WO2020093993A1 - 一种抗pd-1抗体和法米替尼联合在制备治疗肿瘤的药物中的用途 - Google Patents

一种抗pd-1抗体和法米替尼联合在制备治疗肿瘤的药物中的用途 Download PDF

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Publication number
WO2020093993A1
WO2020093993A1 PCT/CN2019/115608 CN2019115608W WO2020093993A1 WO 2020093993 A1 WO2020093993 A1 WO 2020093993A1 CN 2019115608 W CN2019115608 W CN 2019115608W WO 2020093993 A1 WO2020093993 A1 WO 2020093993A1
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Prior art keywords
cancer
antibody
famitinib
pharmaceutically acceptable
acceptable salt
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PCT/CN2019/115608
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English (en)
French (fr)
Inventor
张连山
杨清
王泉人
黄晓星
廖成
杨昌永
叶定伟
吴晓华
Original Assignee
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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Application filed by 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 filed Critical 江苏恒瑞医药股份有限公司
Priority to US17/288,894 priority Critical patent/US20220251203A1/en
Priority to EP19881012.9A priority patent/EP3878468A4/en
Priority to MX2021004812A priority patent/MX2021004812A/es
Priority to AU2019375808A priority patent/AU2019375808A1/en
Priority to KR1020217014341A priority patent/KR20210089168A/ko
Priority to CN202311363969.0A priority patent/CN117298270A/zh
Priority to CN201980049882.1A priority patent/CN112543646B/zh
Priority to CA3117819A priority patent/CA3117819A1/en
Priority to JP2021522987A priority patent/JP2022512822A/ja
Priority to BR112021007836-3A priority patent/BR112021007836A2/pt
Publication of WO2020093993A1 publication Critical patent/WO2020093993A1/zh

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    • 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
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • 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

Definitions

  • the present disclosure relates to the use of an anti-PD-1 antibody and famitinib or a pharmaceutically acceptable salt thereof in the preparation of a medicine for treating tumors.
  • Cancer has many genetic and epigenetic changes that produce new antigens that can be recognized by the immune system.
  • the adaptive immune system including T and B lymphocytes, has strong anti-cancer potential, with broad capabilities and fine specificity to respond to various tumor antigens.
  • the immune system exhibits considerable plasticity and memory components. Successful use of all these attributes of the adaptive immune system will make immunotherapy unique among all cancer treatment modalities.
  • Cancer immunotherapy has focused on methods of enhancing anti-tumor immune responses by adoptive transfer of activated effector cells, immunization against relevant antigens, or provision of non-specific immunostimulants such as cytokines.
  • specific immune checkpoint pathway inhibitors has begun to become a new type of immunotherapy for cancer, such as the CTLA antibody Ipilimumab for the treatment of advanced melanoma (Hodi et al., 2010), specifically bind to programmed death receptor (PD-1) nivolumab or pembrolizumab and so on.
  • the PD-1 antibody specifically recognizes and binds to PD-1 on the surface of lymphocytes, blocking the PD-1 / PD-L1 signaling pathway, thereby activating the immune killing effect of T cells on tumors, and regulating the body's immune system to clear tumor cells in the body.
  • WO2015085847 discloses a new anti-PD-1 antibody.
  • the PD-1 antibody is in the stage of clinical trials and has shown a certain anti-tumor effect.
  • the famitinib group 25 mg, 1 day / time, 42 days is a cycle
  • PFS progression-free survival
  • ORR objective response rate
  • DCR disease control rate
  • mOS median survival time
  • the present disclosure provides the use of an anti-PD-1 antibody or antigen-binding fragment thereof in combination with famitinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating tumors.
  • the light chain variable region of the PD-1 antibody comprises LCDR1, LCDR2 and LCDR1 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively.
  • LCDR3 the light chain variable region of the PD-1 antibody
  • the heavy chain variable region of the PD-1 antibody comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively.
