛋白作为载体的紫杉醇纳米微粒冻干剂，采用纳米技术将紫杉醇与人血清白蛋白结合制成纳米微粒的新剂型。相比紫杉醇，紫杉醇白蛋白拥有更好的药代动力学属性，更快更高的组织分布，其分布速度是排出速度的40倍，其与肿瘤间质的白蛋白受体结合，肿瘤组织紫杉醇浓度较传统紫杉醇高26％。在一些实施方案中，所述紫杉醇选自紫杉醇白蛋白。
另一方面，本公开用途中进一步包括向肿瘤患者如三阴性乳腺癌患者施用法米替尼或其可药用盐。
本公开中所述PD-1抗体或其抗原结合片段联合法米替尼以及紫杉类化合物在制备治疗肿瘤疾病的药物用途中，根据金氏公式计算，该三药联合治疗方案展现药物的协同作用。
在本公开用途中所述肿瘤示例选自但不限于乳腺癌(如三阴性乳腺癌)、肺癌、胃癌、结直肠癌(如直肠癌、结直肠癌)、肾癌(如肾细胞癌)、肝癌(如肝细胞癌)、黑素瘤(如转移性黑色瘤)、非小细胞肺癌、胰腺癌、实体瘤、淋巴癌(如霍奇金淋巴瘤、非霍奇金淋巴瘤、淋巴母细胞T细胞淋巴瘤、伯基特淋巴瘤、滤泡性淋巴瘤)，优选为非小细胞肺癌、乳腺癌、黑素瘤、淋巴癌(如霍奇金淋巴瘤、非霍奇金淋巴瘤、淋巴母细胞T细胞淋巴瘤、伯基特淋巴瘤、滤泡性淋巴瘤)或肾癌。
在一些实施方案中，所述乳腺癌选自三阴性乳腺癌。期刊文献(J.Cancer Cell,2019,35:1-13)根据亚型表面蛋白的不同特征，将三阴性乳腺癌分为4个亚型：免疫调节型(IM)、腔面雄激素受体型(LAR)、基底样免疫抑制型(BLIS)、间质型(MES)。免疫调节型(IM)型的特征是在基因表达数据中观察到免疫细胞的信号转导升高，H&E染色证实了基质细胞和肿瘤浸润性淋巴细胞(TILs)增多。在一些实施方案中，本公开用途中所述肿瘤选自免疫调节型的。
进一步地，在一些实施方案中，所述三阴性乳腺癌患者为既往未使用过紫杉醇类或辅助/新辅助治疗阶段使用过紫杉醇类药物但从治疗结束至复发间隔时间大于6个月者，优选地，所述三阴性乳腺癌患者为晚期阶段未接受过系统性抗肿瘤治疗。
在一些实施方案中，所述三阴性乳腺癌患者为治疗失败的(难治性三阴性乳腺)。治疗失败的定义：经过国内能获得常用的化疗药物包括蒽环类、紫杉类、铂类、卡培他滨、吉西他滨及长春瑞滨，上述常用的化药物治疗失败，入组前患者病情未得到有效控制，病情处于进展的患者。
根据疾病的类型和严重性，分别给予人类受试者不同剂量的PD-1抗体或抗原结合片 段、法米替尼或紫杉类化合物。
在一些实施方案中，所述抗PD-1抗体或其抗原结合片段在人类受试者中的施用剂量(按患者体重给药)选自0.1～10.0mg/kg，优选0.1mg/kg、0.2mg/kg、0.3mg/kg、0.4mg/kg、0.5mg/kg、0.6mg/kg、0.7mg/kg、0.8mg/kg、0.9mg/kg、1.0mg/kg、1.2mg/kg、1.4mg/kg、1.6mg/kg、1.8mg/kg、2.0mg/kg、2.2mg/kg、2.4mg/kg、2.6mg/kg、2.8mg/kg、3.0mg/kg、3.2mg/kg、3.4mg/kg、3.6mg/kg、3.8mg/kg、4.0mg/kg、4.2mg/kg、4.4mg/kg、4.6mg/kg、4.8mg/kg、5.0mg/kg、5.2mg/kg、5.4mg/kg、5.6mg/kg、5.8mg/kg、6.0mg/kg、6.2mg/kg、6.4mg/kg、6.6mg/kg、6.8mg/kg、7.0mg/kg、7.2mg/kg、7.4mg/kg、7.6mg/kg、7.8mg/kg、8.0mg/kg、8.2mg/kg、8.4mg/kg、8.6mg/kg、8.8mg/kg、9.0mg/kg、9.2mg/kg、9.4mg/kg、9.6mg/kg、9.8mg/kg、10.0mg/kg或两数值之间任意数值。
