WO2019129168A1 - Pd-1抗体和阿帕替尼联合治疗三阴性乳腺癌的用途 - Google Patents

Pd-1抗体和阿帕替尼联合治疗三阴性乳腺癌的用途 Download PDF

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WO2019129168A1
WO2019129168A1 PCT/CN2018/124563 CN2018124563W WO2019129168A1 WO 2019129168 A1 WO2019129168 A1 WO 2019129168A1 CN 2018124563 W CN2018124563 W CN 2018124563W WO 2019129168 A1 WO2019129168 A1 WO 2019129168A1
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antibody
seq
apatinib
antigen
binding fragment
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PCT/CN2018/124563
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English (en)
French (fr)
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王泉人
戴宗飞
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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 BR112020011796-0A priority Critical patent/BR112020011796A2/pt
Priority to CN201880059102.7A priority patent/CN111065412B/zh
Priority to KR1020207017977A priority patent/KR20200105825A/ko
Priority to AU2018396889A priority patent/AU2018396889A1/en
Priority to RU2020123428A priority patent/RU2774721C2/ru
Priority to US16/956,765 priority patent/US20210363253A1/en
Priority to CA3086429A priority patent/CA3086429A1/en
Priority to MX2020006368A priority patent/MX2020006368A/es
Priority to EP18893813.8A priority patent/EP3733202A4/en
Priority to JP2020535616A priority patent/JP2021508699A/ja
Publication of WO2019129168A1 publication Critical patent/WO2019129168A1/zh

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    • 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
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • 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
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • 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
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]

Definitions

  • the present invention relates to the use of an anti-PD-1 antibody or antigen-binding fragment thereof in combination with apatinib or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of triple negative breast cancer.
  • breast cancer is the sum of a class of diseases, at least divided into four subtypes of luminal A, luminal B, HER2 overexpression and three negative types. Among them, Sanyin breast cancer accounts for about 15% of total breast cancer cases, and has the characteristics of high early recurrence rate, high distant metastasis rate and poor prognosis. Because of the lack of effective targeted therapy drugs, the current international treatment consensus (ABC3) only recommends low-toxic chemotherapy, but chemotherapy resistance often occurs during the treatment. Therefore, the search for effective targeted drugs for triple-negative breast cancer has become a hot and difficult problem in research.
  • the small molecule tyrosine kinase inhibitor Apatinib disclosed in WO2005000232A has a highly selective competition for the ATP binding site of VEGFR-2 in cells, blocks downstream signal transduction, inhibits tumor angiogenesis, and finally reaches
  • the structural formula of apatinib is as shown in formula (I).
  • CN101676267A discloses a series of salts of apatinib, such as mesylate, hydrochloride, maleate, and the like.
  • the pre-clinical animal experiments disclosed in CN101675930A also show that apatinib combined with cytotoxic drugs such as oxaliplatin, 5-Fu, docetaxel, and doxorubicin can significantly increase the therapeutic effect.
  • the present invention provides the use of a combination of apatinib or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or antigen-binding fragment thereof for the preparation of a medicament for treating triple negative breast cancer.
  • the invention also provides the use of an anti-PD-1 antibody or antigen-binding fragment thereof for the preparation of a medicament for treating triple negative breast cancer.
  • the triple negative breast cancer of the present invention refers to a breast cancer in which the estrogen receptor (ER), the progesterone receptor (PR) and the proto-oncogene Her-2 are both negative.
  • the anti-PD-1 antibody or antigen-binding fragment thereof is selected from the group consisting of: 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 SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively
  • the LCDR1, LCDR2 and LCDR3 are shown; the heavy chain variable region 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 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 has a 0-10 amino acid change in the light chain variable region; More preferably, it is an 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; the variant preferably has an amino acid change of 0-10 in the heavy chain variable region; more preferably Amino acid changes in G44R.
  • variable region sequences of the heavy and light chains of the aforementioned humanized antibodies are as follows:
  • 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 triple negative breast cancer patient is subjected to chemotherapy failure or intolerance.
  • the drug for chemotherapy is selected from one or more of the group consisting of anthracyclines, taxanes, vinorelbine, capecitabine, gemcitabine, and platinum drugs.