  • the PD-1 antibody is a humanized antibody.
  • the humanized antibody comprises the light chain variable region shown in SEQ ID NO: 10 or a variant thereof, the variant is preferably in the light chain variable region shown in SEQ ID NO: 10
  • the humanized antibody comprises the heavy chain variable region shown in SEQ ID NO: 9 or a variant thereof, the variant is preferably in SEQ ID NO:
  • the heavy chain variable region shown in 9 has an amino acid change of 0-10, more preferably an amino acid change of G44R.
  • the humanized antibody comprises the light chain shown in SEQ ID NO: 8 or a variant thereof.
  • the variant preferably has 0-10 amino acid changes in the light chain variable region, more preferably A43S amino acid changes;
  • the humanized antibody comprises the heavy chain shown in SEQ ID NO: 7 or a variant thereof, the variant preferably has 0-10 amino acid changes in the heavy chain variable region, more preferably G44R Amino acid changes.
  • the humanized antibody contains a light chain as shown in SEQ ID NO: 8, and a heavy chain as shown in SEQ ID NO: 7.
  • sequences of the heavy and light chains of the humanized antibody are as follows:
  • the combined anti-PD-1 antibody or antigen-binding fragment thereof described in the present disclosure and famitinib or a pharmaceutically acceptable salt thereof have a synergistic effect.
  • the anti-PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dosage of 0.1 to 10.0 mg / kg, and may be 0.1 mg / 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, 3.0mg / kg, 3.2mg / kg,
  • the PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dosage of 10-300 mg, which may be 10.0 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 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,
  • the administration frequency of the anti-PD-1 antibody or antigen-binding fragment thereof in 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 three weeks.
  • the anti-PD-1 antibody or antigen-binding fragment thereof in the present disclosure is administered at a dose of 50 to 300 mg / 2-3 weeks, more preferably 200 mg / 2-3 weeks.
  • the administration dose of famitinib or its pharmaceutically acceptable salt in human subjects is 0.1 to 10.0 mg / kg, which may be 0.1 mg / 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, 3.0mg / kg, 3.2mg /
  • the dose of famitinib or a pharmaceutically acceptable salt thereof in a human subject is 0.1-100 mg, which may be 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6mg, 0.7mg, 0.8mg, 0.9mg, 1.0mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg , 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg or any value between any two values, It is preferably 1 to 20 mg, 0.1 mg
  • the frequency of administration of famitinib or pharmaceutically acceptable thereof 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, three days a week, once a day, four days a week, once a day, five days a week, once a day.
  • the anti-PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dosage of 10-300 mg, and the famitinib or a pharmaceutically acceptable salt thereof is administered in a human subject
  • the dosage in is 0.1 ⁇ 100mg.
  • the anti-PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dosage of 10-300 mg once every 2-3 weeks, and the famitinib or its pharmaceutically acceptable
  • the dosage of salt administration in human subjects is 0.1 to 100 mg once a day.
  • the anti-PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dose of 50 to 300 mg, and the famitinib or a pharmaceutically acceptable salt thereof is administered in a human subject
  • the administered dose in is 1-20 mg.
  • the anti-PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dose of 50 to 300 mg once every 2-3 weeks, and the famitinib or its pharmaceutically acceptable
  • the dosage of salt administered to human subjects is 1-20 mg once a day.
  • the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 200 mg in a human subject, and the famitinib or a pharmaceutically acceptable salt thereof in a human subject
  • the administered dose is 1-20 mg.
  • the anti-PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dose of 200 mg once every 2-3 weeks, and the famitinib or a pharmaceutically acceptable salt thereof is at The administered dose in human subjects is 1-20 mg once a day.
  • the anti-PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dose of 200 mg once every 3 weeks, and the famitinib or its pharmaceutically acceptable salt is administered to humans
  • the administered dose in the test subjects is 1-20 mg once a day.