在另一选实施方案中，所述PD-1抗体或其抗原结合片段在人类受试者中的施用剂量为1～600mg，优选1.0mg、1.2mg、1.4mg、1.6mg、1.8mg、2.0mg、2.2mg、2.4mg、2.6mg、2.8mg、3.0mg、3.2mg、3.4mg、3.6mg、3.8mg、4.0mg、4.2mg、4.4mg、4.6mg、4.8mg、5.0mg、5.2mg、5.4mg、5.6mg、5.8mg、6.0mg、6.2mg、6.4mg、6.6mg、6.8mg、7.0mg、7.2mg、7.4mg、7.6mg、7.8mg、8.0mg、8.2mg、8.4mg、8.6mg、8.8mg、9.0mg、9.2mg、9.4mg、9.6mg、9.8mg、10.0mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、145mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、195mg、200mg、205mg、210mg、215mg、220mg、225mg、230mg、235mg、240mg、245mg、250mg、255mg、260mg、265mg、270mg、275mg、280mg、285mg、290mg、295mg、300mg、305mg、310mg、315mg、320mg、325mg、330mg、335mg、340mg、345mg、350mg、355mg、360mg、365mg、370mg、375mg、380mg、385mg、390mg、395mg、400mg、405mg、410mg、415mg、420mg、425mg、430mg、435mg、440mg、445mg、450mg、455mg、460mg、465mg、470mg、475mg、480mg、485mg、490mg、495mg、500mg、505mg、510mg、515mg、520mg、525mg、530mg、535mg、540mg、545mg、550mg、555mg、560mg、565mg、570mg、575mg、580mg、585mg、590mg、595mg、600mg。
在一些实施方案中，所述紫杉类化合物在人类受试者中的施用剂量选自50～400mg/m 2，优选50mg/m 2、55mg/m 2、60mg/m 2、65mg/m 2、70mg/m 2、75mg/m 2、80mg/m 2、85mg/m 2、90mg/m 2、95mg/m 2、100mg/m 2、105mg/m 2、110mg/m 2、115mg/m 2、120mg/m 2、125mg/m 2、130mg/m 2、135mg/m 2、140mg/m 2、145mg/m 2、150mg/m 2、155mg/m 2、160mg/m 2、165mg/m 2、170mg/m 2、175mg/m 2、180mg/m 2、185mg/m 2、190mg/m 2、195mg/m 2、200mg/m 2、205mg/m 2、210mg/m 2、215mg/m 2、220mg/m 2、225mg/m 2、230mg/m 2、235mg/m 2、240mg/m 2、245mg/m 2、250mg/m 2、255mg/m 2、260mg/m 2、265mg/m 2、270mg/m 2、275mg/m 2、280mg/m 2、285mg/m 2、290mg/m 2、295mg/m 2、300mg/m 2、305mg/m 2、310mg/m 2、315mg/m 2、320mg/m 2、325mg/m 2、330mg/m 2、335mg/m 2、340mg/m 2、345mg/m 2、350mg/m 2、355mg/m 2、360mg/m 2、 365mg/m 2、370mg/m 2、375mg/m 2、380mg/m 2、385mg/m 2、390mg/m 2、395mg/m 2、400mg/m 2或两数值之间任意数值。