  • the anthracyclines of the present invention include doxorubicin, epirubicin, idarubicin, daunorubicin, nemoubiubicin and derivatives thereof.
  • the taxanes of the present invention include paclitaxel, docetaxel, paclitaxel liposome, albumin-bound paclitaxel, and the like.
  • the platinum-based drugs of the present invention include carboplatin, cisplatin, oxaliplatin, nedaplatin, lobaplatin, satraplatin, cycloplatin, and miboplatin. , Enloplatin, Iproplatin, Dicycloplatin, etc.
  • the dose of the PD-1 antibody or antigen-binding fragment thereof is selected from the group consisting of 1-10 mg/kg, preferably from 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, more preferably 1 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 10 mg/kg.
  • the PD-1 antibody or antigen-binding fragment thereof is selected from the group consisting of 50-600 mg, preferably from 50 mg, 60 mg, 70 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 600 mg, more preferably from 60 mg, 100 mg, 200 mg, 400 mg, 600 mg.
  • the dose of apatinib or a pharmaceutically acceptable salt thereof is selected from the group consisting of 100-500 mg, preferably from 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 500 mg, more preferably 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg
  • the PD-1 antibody or antigen-binding fragment thereof is administered once a week, once every two weeks, once every three weeks, once a month, the apatinib or the same
  • the frequency of administration of the pharmaceutically acceptable salt is once a day, once every two days, once every three days, two days after the administration for two days, and seven days after the administration for seven days.
  • the invention relates to "combination" as a mode of administration, which means administering at least one dose of apafitini and at least one dose of PD-1 antibody within a certain period of time, wherein both substances exhibit pharmacological effects.
  • the time period may be within one administration period, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours, more preferably within 12 hours.
  • Apatinib and PD-1 antibodies can be administered simultaneously or sequentially. Such a term includes treatment in which apafitinib and PD-1 antibodies are administered by the same route of administration or by different routes of administration.
  • the combined modes of administration of the present invention are selected from the group consisting of simultaneous administration, independent formulation and co-administration or independently formulated and administered sequentially.
  • the 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 PD-1 antibody or antigen-binding fragment thereof is administered in an amount of 60 to 600 mg, intravenously infused every three to three weeks; and apatinib or The pharmaceutically acceptable salt is used in an amount of 250 mg to 500 mg orally, once every two days.
  • the PD-1 antibody or antigen-binding fragment thereof is administered in an amount of 60 to 600 mg, intravenously infused every three to three weeks; and apatinib or The pharmaceutically acceptable salt is used in an amount of 250 mg to 500 mg, orally, and is administered for five days for two days.
  • the PD-1 antibody or antigen-binding fragment thereof is administered in an amount of 60 to 600 mg, intravenously infused every three to three weeks; and apatinib or The pharmaceutically acceptable salt is used in an amount of 250 mg to 500 mg, orally, and is administered for seven days for seven days.
  • the PD-1 antibody or antigen-binding fragment thereof is administered in an amount of 200 mg, intravenously infused every two weeks; apatinib or a drug thereof
  • the amount of salt used is 375 mg, orally, once a day.
  • the PD-1 antibody or antigen-binding fragment thereof is administered in an amount of 200 mg, intravenously infused every two weeks; apatinib or a drug thereof
  • the amount of the salt used was 375 mg, orally, and the drug was administered for 5 days for 2 days.
  • the PD-1 antibody or antigen-binding fragment thereof is administered in an amount of 200 mg, intravenously infused every two weeks; apatinib or a drug thereof
  • the amount of the salt used was 375 mg, orally, and the drug was administered for 7 days for 7 days.
  • the PD-1 antibody or antigen-binding fragment thereof is administered in an amount of 200 mg, intravenously infused every two weeks; apatinib or a drug thereof
  • the amount of salt used is 250 mg, orally, once a day.
  • the PD-1 antibody or antigen-binding fragment thereof is administered in an amount of 200 mg, intravenously infused every two weeks; apatinib or a drug thereof
  • the amount of the salt used was 250 mg, orally, and the drug was administered for 5 days for 2 days.
  • the PD-1 antibody or antigen-binding fragment thereof is administered in an amount of 200 mg, intravenously infused every two weeks; apatinib or a drug thereof
  • the amount of the salt used was 250 mg, orally, and the drug was administered for 7 days for 7 days.