  • the AUC of famitinib or a pharmaceutically acceptable salt thereof is increased compared to administration of an equal dose of famitinib or a pharmaceutically acceptable salt thereof alone At least 15% (including 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% , 30% or higher), preferably at least 20%, most preferably at least 25%.
  • the Cmax of famitinib or a pharmaceutically acceptable salt thereof is increased by at least 15 compared to administration of an equivalent dose of famitinib or a pharmaceutically acceptable salt thereof alone % (Including 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30% Or higher), preferably at least 20%.
  • the PD-1 antibody is administered by injection, such as subcutaneous or intravenous injection, and the PD-1 antibody needs to be formulated into an injectable form before injection.
  • a particularly preferred injectable form of the PD-1 antibody is an injection solution or a lyophilized powder injection, which contains the PD-1 antibody, a buffer, a stabilizer, and optionally a surfactant.
  • the buffer may 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 , Most preferably polysorbate 20.
  • the most preferred injectable forms of PD-1 antibody include PD-1 antibody, acetate buffer, trehalose, and polysorbate 20.
  • the present disclosure provides the above-mentioned anti-PD-1 antibody combined with famitinib or a pharmaceutically acceptable salt thereof as a therapeutic preparation for the treatment of tumor drugs.
  • the present disclosure provides the above anti-PD-1 antibody in combination with famitinib or a pharmaceutically acceptable salt thereof as a drug for reducing adverse drug reactions.
  • the adverse drug reactions are selected from anti-PD-1 antibodies or caused by fami Caused by tinib or its pharmaceutically acceptable salts.
  • the adverse reactions described in the use of the present disclosure are preferably those of anti-PD-1 antibodies, and most preferably reactive capillary hyperplasia.
  • the reactive capillary hyperplasia is compared to the administration of an equivalent dose of anti-PD-1 antibody (such as the sequence of the heavy and light chains such as SEQID NO: 7 and SEQID NO: 8 in the present disclosure)
  • the incidence rate is not higher than 15% (including 15%, 14.5%, 14%, 13.5%, 13%, 12.5%, 12%, 11.5%, 11%, 10.5%, 10%, 9.5%, 9%, 8.5% , 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4%, 4.5%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1% or less), It is preferably not higher than 2.5%.
  • the present disclosure provides the above-mentioned anti-PD-1 antibody in combination with famitinib or a pharmaceutically acceptable salt thereof as a drug for reducing the dose of anti-PD-1 antibody alone and / or famitinib or its pharmaceutically acceptable salt alone.
  • a method for treating tumors which includes administering the above-mentioned anti-PD-1 antibody and famitinib or a pharmaceutically acceptable salt thereof to a patient.
  • a method for reducing the dose of anti-PD-1 antibody alone and / or the dose of famitinib or a pharmaceutically acceptable salt thereof comprising administering the above-mentioned anti-PD-1 antibody in combination with fami to a patient Tinib or its pharmaceutically acceptable salts.
  • the dose of famitinib or a pharmaceutically acceptable salt thereof is 10% to 100% (including 10%, 15%, 20%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 90%, 95%), preferably 10% to 75%, more preferably 75 %, 50%, 25%, 12.5%.
  • the dose of anti-PD-1 antibody when combined with famitinib or a pharmaceutically acceptable salt thereof, is 10% to 100% (including 10%, 15%, 20%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 90%, 95%), preferably 10% to 50%.
  • the present disclosure also provides a method of reducing adverse reactions caused by an anti-PD-1 antibody or antigen-binding fragment thereof, famitinib or a pharmaceutically acceptable salt thereof, including co-administering famitinib or a pharmaceutically acceptable drug to a patient Salt and the aforementioned PD-1 antibody, the adverse reaction is preferably an anti-PD-1 antibody, and most preferably reactive capillary hyperplasia.
  • the adverse reactions described in this disclosure are preferably those of anti-PD-1 antibodies, and most preferably reactive capillary hyperplasia.