在另一些实施方案中，所述法米替尼或其可药用盐在人类受试者中的施用剂量选自1-250mg，可以为1.0mg、1.2mg、1.4mg、1.6mg、1.8mg、2.0mg、2.2mg、2.4mg、2.6mg、2.8mg、3.0mg、3.2mg、3.4mg、3.6mg、3.8mg、4.0mg、4.2mg、4.4mg、4.6mg、4.8mg、5.0mg、5.2mg、5.4mg、5.6mg、5.8mg、6.0mg、6.2mg、6.4mg、6.6mg、6.8mg、7.0mg、7.2mg、7.4mg、7.6mg、7.8mg、8.0mg、8.2mg、8.4mg、8.6mg、8.8mg、9.0mg、9.2mg、9.4mg、9.6mg、9.8mg、10.0mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、145mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、195mg、200mg、205mg、210mg、215mg、220mg、225mg、230mg、235mg、240mg、245mg、250mg或任意两数值间任意值，优选12mg、20mg、100mg、150mg、200mg或250mg。
另一方面，本公开所述抗PD-1抗体或其抗原结合片段的给药频为一日一次、两日一次、三日一次、四日一次、五日一次、六日一次、一周一次、二周一次、三周一次、四周一次或一月一次，优选二周一次或三周一次。
在一些实施方案中，所述紫杉类化合物如紫杉醇白蛋白的给药频次为一日一次，两日一次，三日一次，一周一次，两周一次，每周一次、连用三周停一周。
在一些实施方案中，所述法米替尼或其可药用盐的给药频率为一日一次，两日一次，三日一次，四日一次，五日一次，六日一次，一周一次，每周给药三日、一日一次，每周给药四日、一日一次，每周给药五日、一日一次。
在一些实施方案中，所述PD-1抗体或其抗原结合片段在人类受试者中的施用剂量(按患者体重给药)0.1～10.0mg/kg；所述紫杉类化合物如紫杉醇白蛋白在人类受试者中的施用剂量选自50～400mg/m 2。
在一些实施方案中，所述PD-1抗体或其抗原结合片段在人类受试者中的施用剂量1～600mg，优选200mg；所述紫杉类化合物如紫杉醇白蛋白在人类受试者中的施用剂量选自50～400mg/m 2。
在一些实施方案中，所述PD-1抗体或其抗原结合片段在人类受试者中的施用剂量200mg；所述紫杉类化合物如紫杉醇白蛋白在人类受试者中的施用剂量选自100mg/m 2。
在一些实施方案中，所述PD-1抗体或其抗原结合片段在人类受试者中的施用剂量(按患者体重给药)0.1～10.0mg/kg，每二周一次；所述紫杉类化合物如紫杉醇白蛋白在人类受试者中的施用剂量选自50～400mg/m 2，每周一次。进一步地，所述紫杉醇白蛋白人类受试者中的施用剂量选自50～400mg/m 2，每周一次、联用三周停药一次。
在一些实施方案中，所述PD-1抗体或其抗原结合片段在人类受试者中的施用剂量200mg，每二周一次；所述紫杉类化合物如紫杉醇白蛋白在人类受试者中的施用剂量选自100mg/m 2，每周一次、联用三周停药一次。
在一些实施方案中，所述PD-1抗体或其抗原结合片段在人类受试者中的施用剂量(按患者体重给药)0.1～10.0mg/kg；所述法米替尼或其可药用盐在人类受试者中的施用剂量选自1-850mg；所述紫杉类化合物如紫杉醇白蛋白在人类受试者中的施用剂量选自50～400mg/m 2。