  • the PD-1 antibody is administered by injection, for example subcutaneously or intravenously, and the PD-1 antibody is formulated in an injectable form prior to injection.
  • a particularly preferred injectable form of the PD-1 antibody is an injection or lyophilized powder comprising a PD-1 antibody, a buffer, a stabilizer, and optionally a surfactant.
  • the buffering agent may be selected from one or more of the group consisting of acetate, citrate, succinate, and phosphate.
  • the stabilizer may be selected from sugars or amino acids, preferably disaccharides such as sucrose, lactose, trehalose, maltose.
  • the surfactant is selected from the group consisting of polyoxyethylene hydrogenated castor oil, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, preferably the polyoxyethylene sorbitan fatty acid ester is polysorbate 20, 40, 60 or 80. Most preferred is polysorbate 20.
  • injectable forms of the most preferred PD-1 antibodies comprise PD-1 antibody, acetate buffer, trehalose and polysorbate 20.
  • the present invention provides the above anti-PD-1 antibody or antigen-binding fragment thereof in combination with the above-mentioned apatinib or a pharmaceutically acceptable salt thereof as a medicament for reducing adverse drug reactions, preferably, the adverse drug reaction is selected from the group consisting of anti-PD-1 antibodies Or an antigen-binding fragment thereof is caused by or caused by apatinib or a pharmaceutically acceptable salt thereof.
  • the anti-PD-1 antibody or antigen-binding fragment thereof when used in combination with apatinib or a pharmaceutically acceptable salt thereof, can be reduced and/or Or an immune-mediated adverse drug reaction; preferably, the adverse reaction is selected from a vascular-related adverse reaction.
  • the present invention also provides a pharmaceutical kit or a pharmaceutical kit comprising the above anti-PD-1 antibody or antigen-binding fragment thereof and the above-mentioned apatinib or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a method of treating triple negative breast cancer comprising administering to the patient the above PD-1 antibody or antigen-binding fragment thereof and the above-mentioned apatinib or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned effective amount of the PD-1 antibody or antigen-binding fragment thereof and apatinib or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable agents Formulation, diluent or carrier.
  • 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 which is recognized by an antibody or antigen-binding fragment of the present invention.
  • Treatment failure means that the subject is accompanied by a measurable tumor lesion at baseline and is disease progression (PD) or intolerable according to the RECIST 1.1 efficacy assessment criteria.
  • Total survival refers to the period from random period to death from any cause. For subjects who survived at the last follow-up, their OS was censored as data at the last follow-up. In the subjects who were lost to follow-up, the OS was counted as data censored by the last confirmed survival time before the loss of follow-up.
  • the data censored OS is defined as the time from random grouping to censoring.
  • Objective response rate refers to the proportion of patients whose tumor shrinks to a certain extent and remains for a certain period of time, including cases of CR and PR.
  • Tumor remission assessment criteria (RECIST 1.1 criteria) were used to assess objective tumor remission. Subjects must be accompanied by measurable tumor lesions at baseline, and the efficacy criteria were divided into complete response (CR), partial response (PR), stable (SD), and progression (PD) according to RECIST 1.1 criteria.
  • DCR Disease Control Rate
  • CR Complete remission
  • Partial remission The sum of the target lesion diameters is at least 30% less than the baseline level.
  • PD Disease progression: reference to the minimum of the sum of all measured target lesion diameters throughout the experimental study, with a diameter and relative increase of at least 20% (referenced to baseline values if the baseline measurement is minimal); In addition, the absolute value of the diameter and the absolute value must be increased by at least 5 mm (one or more new lesions are also considered to be disease progression).
  • Stable disease The extent of target lesion reduction did not reach PR, and the degree of increase did not reach PD level. Between the two, the minimum value of the sum of diameters could be used as a reference.
  • Figure 1 shows changes in baseline basal diameter of target lesions in the continuous administration group of apatinib
  • Figure 2 shows changes in target basal diameter of apafitini with 7-day 7-day target lesions
  • Example 1 Clinical study of anti-PD-1 antibody combined with apatinib mesylate in the treatment of triple-negative breast cancer
  • the sequence of the heavy and light chain of the PD-1 antibody is SEQ ID NO: 7 and SEQ ID NO: 8. 200 mg/sp. in the present invention, and is formulated into 20 mg/ml for use.