  • the reactive capillary hyperplasia is compared to the administration of an equivalent dose of anti-PD-1 antibody (such as the sequence of the heavy and light chains such as SEQID NO: 7 and SEQID NO: 8 in the present disclosure)
  • the incidence rate is not higher than 15% (including 15%, 14.5%, 14%, 13.5%, 13%, 12.5%, 12%, 11.5%, 11%, 10.5%, 10%, 9.5%, 9%, 8.5% , 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4%, 4.5%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1% or less), It is preferably not higher than 2.5%.
  • the present disclosure also provides a pharmaceutical kit, or a pharmaceutical packaging box, or a pharmaceutical combination, which contains famitinib or a pharmaceutically acceptable salt thereof, and a PD-1 antibody.
  • the present disclosure also provides an anti-PD-L1 antibody or anti-CTAL-4 antibody, and the use of famitinib or a pharmaceutically acceptable salt thereof in the preparation of a medicine for treating tumors.
  • the anti-PD-L1 antibody or its antigen-binding fragment or anti-CTAL-4 antibody or its antigen-binding dose in a human subject is 0.1 to 10.0 mg / dose according to the weight of the patient kg, can be 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, 1.0 mg / 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, 3.0 mg / kg, 3.2mg / kg, 3.4mg / kg, 3.6mg / kg, 3.8mg / kg, 4.0mg / kg,
  • the dose of the PD-L1 antibody or antigen-binding fragment thereof or anti-CTAL-4 antibody or antigen-binding fragment thereof in a human subject is 50-700 mg, which may be 50 mg, 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, 270
  • the frequency of administration of the anti-PD-L1 antibody or its antigen-binding fragment or anti-CTAL-4 antibody or its antigen-binding fragment in 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.
  • the anti-PD-L1 antibody or antigen-binding fragment or anti-CTAL-4 antibody or antigen-binding fragment described in the present disclosure is administered in a human subject at a dosage of 50 to 600 mg / 2-3 Once a week, more preferably 200 mg / every 2-3 weeks.
  • the dose of the anti-PD-L1 antibody or antigen-binding fragment thereof or anti-CTAL-4 antibody or antigen-binding fragment thereof in a human subject is 50-700 mg once every 2-3 weeks,
  • the dosage of famitinib or its pharmaceutically acceptable salt in human subjects is 0.1-100 mg once a day.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof or anti-CTAL-4 antibody or antigen-binding fragment thereof is administered in a human subject at a dose of 50 to 600 mg, and the famitinib Or a pharmaceutically acceptable salt thereof is administered in a human subject at a dosage of 1-20 mg.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof or anti-CTAL-4 antibody or antigen-binding fragment thereof is administered to a human subject at a dose of 50 to 600 mg once every 2-3 weeks,
  • the administration dose of the famitinib or its pharmaceutically acceptable salt in human subjects is 1-20 mg once a day.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof or anti-CTAL-4 antibody or antigen-binding fragment thereof is administered in a human subject at a dose of 200 mg, and the famitinib or its The dosage of pharmaceutically acceptable salts in human subjects is 1-20 mg.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof or anti-CTAL-4 antibody or antigen-binding fragment thereof is administered in a human subject at a dose of 200 mg once every 2-3 weeks, Famitinib or its pharmaceutically acceptable salt is administered to human subjects at a dose of 1-20 mg once a day.
  • the PD-L1 antibody or anti-CTAL-4 antibody is administered by injection, such as subcutaneous or intravenous injection, and the PD-L1 antibody or anti-CTAL-4 antibody needs to be injected before injection Formulated into an injectable form.
  • the present disclosure provides the above anti-PD-L1 antibody or anti-CTAL-4 antibody in combination with famitinib or a pharmaceutically acceptable salt thereof as a drug for reducing adverse drug reactions.