在一些实施方案中，所述PD-1抗体或其抗原结合片段在人类受试者中的施用剂量1～600mg，优选200mg；所述法米替尼或其可药用盐在人类受试者中的施用剂量选自1-850mg；所述紫杉类化合物如紫杉醇白蛋白在人类受试者中的施用剂量选自50～400mg/m 2。
在一些实施方案中，所述PD-1抗体或其抗原结合片段在人类受试者中的施用剂量200mg；所述法米替尼或其可药用盐在人类受试者中的施用剂量选自20mg；所述紫杉类化合物如紫杉醇白蛋白在人类受试者中的施用剂量选自100mg/m 2。
在一些实施方案中，所述PD-1抗体或其抗原结合片段在人类受试者中的施用剂量(按患者体重给药)0.1～10.0mg/kg，每二周一次；所述法米替尼或其可药用盐在人类受试者中的施用剂量选自1-850mg，每日一次；所述紫杉类化合物如紫杉醇白蛋白在人类受试者中的施用剂量选自50～400mg/m 2，每周一次。进一步地，所述紫杉醇白蛋白人类受试者中的施用剂量选自50～400mg/m 2，每周一次、每三周停药一次。
在一些实施方案中，所述PD-1抗体或其抗原结合片段在人类受试者中的施用剂量200mg，每二周一次；所述法米替尼或其可药用盐在人类受试者中的施用剂量选自20mg，每日一次；所述紫杉类化合物如紫杉醇白蛋白在人类受试者中的施用剂量选自100mg/m 2，每周一次、联用三周停药一次。
本公开所述法米替尼可药用盐为法米替尼与酸成盐获得，包括但不限于甲磺酸盐、马来酸盐、酒石酸盐、琥珀酸盐、醋酸盐、二氟醋酸盐、富马酸盐、柠檬酸盐、枸橼酸盐、苯磺酸盐、苯甲酸盐、萘磺酸盐、乳酸盐、苹果酸盐、盐酸盐、氢溴酸盐、硫酸盐、以及磷酸盐，优选甲磺酸盐、马来酸盐、苹果酸盐。在一些所述方案中，所述法米替尼可药用盐为法米替尼苹果酸盐。
本公开还提供了一种治疗肿瘤疾病的方法，包括给予肿瘤患者如三阴性乳腺癌患者有效治疗量的PD-1抗体或抗原结合片段、法米替尼或其可药用盐。在一些实施方案中，所述方法包括给予肿瘤患者有效治疗量的PD-1抗体或其抗原结合片段和紫杉类化合物。
进一步地，前述治疗肿瘤疾病的方法还包括向肿瘤患者如三阴性乳腺癌患者施用有效治疗量的法米替尼或其可药用盐。
在一些实施方案中，所述方法包括给予肿瘤患者有效治疗量的PD-1抗体或其抗原结合片段，法米替尼或其可药用盐以及紫杉类化合物如紫杉醇白蛋白。
本公开还提供了用于治疗肿瘤疾病如三阴性乳腺癌的PD-1抗体或其抗原结合片段，其中所述PD-1抗体或其抗原结合片段与紫杉类化合物组合施用。进一步地，在一些实施方案中，前述用途的PD-1抗体或其抗原结合片段还与法米替尼或其可药用盐组合施用。
本公开还提供了用于治疗肿瘤疾病如三阴性乳腺癌的法米替尼或其可药用盐，其中 所述法米替尼或其可药用盐与PD-1抗体或其抗原结合片段、紫杉类化合物组合施用。
本公开还提供了用于治疗肿瘤疾病如三阴性乳腺癌的紫杉类化合物，其中所述紫杉类化合物与PD-1抗体或其抗原结合片段、法米替尼或其可药用盐组合施用。
本公开另一方面还提供了一种药物组合，其包含有效治疗量的PD-1抗体或抗原结合片段和紫杉类化合物如紫杉醇白蛋白。
进一步地，所述药物组合还含有法米替尼或其可药用盐。在一些实施方案中，所述药物组合中包含有效治疗量的PD-1抗体或其抗原结合片段，法米替尼或其可药用盐以及紫杉类化合物如紫杉醇白蛋白。
本公开所述的方案中，所述的联合任选的还包含其他组分，所述其他组分包括但不限于其他抗肿瘤药等。
另一方面，本公开所述PD-1抗体或其抗原结合片段联合法米替尼和/或紫杉类化合物如紫杉醇白蛋白减少药物不良反应的药物，优选地，所述药物不良反应选自由PD-1抗体或抗原结合片段，法米替尼，或紫杉类化合物如紫杉醇白蛋白引起。