  • PD-1 antibody 200mg intravenous infusion, once every two weeks + 375mg apatinib, oral, once daily
  • PD-1 antibody 200mg intravenous infusion, once every two weeks + 375mg apatinib, oral, oral seven days, 7 days of withdrawal
  • PD-1 antibody 200mg intravenous infusion, once every two weeks + apatinib 250mg, orally, once a day
  • PD-1 antibody 200mg intravenous infusion, once every two weeks + apatinib 250mg, oral, oral seven days, withdrawal for 7 days
  • PD-1 antibody was administered intravenously, fixed dose 200mg, intravenous infusion, each infusion for 30min (not less than 20min, not more than 60min), once every 2 weeks, 1 cycle every 4 weeks, The longest medication period is 2 years.
  • Apatinib was orally administered after meals, once a day, one tablet each time (250 mg/tablet or 375 mg/tablet) for 7 days or 7 days, and suspended for 7 days/14 days.
  • the study drug may be dose suspended, down-regulated, and terminated during the study based on the toxic side effects of the study drug.
  • the PD-1 antibody allowed the dose to be suspended, and the drug was suspended for a maximum of 8 weeks.
  • the delayed administration of the PD-1 antibody was more than 3 days after the planned administration time, and the drug was not administered at the time. Dosing at a dose of 200 mg.
  • PD-1 antibodies can be adjusted down to 3 mg/kg, q2w, for subjects with low body weight.
  • Dose adjustments due to apatini-related toxicity include: dose suspension (maximum of 28 days), dose downregulation (375 mg/d dose group), and dose termination.
  • dose suspension maximal of 28 days
  • dose downregulation 375 mg/d dose group
  • dose termination 375 mg/d dose group
  • the two groups received PD-1 antibody 200mg, IV, q2W; apatinib 250mg daily oral and PD-1 antibody, IV, q2W; apatinib 250mg every 14d for 7d, 7 days of treatment.
  • a total of 19 patients were enrolled, including 10 consecutive patients in the group, 7 in 7 groups and 9 in group. 17 patients were evaluable, including 8 patients in the continuous drug group, 7 patients in 7 groups and 9 patients.
  • the first dose of the continuous drug group was evaluated in 3 patients with PR, SD2, and PD3 with an ORR of 37.5% and a DCR of 62.5%.