  • the adverse drug reactions are selected from anti-PD-L1
  • the antibody or anti-CTAL-4 antibody is caused by or caused by famitinib or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides the above-mentioned anti-PD-L1 antibody in combination with famitinib or a pharmaceutically acceptable salt thereof as a drug for reducing the dose of anti-PD-L1 antibody alone and / or the dose of famitinib or its pharmaceutically acceptable salt alone.
  • the present disclosure provides the above anti-CTAL-4 antibody in combination with famitinib or a pharmaceutically acceptable salt thereof as a drug for reducing the dose of anti-CTAL-4 antibody alone and / or the dose of famitinib or a pharmaceutically acceptable salt alone.
  • a method for treating tumors which includes administering to the patient the above-mentioned anti-PD-L1 antibody or anti-CTAL-4 antibody and famitinib or a pharmaceutically acceptable salt thereof.
  • a method for reducing the dose of anti-PD-L1 antibody alone and / or the dose of famitinib or a pharmaceutically acceptable salt thereof comprising administering the above-mentioned anti-PD-L1 antibody to fami Tinib or its pharmaceutically acceptable salts.
  • a method of reducing the dose of anti-CTAL-4 antibody alone and / or the dose of famitinib or a pharmaceutically acceptable salt thereof comprising administering the above anti-CTAL-4 antibody in combination with fami Tinib or its pharmaceutically acceptable salts.
  • the dose of famitinib or a pharmaceutically acceptable salt thereof is 10% to 100% (including 10%, 15%, 20%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 90%, 95%), preferably 10% to 75%, more preferably 75 %, 50%, 25%, 12.5%.
  • the dose of anti-PD-L1 antibody when used in combination with famitinib or a pharmaceutically acceptable salt thereof, is 10% to 100% (including 10%, 15%, 20%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 90%, 95%), preferably 10% to 50%.
  • the administration dose of famitinib or a pharmaceutically acceptable salt thereof is 10% to 100% of its single administration dose, preferably 10% to 75 %, More preferably 75%, 50%, 25%, 12.5%.
  • the dose of anti-CTAL-4 antibody when used in combination with famitinib or a pharmaceutically acceptable salt thereof, is 10% to 100%, preferably 10% to 50% of the dose of anti-CTAL-4 antibody administered alone.
  • the present disclosure also provides a pharmaceutical kit, or a pharmaceutical packaging box, which contains famitinib or a pharmaceutically acceptable salt thereof, and a PD-L1 antibody or a CTAL-4 antibody.
  • examples of the tumor are selected from but not limited to: breast cancer (such as triple negative breast cancer), lung cancer, gastric cancer, intestinal cancer (such as rectal cancer, colorectal cancer), kidney cancer (such as renal cells Cancer), liver cancer (such as primary liver cancer, hepatocellular carcinoma, cholangiocarcinoma, metastatic liver cancer, secondary liver cancer), melanoma (such as metastatic melanoma), non-small cell lung cancer, urothelial carcinoma ( (Such as bladder cancer, ureter, urethral cancer), cervical cancer, ovarian cancer (such as recurrent ovarian cancer), endometrial cancer, lymphoblastic T cell leukemia, chronic myeloid leukemia, thyroid cancer, chronic lymphocytic leukemia, hair Cellular leukemia, acute lymphoblastic leukemia, acute myeloid leukemia (AML), chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, immunoblastic large cell leukemia, mantle
  • the tumors used in the present disclosure are non-small cell lung cancer, thyroid cancer, breast cancer (such as triple negative breast cancer), melanoma (such as metastatic melanoma), kidney cancer, and urothelial cancer (such as bladder cancer, ureter, urethral cancer), cervical cancer, thyroid cancer, ovarian cancer (such as recurrent ovarian cancer), endometrial cancer, bowel cancer or liver cancer.
  • the tumor patient has been treated with platinum drugs.
  • platinum drugs For example, patients who have failed platinum therapy or are intolerable, or have progressed or relapsed within 6 months of or after receiving platinum therapy.