本公开所述PD-1抗体或其抗原结合片段联合法米替尼和/或紫杉类化合物如紫杉醇白蛋白作为降低抗PD-1抗体或抗原结合片段，法米替尼或其可药用盐，或紫杉类化合物如紫杉醇白蛋白单独施用剂量的药物。在一些实施方案中，与PD-1抗体或其抗原结合片段联合使用时，所述法米替尼或紫杉类化合物如紫杉醇白蛋白的施用量为单独施用剂量的10％～100％，优选10％～75％，更优选75％、50％、25％、12.5％。在一些实施方案中，与法米替尼或紫杉类化合物如紫杉醇白蛋白联合使用时，所述PD-1抗体或抗原结合片段的施用量为单独施用剂量的10％～100％，优选10％～75％，更优选75％、50％、25％、12.5％。
在可选实施方案中，所述抗PD-1抗体或其抗原结合片段以注射的方式给药，例如皮下或静脉注射，注射前需将抗PD-1抗体或其抗原结合片段配制成可注射的形式。特别优选的抗PD-1抗体或其抗原结合片段的可注射形式是注射液或冻干粉针，例如抗PD-1抗体的可注射形式，其包含抗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。
如无相反解释，本公开中术语具有如下含义：
本披露关于“联合”或“联用”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抗体或其抗原结合片段，紫杉类化合物如紫杉醇白蛋白，和/或法米替尼，其中两种或三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，更优选12小时以内。可以同时或依次给予PD-1抗体或其抗原结合片段，紫杉类化合物如紫杉醇白蛋白，和/或法米替尼。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抗体或其抗原结合片段，紫杉类化合物如紫杉醇白蛋白，和/或法米替尼。本申请所述联合的给 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。
本披露中所述“有效量”或“有效治疗量”包含足以改善或预防医学病症的症状或病症的量。有效量还意指足以允许或促进诊断的量。用于特定患者或兽医学受试者的有效量可依据以下因素而变化：如待治疗的病症、患者的总体健康情况、给药的方法途径和剂量以及副作用严重性。有效量可以是避免显著副作用或毒性作用的最大剂量或给药方案。
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。为避免免疫原性下降的同时，引起的活性下降，可对所述的人抗体可变区框架序列进行最少反向突变或回复突变，以保持活性。本公开的人源化抗体也包括进一步由噬菌体展示对CDR进行亲和力成熟后的人源化抗体。
本公开中所述的“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-L1结合的Fv片段ScFv片段；其包含本公开所述抗体的选自SEQ ID NO:1至SEQ ID NO:12中的一个或多个CDR区。Fv片段含有抗体重链可变区和轻链可变区，但没有恒定区，并具有全部抗原结合位点的最小抗体片段。一般地，Fv抗体还包含在VH和VL结构域之间的多肽接头，且能够形成抗原结合所需的结构。也可以用不同的连接物将两个抗体可变区连接成一条多肽链，称为单链抗体(single chain antibody)或单链Fv(sFv)。本公开的术语“与PD-L1结合”，指能与人PD-L1相互作用。本公开的术语“抗原结合位点”指抗原上不连续的，由本公开抗体或抗原结合片段识别的三维空间位点。
本披露中所述“毒性不可耐受”是指因药物引起的不良反应不能继续接受治疗。