  • the PD-1 antibody of the present invention in combination with apafitini is well tolerated and safe in subjects with triple negative breast cancer, and the majority of subjects are treated for disease progression. There was almost no capillary hemangioma in the continuous administration group, which was significantly better than the incidence of capillary hemangioma when PD-1 antibody was used alone in the phase I clinical trial.

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Abstract

本发明涉及PD-1抗体和阿帕替尼联合治疗三阴性乳腺癌的用途。具体而言，本发明涉及一种抗PD-1抗体和阿帕替尼联合在制备三阴性乳腺癌的药物中的用途。

Description

PD-1抗体和阿帕替尼联合治疗三阴性乳腺癌的用途 技术领域
本发明涉及一种抗PD-1抗体或其抗原结合片段和阿帕替尼或其可药用盐联合在制备治疗三阴性乳腺癌的药物中的用途。
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。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。其中三阴乳腺癌约占总乳腺癌病例大约15％，具有早期复发率高、远处转移率高、预后差等特点。三阴乳腺癌因为缺乏有效的靶向治疗药物，目前国际治疗共识(ABC3)仅推荐低毒化疗，但治疗过程中常常会出现化疗耐药的现象。因此寻找三阴乳腺癌的有效靶向药物成为研究的热点和难点问题。
WO2005000232A公开的小分子酪氨酸激酶抑制剂阿帕替尼(Apatinib)具备高度选择性竞争细胞内VEGFR-2的ATP结合位点，阻断下游信号转导，抑制肿瘤新生血管的生成，最终达到治疗肿瘤的目的，阿帕替尼的结构式如式(I)所示。
Figure PCTCN2018124563-appb-000001
CN101676267A公开了阿帕替尼的一系列盐，例如甲磺酸盐、盐酸盐、马来酸盐等。CN101675930A公开的临床前的动物实验也显示阿帕替尼联用细胞毒类药物如奥沙利铂、5-Fu、多西他赛、阿霉素，能明显增加其疗效。
近年来，肿瘤免疫治疗取得了突破性进展。多项临床研究表明抗PD-1/PD-L1抗体在黑色素瘤、肾癌、非小细胞肺癌、乳腺癌等多种晚期实体瘤中显示了不俗 的疗效，其客观有效率(ORR)在不同实体瘤中约10％-40％，其中在恶性黑色素瘤中最高(约36％-53％)。WO2015085847A公开了一种新的抗PD-1抗体，目前正处于临床试验阶段，已经显示出一定的抗肿瘤作用。但是，许多三阴乳腺癌患者单用抗PD-1/PD-L1抗体并未获得良好的疗效(Nanda R,Chow LQ,Dees EC et al.Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer:Phase Ib KEYNOTE-012Study.J Clin Oncol 2016；34:2460-2467)，因此找到能与抗PD-1/PD-L1抗体联用并增强其疗效的靶向药物具有重要意义。
发明内容
本发明提供一种阿帕替尼或其可药用盐和抗PD-1抗体或其抗原结合片段联合在制备治疗三阴性乳腺癌癌的药物中的用途。
本发明还提供一种抗PD-1抗体或其抗原结合片段在制备治疗三阴性乳腺癌的药物中的用途。
本发明所述的三阴性乳腺癌是指雌激素受体(ER)、孕激素受体(PR)和原癌基因Her-2均为阴性的乳腺癌。
在本发明一个优选的实施方案中，其中所述抗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。
在本发明一个优选的实施方案中，其中所述抗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。
其中，前面所述的各CDR序列如下表所示：
名称 序列 编号
HCDR1 SYMMS SEQ ID NO：1
HCDR2 TISGGGANTYYPDSVKG SEQ ID NO：2
HCDR3 QLYYFDY SEQ ID NO：3
LCDR1 LASQTIGTWLT SEQ ID NO：4
LCDR2 TATSLAD SEQ ID NO：5
LCDR3 QQVYSIPWT SEQ ID NO：6
优选的，所述的PD-1抗体为人源化抗体。
优选的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 PCTCN2018124563-appb-000002
轻链可变区