  • the tumor for use in the present disclosure is renal cancer (renal cell carcinoma).
  • it is advanced renal clear cell carcinoma diagnosed by tissue or cytology (mixed tumor, such as renal clear cell carcinoma).
  • the renal cell carcinoma patient in the use of the present disclosure has been previously treated with interleukin-2 and / or anti-angiogenesis targeted drugs and failed.
  • the tumor in the use of the present disclosure is urothelial cancer (eg, bladder cancer, ureter, urethral cancer).
  • urothelial cancer eg, bladder cancer, ureter, urethral cancer
  • it is a tissue or cytologically diagnosed incurable urothelial carcinoma (eg, including renal pelvis cancer, ureteral cancer, bladder cancer, and urethral cancer, and mixed cancer, such as histological type is a transitional cell carcinoma subtype).
  • the patient with urothelial cancer has been treated with platinum drugs.
  • platinum drugs For example, patients who have failed or are intolerant to platinum therapy, or have progressed or relapsed during or after platinum therapy.
  • the tumor in the use of the present disclosure is cervical cancer.
  • it is histologically or cytologically confirmed advanced cervical squamous cell carcinoma.
  • the cervical cancer patient has failed previous treatment with ⁇ 1 line system.
  • the tumor in the use of the present disclosure is ovarian cancer, preferably, recurrent ovarian cancer, further, recurrent ovarian epithelial cancer, fallopian tube cancer, or primary peritoneal cancer confirmed by histopathology .
  • the patient with recurrent ovarian cancer has been treated with platinum drugs.
  • platinum drugs For example, patients who have failed or are intolerant to platinum therapy, or have progressed or relapsed within 6 months of receiving platinum treatment regimens or after treatment ends (complete with 4 courses and above).
  • the tumor in the use of the present disclosure is endometrial cancer, preferably, endometrial cancer diagnosed by histopathology.
  • the patient with endometrial cancer has been treated with platinum drugs.
  • platinum drugs for example, for example, patients who have failed platinum therapy or are intolerable, or have progressed or relapsed within 6 months of receiving platinum treatment regimens or after treatment ends (complete with 4 courses or more).
  • the present disclosure also provides a use of famitinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a condition benefiting from inhibition of TYRO3 and / or AXL and / or MER.
  • the present disclosure also provides a method for treating a condition benefiting from the inhibition of TYRO3 and / or AXL and / or MER by famitinib or a pharmaceutically acceptable salt thereof, comprising administering the above famitinib or a pharmaceutically acceptable drug to a patient salt.
  • the famitinib or a pharmaceutically acceptable salt thereof can be used alone or in combination.
  • the famitinib or a pharmaceutically acceptable salt thereof can be administered alone or in combination.
  • lymphoblastic T Cellular leukemia chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myeloid leukemia (AML), chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, immune mother Large cell leukemia, mantle cell leukemia, multiple myeloma megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, multiple myeloma, plasmacytoma, Hodgkin's lymphoma , Non-Hodgkin's lymphom
  • the pharmaceutically acceptable salts of famitinib described in this disclosure are selected from but not limited to mesylate, maleate, tartrate, succinate, acetate, difluoroacetate, fumarate , Citrate, citrate, benzenesulfonate, benzoate, naphthalenesulfonate, lactate, malate, hydrochloride, hydrobromide, sulfate, and phosphate, preferably Malate.
  • the dosage of the pharmaceutically acceptable salt of famitinib in the present disclosure in human subjects is calculated as a free base.
  • the AUC mentioned in this application refers to the average AUC0-24 of the patient after single or multiple administrations reach steady state, preferably the average AUC0-24 (ie AUCss) of the patient after multiple administrations reach steady state.
  • the present disclosure regarding "combination” is a mode of administration, which refers to the administration of at least one dose of famitinib or a pharmaceutically acceptable salt within a certain period of time, and at least one dose of anti-PD-1 antibody or its antigen Combining fragments, both of which show pharmacological effects.