无进展生存期(PFS)：从随机开始到首次记录前例腺癌客观进展日期或到任何原因导致死亡的时间，以先出现者为准。
总生存期(OS)指从随机期至任何原因导致死亡的期。末次随访时仍存活的受试者，其OS以末次随访时间计为数据删失。失访的受试者，其OS以失访前末次证实存活时间计为数据删失。数据删失的OS定义为从随机分组到删失的时间。
客观缓解率(Objective response rate，ORR)指肿瘤缩小达到一定并且保持一定时间的病人的比例，包含了CR和PR的病例。采用实体瘤缓解评估标准(RECIST 1.1标准)来评定肿瘤客观缓解。受试者在基线时必须伴有可测量的肿瘤病灶，疗效评定标准根据RECIST 1.1标准分为完全缓解(CR)、部分缓解(PR)、稳定(SD)、进展(PD)。
缓解持续时间(DoR)：首次PR或者CR至首次PD或者死亡的时间。
疾病控制率(Disease Control Rate，DCR)指经确认的完全缓解、部分缓解和疾病稳定(≥8周)病例数在可评价疗效患者中的百分比。
靶病灶评估
完全缓解(CR)：所有靶病灶消失，全部病理淋巴结(包括靶结节和非靶结节)短直径必须减少至＜10mm。
部分缓解(PR)：靶病灶直径之和比基线水平减少至少30％。
疾病进展(PD)：以整个实验研究过程中所有测量的靶病灶直径之和的最小值为参照，直径和相对增加至少20％(如果基线测量值最小就以基线值为参照)；除此之外，必须满足直径和的绝对值增加至少5mm(出现一个或多个新病灶也视为疾病进展)。
疾病稳定(SD)：靶病灶减小的程度没达到PR，增加的程度也没达到PD水平，介于两者之间，研究时可以直径之和的最小值作为参考。
非靶病灶的评估
完全缓解(CR)：所有非靶病灶消失，且肿瘤标记物恢复至正常水平。所有淋巴结为非病理尺寸(短径＜10mm)。
非完全缓解/非疾病进展：存在一个或多个非靶病灶和/或持续存在肿瘤标记物水平超出正常水平。
疾病进展：已存在的非靶病灶出现明确进展。注：出现一个或多个新病灶也被视为疾病进展。
本研究显著毒性定义为在DLT观察期内发生的与研究药物相关的下述任一事件(分级标准参照NCI CTCAE 5.0)
(1)非血液学毒性：III/IV度非血液学毒性(胃肠道毒性(如恶心呕吐)及电解质紊乱须为最佳治疗后仍持续为III/IV度，但不包括：脱发；具有确定原因的发热，如肿瘤或感染；肿瘤骨转移引起的疼痛；碱性磷酸酶、肌酸激酶、乳酸脱氢酶或脂肪酶升高但不伴有相关显著临床症状等)；II度及以上心功能不全、肾功能损害、神经毒性；
(2)血液学毒性：IV度血液学毒性，如IV度的中性粒细胞减少、贫血、血小板减少等，或III度中性粒细胞减少伴≧38℃发热、III度血小板减少伴明显的临床出血倾向。
附图说明
图1：不同亚型三阴性乳腺癌患者经治疗后随访PFS(横坐标为生存时间，纵坐标为无进展生存期(PFS)；BLIS，基底样免疫抑制型患者；IM，免疫调节型患者；LAR，腔面雄激素受体型患者；MES，间质型患者)
具体实施方式
以下结合实施例用于进一步描述本公开，但这些实施例并非限制本公开的范围。
实施例1
入组标准：
1、经组织学证实的浸润性三阴性乳腺癌(具体定义：免疫组化检测ER<1％肿瘤细胞阳性定义为ER阴性，PR<1％肿瘤细胞阳性定义为PR阴性，HER2 0-1+或者HER2为++但经过FISH或者CISH检测为阴性，无扩增，定义为HER2阴性)；
2、局部晚期乳腺癌(无法进行根治性局部治疗)或复发转移性乳腺癌；
3、难治性三阴性乳腺癌(现有治疗已经失败)，具体定义：经过国内能获得常用的化疗药物包括蒽环类、紫杉类、铂类、卡培他滨、吉西他滨及长春瑞滨，上述常用的化药物治疗失败，入组前患者病情未得到有效控制，病情处于进展的患者。