Figure PCTCN2018124563-appb-000003
优选的人源化抗体轻链序列为如SEQ ID NO:8所示的序列或其变体；所述的变体优选在轻链可变区有0-10的氨基酸变化；更优选为A43S的氨基酸变化。所述人源化抗体重链序列为如SEQ ID NO:7所示的序列或其变体；所述变体优选在重链可变区有0-10的氨基酸变化；更优选为G44R的氨基酸变化。
在本发明一个优选的实施方案中，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 PCTCN2018124563-appb-000004
Figure PCTCN2018124563-appb-000005
轻链
Figure PCTCN2018124563-appb-000006
在本发明一个优选的实施方案中，其中所述三阴性乳腺癌患者是经受化学治疗失败或者不可耐受的。
在本发明一个优选的实施方案中，其中所述化疗的药物选自蒽环类、紫杉类、长春瑞滨、卡培他滨、吉西他滨、铂类药物中一种或多种组合。
本发明所述的蒽环类药物包括多柔比星、表柔比星、伊达比星、柔红霉素、奈莫柔比星及其衍生物等。
本发明所述的紫杉类药物包括紫杉醇、多西他赛、紫杉醇脂质体、白蛋白结合型紫杉醇等。
本发明所述的铂类药物包括卡铂、顺铂、奥沙利铂、奈达铂(Nedaplatin)、乐铂(lobaplatin)、沙铂(satraplatin)、环铂(cycloplatin)、米铂(Miboplatin)、Enloplatin、Iproplatin、Dicycloplatin等。
在本发明一个优选的实施方案中，其中所述的PD-1抗体或其抗原结合片段剂量选自1-10mg/kg，优选自1mg/kg、2mg/kg、3mg/kg、4mg/kg、5mg/kg、6mg/kg、7mg/kg、8mg/kg、9mg/kg、10mg/kg，更优选1mg/kg、3mg/kg、4mg/kg、5mg/kg、6mg/kg、10mg/kg。
在本发明一个优选的实施方案中，其中所述的PD-1抗体或其抗原结合片段剂量选自50-600mg，优选自50mg、60mg、70mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、375mg、400mg、425mg、450mg、475mg、500mg、 600mg，更优选自60mg、100mg、200mg、400mg、600mg。
在本发明一个优选的实施方案中，其中所述阿帕替尼或其可药用盐剂量选自100-500mg，优选自100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg、400mg、500mg，更优选200mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg
在本发明一个优选的实施方案中，其中所述PD-1抗体或其抗原结合片段的给药频次为一周一次、两周一次、三周一次、一月一次，所述阿帕替尼或其可药用盐的给药频次为一日一次、两日一次、三日一次、给药五天停药两天、给药七天停药七天。
本发明关于“联合”是一种给药方式，是指在一定时间期限内给予至少一种剂量的阿帕替尼和至少一种剂量的PD-1抗体，其中两种物质都显示药理学作用。所述的时间期限可以是一个给药周期内，优选4周内，3周内，2周内，1周内，或24小时以内，更优选12小时以内。可以同时或依次给予阿帕替尼和PD-1抗体。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阿帕替尼和PD-1抗体。本发明所述联合的给药方式选自同时给药、独立地配制并共给药或独立地配制并相继给药。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。
在本发明一个优选的实施方案中，在给药时，其中所述的PD-1抗体或其抗原结合片段的用量是60至600mg，静脉输注，每一至三周一次；阿帕替尼或其可药用盐的用量是250mg至500mg，口服，每一到两日一次。
在本发明一个优选的实施方案中，在给药时，其中所述的PD-1抗体或其抗原结合片段的用量是60至600mg，静脉输注，每一至三周一次；阿帕替尼或其可药用盐的用量是250mg至500mg，口服，给药五天停药两天。
在本发明一个优选的实施方案中，在给药时，其中所述的PD-1抗体或其抗原结合片段的用量是60至600mg，静脉输注，每一至三周一次；阿帕替尼或其可药用盐的用量是250mg至500mg，口服，给药七天停药七天。
在本发明一个优选的实施方案中，在给药时，其中所述的PD-1抗体或其抗原结合片段的用量是200mg，静脉输注，每两周一次；阿帕替尼或其可药用盐的用量是375mg，口服，每日一次。
在本发明一个优选的实施方案中，在给药时，其中所述的PD-1抗体或其抗原结合片段的用量是200mg，静脉输注，每两周一次；阿帕替尼或其可药用盐的用量是375mg，口服，给药5天停药2天。
在本发明一个优选的实施方案中，在给药时，其中所述的PD-1抗体或其抗原结合片段的用量是200mg，静脉输注，每两周一次；阿帕替尼或其可药用盐的用量是375mg，口服，给药7天停药7天。