  • the time period may be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours.
  • Famitinib or a pharmaceutically acceptable salt and an anti-PD-1 antibody or antigen-binding fragment thereof can be administered simultaneously or sequentially.
  • This period includes treatments in which famitinib or a pharmaceutically acceptable salt and an anti-PD-1 antibody or antigen-binding fragment thereof are administered through the same route of administration or different routes of administration.
  • the combined administration method of the present disclosure is selected from simultaneous administration, independently formulated and co-administered, or independently formulated and sequentially administered.
  • the overall survival period refers to the period from random period to death from any cause. For subjects who were still alive at the last follow-up, the OS was deleted based on the time of the last follow-up. For the lost follow-up, the OS is calculated as data deletion based on the last confirmed survival time before the follow-up.
  • the OS for data censoring is defined as the time from random grouping to censoring.
  • Objective response rate refers to the proportion of patients whose tumor shrinkage reaches a certain level and remains for a certain period of time, including cases of CR and PR.
  • Use solid tumor response evaluation criteria (RECIST 1.1 standard) to assess objective tumor response. Subjects must be accompanied by measurable tumor lesions at baseline. The evaluation criteria for efficacy are divided into complete response (CR), partial response (PR), stability (SD), and progression (PD) according to RECIST 1.1.
  • DCR Disease Control Rate
  • CR Complete remission
  • Partial remission The sum of target lesion diameters is reduced by at least 30% from the baseline level.
  • PD Disease progression: the minimum value of the sum of the diameters of all the measured target lesions in the entire experimental study is taken as a reference, and the diameter and the relative increase are at least 20% (if the baseline measurement value is the smallest, the baseline value is used as a reference); otherwise
  • the absolute value of the sum of diameters must be increased by at least 5 mm (the appearance of one or more new lesions is also regarded as disease progression).
  • SD Disease stabilization
  • the reagents, biological samples or actives used in this disclosure can be obtained commercially, for example, the human PD-1 transgenic mice used, 4-5 weeks old, can be purchased from Cephrim Biosciences, Inc, UK.
  • Human PD-1 transgenic mice were used as test animals to evaluate the combination of PD-1 antibody and famitinib on the transplanted tumor C57 of mouse colon cancer cells MC-38 (PD-L1) with the PD-L1 gene. The efficacy of human PD-1 transgenic mice.
  • Compound A PD-1 antibody, the sequence of its heavy and light chains is as SEQID NO: 7 and SEQID NO: 8. 200 mg / bottle in a 20 mg / ml reserve for use in the present disclosure.
  • Compound B Famitinib malate can be prepared according to the method in patent application WO2007085188.
  • MC38 cells (5x105) were inoculated subcutaneously on the right rib of 40 human PD-1 transgenic mice (including male and female genders).
  • 32 were randomly selected 4 groups, 8 animals in each group. After grouping, they were given vehicle control, compound A by intraperitoneal injection, compound by oral gavage and combination of the two. Measure the tumor volume twice a week, weigh it, and record the data.
  • mice in each group were normal, showing no obvious toxic and side effects.
  • Example 2 Effect of famitinib malate on TYRO3, AXL, MER kinase activity in vitro
  • kinase and peptide substrates were mixed with Famitinib malate (1nM, 3nM, 10nM, 30nM, 100nM, 300nM, 1 ⁇ M, 3 ⁇ M, 10 ⁇ M) and incubated at room temperature for 60min.
  • Famitinib malate (1nM, 3nM, 10nM, 30nM, 100nM, 300nM, 1 ⁇ M, 3 ⁇ M, 10 ⁇ M
  • Magnesium acetate and [gamma-33P] -ATP were added to start the kinase-catalyzed reaction, and the reaction was performed at room temperature for 40 minutes. After the reaction, 3% phosphoric acid solution was added to terminate the reaction.