同时在较早的治疗期间或标准治疗后的疾病进展期间对每位患者进行了TNBC IHC分型和分子肿瘤生物标志物评估，分为免疫调节型(IM)、腔面雄激素受体型(LAR)、基底样免疫抑制型(BLIS)、间质型(MES)患者。再根据患者的亚型和基因特征将其分配到不同治疗组中。
Figure PCTCN2020117007-appb-000005
Figure PCTCN2020117007-appb-000006
备注：吡咯替尼、PD-1抗体(卡瑞利珠单抗，轻链序列如SEQ ID NO:8所示，和重链序列如SEQ ID NO:7所示)、SHR3162、SHR3680、SHR6390由江苏恒瑞医药股份有限公司生产提供
结果分析：
免疫调节型(IM)组别：入组18例，在14例可评价患者中，客观缓解率(Objective response rate，ORR)为64.3％，疾病控制率(Disease Control Rate，DCR)为85.7％。与基线相比，9例患者的肿瘤负荷明显降低(即部分缓解[PR])，肿瘤负荷和治疗功效的降低在相对较长的时间内得以维持，中位反应持续时间为21周(从19到32周不等)。在11位缓解者(其最佳反应不是疾病进展[PD])中，有8位在疾病进展后停止治疗(其特征在于靶病变的生长和/或新病变的出现)。其余3位反应者仍在接受治疗，迄今为止已接受nab-紫杉醇抗PD-1治疗2至7.3个月。
另外，中位随访89天后，中位PFS为66天(95％CI为39至93天)。相比其他亚型，IM亚型的预后最好，而MES亚型的预后最差(见附图1)。
另一方面，基底样免疫抑制型(BLIS)组别：入组24例，在16例可评价患者中，客观缓解率(Objective response rate，ORR)为37.5％，疾病控制率(Disease Control Rate，DCR)为50％。6位患者经历了最初的PR，反应的中位持续时间为27周(从12周到49周)，8例患者中，5例在病情进展后停止治疗，2例因严重不良事件(SAEs)停止治疗，1例锁骨上淋巴结转移患者在接受阿帕替尼治疗30.4周后出现完全缓解(CR)。经2个治疗周期，患者的客观缓解率(Objective response rate，ORR)为37.5％，临床获益率(完全缓解(CR)+部分缓解(PR)+疾病稳定(SD)>6个月，CBR)为50％，显示出良好的临床效益，但疗效并不持久，并观察到严重的副作用，如2例患者在病情进展前出现严重高血压和蛋白尿，不幸退出治疗，这种靶向治疗的严重不良反应可能会限制其在难治性三阴乳腺癌中的广泛应用。
实施例2
入组标准：
1.经病理检测证实的晚期三阴性浸润性乳腺癌，同时满足以下条件：三阴性乳腺癌定义为雌激素受体(ER)、孕激素受体(PR)及人表皮生长因子受体2(HER-2)均经病理检测判定为阴性的乳腺癌患者。具体为：ER阴性：IHC<1％，PR阴性：IHC<1％，HER2阴性：IHC-/+或IHC++但FISH/CISH为阴性。所有标本需经本研究参研中心的病理科核实且复发转移者需对其分子分型再次复核。
2、既往未使用过紫杉醇类或辅助/新辅助治疗阶段使用过紫杉醇类药物但从治疗结束至复发间隔时间大于6个月者；晚期阶段未接受过系统性抗肿瘤治疗(化疗、靶向治疗等)
给药方案(每4周一周期)：
化合物A，PD-1抗体(卡瑞利珠单抗，轻链序列如SEQ ID NO:8所示，和重链序列如SEQ ID NO:7所示)，200mg、每二周一次、静脉注射，江苏恒瑞药业股份有限公司；
化合物B，紫杉醇白蛋白，100mg/m 2，每周给药1次、连用三周停一周(第1、8、15天)，静脉注射，江苏恒瑞药业股份有限公司；