在本发明一个优选的实施方案中，在给药时，其中所述的PD-1抗体或其抗原结合片段的用量是200mg，静脉输注，每两周一次；阿帕替尼或其可药用盐的用量是250mg，口服，每日一次。
在本发明一个优选的实施方案中，在给药时，其中所述的PD-1抗体或其抗原结合片段的用量是200mg，静脉输注，每两周一次；阿帕替尼或其可药用盐的用量是250mg，口服，给药5天停药2天。
在本发明一个优选的实施方案中，在给药时，其中所述的PD-1抗体或其抗原结合片段的用量是200mg，静脉输注，每两周一次；阿帕替尼或其可药用盐的用量是250mg，口服，给药7天停药7天。
在本发明一个优选的实施方案中，所述的PD-1抗体以注射的方式给药，例如皮下或静脉注射，注射前需将PD-1抗体配制成可注射的形式。特别优选的PD-1抗体的可注射形式是注射液或冻干粉针，其包含PD-1抗体、缓冲剂、稳定剂，任选地还含有表面活性剂。缓冲剂可选自醋酸盐、柠檬酸盐、琥珀酸盐、以及磷酸盐中的一种或几种。稳定剂可选自糖或氨基酸，优选二糖，例如蔗糖、乳糖、海藻糖、麦芽糖。表面活性剂选自聚氧乙烯氢化蓖麻油、甘油脂肪酸酯、聚氧乙烯山梨醇酐脂肪酸酯，优选所述聚氧乙烯山梨醇酐脂肪酸酯为聚山梨酯20、40、60或80，最优选聚山梨酯20。最为优选的PD-1抗体的可注射形式包含PD-1抗体、醋酸盐缓冲剂、海藻糖和聚山梨酯20。
本发明提供上述抗PD-1抗体或其抗原结合片段联合上述阿帕替尼或其可药用盐作为减少药物不良反应的药物，优选的，所述的药物不良反应选自由抗PD-1抗体或其抗原结合片段引起或由阿帕替尼或其可药用盐引起。
在本发明一个优选的实施方案中，当PD-1抗体或其抗原结合片段与阿帕替尼或其可药用盐联合使用时，可减少由抗PD-1抗体或其抗原结合片段和/或免疫介导的药物不良反应；优选的，所述的不良反应选自血管相关不良反应。
本发明还提供了一种药物套组或者药物包装盒，其中含有上述抗PD-1抗体或其抗原结合片段和上述阿帕替尼或其可药用盐。
本发明还提供了一种治疗三阴性乳腺癌的治疗方法，包括给予患者上述PD-1抗体或其抗原结合片段和上述阿帕替尼或其可药用盐。
本发明还提供了一种药物组合物，其中包含上述的有效量的PD-1抗体或其抗原结合片段和阿帕替尼或其可药用盐，以及一种或多种可药用的赋型剂、稀释剂或载体。
发明详述
一、术语
为了更容易理解本发明，以下具体定义了某些技术和科学术语。除显而易见在本文件中的它处另有明确定义，否则本文使用的所有其它技术和科学术语都具有本发明所属领域的一般技术人员通常理解的含义。
术语“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。
本发明所述“治疗失败”是指受试者在基线时伴有可测量的肿瘤病灶，根据RECIST 1.1疗效评定标准为疾病进展(PD)或不能耐受的。
本发明所述“不能耐受的”是指因药物引起的不良反应不能继续接受治疗。
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。采用肿瘤缓解评估标准(RECIST1.1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)。
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。
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。
附图说明
图1表示阿帕替尼连续给药组靶病灶较基线基径值变化
图2表示阿帕替尼用7天停7天组靶病灶较基线基径值变化
具体实施方式
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：抗PD-1抗体联合甲磺酸阿帕替尼治疗三阴性乳腺癌的临床研究
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20mg/ml备用。
市售甲磺酸阿帕替尼片。
2、入组标准：(1)经病理学确诊的复发转移性三阴性乳腺癌(ER阴性(IHC ER阳性百分比＜1％)、PR阴性(IHC PR阳性百分比＜1％)、HER2阴性(IHC-/+或IHC++但FISH/CISH-))；(2)既往经过蒽环类、紫杉类治疗，治疗失败，复发转移阶段化疗线数<3线；(3)具有可测量的病灶；(4)ECOG评分0-1分。
3、PD-1和阿帕替尼的示例性给药方案如下：
PD-1抗体200mg，静脉输注，每两周一次+阿帕替尼375mg，口服，每日一次
PD-1抗体200mg，静脉输注，每两周一次+阿帕替尼375mg，口服，口服七天，停药7天
PD-1抗体200mg，静脉输注，每两周一次+阿帕替尼250mg，口服，每日一次
PD-1抗体200mg，静脉输注，每两周一次+阿帕替尼250mg，口服，口服七天，停药7天
4、给药方案
PD-1抗体静脉注射给药，固定剂量200mg，静脉滴注给药，每次输注30min(不少于20min，不超过60min)，2周给药1次，每4周为1个周期，最长用药期为2年。
阿帕替尼餐后口服，每日1次，每次1片(250mg/片或375mg/片)连续服药或用药7天，暂停7天/14天。