化合物C，苹果酸法米替尼，20mg，空腹口服给药，每日一次，可按照专利申请ZL200610122000.4中的方法制备。
结果：
入组34例，在已经治疗满三个月以上的16例中，剔除1例双原发，15例可评价患者中，确认完全缓解(CR)或部分缓解(PR)12例，客观缓解率(Objective response rate，ORR)达80％。

Claims (20)

  1. 一种PD-1抗体或其抗原结合片段联合紫杉类化合物在制备治疗三阴性乳腺癌的药物中的用途。
  2. 如权利要求1所述的用途，其中PD-1抗体或其抗原结合片段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。
  3. 如权利要求2所述的用途，其中所述PD-1抗体或其抗原结合片段选自人源化抗体或其片段。
  4. 如权利要求3所述的用途，其中所述PD-1抗体或其抗原结合片段包含SEQ ID NO:10所示的轻链可变区或其变体，所述变体优选在SEQ ID NO:10所示的轻链可变区序列上有0-10的氨基酸变化，更优选为A43S的氨基酸变化；所述PD-1抗体或其抗原结合片段包含SEQ ID NO:9所示的重链可变区或其变体，所述变体优选在SEQ ID NO:9所示的重链可变区序列上有0-10的氨基酸变化，更优选为G44R的氨基酸变化。
  5. 如权利要求4所述的用途，其中所述PD-1抗体或其抗原结合片段包含SEQ ID NO:8所示轻链，和如SEQ ID NO:7所示重链。
  6. 如权利要求5所述的用途，其中所述三阴性乳腺癌患者为免疫调节型的。
  7. 如权利要求1-6所述的用途，其中所述三阴性乳腺癌患者为治疗失败的。
  8. 如权利要求1所述的用途，其中所述紫杉类化合物选自紫杉醇或多西他赛，优选自紫杉醇，更优选紫杉醇白蛋白。
  9. 如权利要求1-8任一项所述的用途，进一步包括法米替尼或其可药用盐。
  10. 如权利要求1所述的用途，其中所述PD-1抗体或抗原结合片段在人类受试者中的施用剂量为50-600mg，优选200mg。
  11. 如权利要求9所述的用途，其中所述法米替尼或其可药用盐在人类受试者中的施用剂量选自1-250mg，优选12mg、20mg、100mg、150mg、200mg或250mg。
  12. 如权利要求1所述的用途，其中所述紫杉类化合物剂量选自50～400mg/m 2。
  13. 如权利要求1-12所述的用途，其中所述PD-1抗体或其抗原结合片段在人类受试者中的施用剂量200mg，每二周一次；所述紫杉类化合物选自紫杉醇白蛋白，施用剂量选自100mg/m 2，每周一次、连用三周停一周。
  14. 如权利要求9或11所述的用途，其中所述法米替尼或其可药用盐在人类受试者中的施用剂量选自20mg，每日一次。
  15. 一种药物组合，其包含有效治疗量的PD-1抗体或其抗原结合片段和紫杉类化合物。
  16. 如权利要求15所述药物组合，进一步包括包含法米替尼或其可药用盐。
  17. 一种用于治疗三阴性乳腺癌的PD-1抗体或其抗原结合片段，其中所述PD-1抗体或其抗原结合片段与紫杉类化合物组合施用。
  18. 如权利要求17所述PD-1抗体或其抗原结合片段，其中所述PD-1抗体或其抗原结合片段还与法米替尼或其可药用盐组合施用。
  19. 一种用于治疗三阴性乳腺癌的法米替尼或其可药用盐，其中所述法米替尼或其可药用盐与PD-1抗体或其抗原结合片段、紫杉类化合物组合施用。
  20. 一种用于治疗三阴性乳腺癌的紫杉类化合物，其中所述紫杉类化合物与PD-1抗体或其抗原结合片段、法米替尼或其可药用盐组合施用。
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