5、剂量调整
研究期间可根据研究药物的毒副作用对研究药物进行剂量暂停、下调及终止。
研究期间PD-1抗体允许剂量暂停，最长允许8周的药物暂停；PD-1抗体延迟给药超过计划给药时间3天，则当次不再给药，待下次计划给药时间继续按200mg剂量给药。
除剂量暂停外，针对体重偏轻的受试者，PD-1抗体可酌情下调至3mg/kg,q2w给药。
因阿帕替尼相关毒性导致的剂量调整包括：剂量暂停(最长不得超过28天)、剂量下调(375mg/d剂量组)及剂量终止。研究期间阿帕替尼只允许剂量下调，可由375mg/d下调至250mg/d，不允许剂量上调。发生阿帕替尼相关毒副反应时，应先予以剂量暂停，待毒性恢复后，酌情予以原剂量用药、剂量下调或剂量终止,，终止阿帕替尼给药后，受试者可继续使用PD-1抗体单药治疗。
6、结果
两组病人分别接受PD-1抗体200mg,IV,q2W；阿帕替尼250mg每日口服和PD-1抗体,IV,q2W；阿帕替尼250mg每14d用药7d、停药7天治疗。已入组19名患者，其中连续用药组10人，用7停7组9人。可评价患者17人，其中连续用药组8人，用7停7组9人。连续用药组首次疗效评估PR 3例，SD2例，PD3例，ORR 37.5％，DCR 62.5％。
  病例数 可评价 PR 确认PR SD ORR DCR
间歇给药组 10 9 0 0 4 0 44.40％
连续给药组 13 13 6 5 3 38.50％ 61.50％
用7停7组首次疗效评估SD4例，PD 5例，ORR 0％，DCR 44.4％。
后续又入组了部分受试者，总计23例，结果如下：
本发明的PD-1抗体联合阿帕替尼在三阴性乳腺癌受试者中耐受性、安全性尚可，多数受试者治疗结束原因为疾病进展。连续给药组基本没有毛细血管瘤发生，明显优于I期临床实验中PD-1抗体单用时的毛细血管瘤发生率。

Claims (14)

  1. 抗PD-1抗体或其抗原结合片段和阿帕替尼或其可药用盐联合在制备治疗三阴性乳腺癌的药物中的用途。
  2. 权利要求1所述的用途，其中所述抗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。
  3. 权利要求1所述的用途，其中所述抗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。
  4. 权利要求3所述的用途，其中所述抗PD-1抗体为人源化抗体。
  5. 权利要求4所述的用途，其中所述人源化抗体的轻链可变区序列为如SEQ ID NO:10所示的序列或其变体，所述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. 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. 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. 权利要求1-7任一项所述的用途，其中所述三阴性乳腺癌是经受过化学治疗失败的。
  9. 权利要求8所述的用途，其中所述化学治疗的药物选自蒽环类、紫杉类、长春瑞滨、卡培他滨、吉西他滨、铂类药物中一种或多种组合。
  10. 权利要求1-9任一项所述的用途，其中所述的PD-1抗体或其抗原结合片段剂量选自1-10mg/kg，优选自1mg/kg、2mg/kg、3mg/kg、4mg/kg、5mg/kg、6mg/kg、7mg/kg、8mg/kg、9mg/kg、10mg/kg，更优选1mg/kg、3mg/kg、4mg/kg、5mg/kg、6mg/kg、10mg/kg。
  11. 权利要求1-9任一项所述的用途，其中所述的PD-1抗体或其抗原结合片段剂量选自50-600mg，优选自50mg、60mg、70mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、375mg、400mg、425mg、450mg、475mg、500mg、600mg，更优选自60mg、100mg、200mg、400mg、600mg。
  12. 权利要求1-9任一项所述的用途，其中所述阿帕替尼或其可药用盐剂量选自100-500mg，优选自100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg、400mg、500mg，更优选200mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg。
  13. 一种药物包装盒，其中含有权利要求1-12任意一项所述的阿帕替尼或其可药用盐和抗PD-1抗体或其抗原结合片段。
  14. 一种药物组合物，其特征在于包含有权利要求1-12任意一项所述的有效量的PD-1抗体或其抗原结合片段和阿帕替尼或其可药用盐，以及一种或多种可药用的赋型剂、稀释剂或载体。
PCT/CN2018/124563 2017-12-29 2018-12-28 Pd-1抗体和阿帕替尼联合治疗三阴性乳腺癌的用途 WO2019129168A1 (zh)

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