  • Compound A The sequences of its heavy and light chains are as SEQID NO: 7 and SEQID NO: 8. 200mg / per bottle in the present disclosure, prepared as 20mg / ml;
  • Compound B Famitinib malate can be prepared according to the method in patent application WO2007085188.
  • renal cell carcinoma histological or cytologically diagnosed advanced renal clear cell carcinoma (mixed tumors, such as renal clear cell carcinoma can be included in the group); the primary foci are surgically removed, and previous interleukin -2 and / or anti-angiogenesis targeted drug treatment, treatment failure;
  • urothelial cancer histologically or cytologically diagnosed urothelial cancer that cannot be cured, including renal pelvis cancer, ureteral cancer, bladder cancer, and urethral cancer, mixed cancer requires the main histological type to be transitional cell carcinoma Type; previous treatment progress or relapse through platinum-containing regimens, and the number of previous system treatment regimens does not exceed 2.
  • recurrent ovarian cancer Histopathologically confirmed recurrent ovarian epithelial cancer, fallopian tube cancer, or primary peritoneal cancer, previously treated with platinum-based regimens, and during the last platinum-based regimen treatment or Progress or relapse within 6 months after the end of treatment (complete with 4 courses or more);
  • Endometrial cancer Endometrial cancer diagnosed by histopathology has been treated with at least platinum-based regimen. After the treatment or during the treatment, the disease relapses or progresses.
  • Compound A intravenous injection, 200 mg, administered once every 3 weeks, once every 3 weeks; Compound B: 20 mg or 15 mg, taken orally, once a day.
  • Endometrial cancer cohort was evaluated in 4 of 5 subjects, 2 subjects showed partial remission (PR), 1 subject showed stable disease (SD), and 1 case showed disease progression ( PD), the objective response rate (ORR) is 50%, and the disease control rate (DCR) is 75%.
  • PR partial remission
  • SD stable disease
  • PD disease progression
  • ORR objective response rate
  • DCR disease control rate
  • PK blood was collected from 9 subjects.
  • Compound A and Compound B are administered together with good tolerance, controllable toxicity, and tolerability.
  • the combined administration can effectively reduce the occurrence of the common adverse reaction of Compound A-reactive capillary hyperplasia, and the effect is better.

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Abstract

本公开提供了一种抗PD-1抗体和法米替尼联合在制备治疗肿瘤的药物中的用途。该技术方案毒性可控、可耐受，同时联合给药能够有效降低抗PD-1抗体的不良反应，如反应性毛细血管增生症的发生。

Description

一种抗PD-1抗体和法米替尼联合在制备治疗肿瘤的药物中的用途 技术领域
本公开中涉及一种抗PD-1抗体和法米替尼或其可药用盐联合在制备治疗肿瘤的药物中的用途。
背景技术
癌症具有许多遗传和表观遗传改变，产生可被免疫系统识别的新抗原。适应性免疫系统，包括T和B淋巴细胞，具有强大的抗癌潜力，具有广泛的能力和精细的特异性，以响应各种肿瘤抗原。此外，免疫系统表现出相当大的可塑性和记忆成分。成功利用适应性免疫系统的所有这些属性将使免疫治疗在所有癌症治疗模式中是独特的。
癌症免疫治疗已经集中在通过激活的效应细胞的过继转移，针对相关抗原的免疫或提供非特异性免疫刺激剂如细胞因子来增强抗肿瘤免疫反应的方法上。近年来，开发特异性免疫检查点途径抑制剂已经开始成为一种新的治疗癌症的免疫治疗方法，例如用于治疗晚期黑色素瘤的CTLA抗体Ipilimumab
Figure PCTCN2019115608-appb-000001
(Hodi等人，2010)，特异性结合程序性死亡受体(PD-1)nivolumab或pembrolizumab等。
PD-1抗体特异性识别并结合淋巴细胞表面PD-1，阻断PD-1/PD-L1信号通路，进而激活T细胞对肿瘤的免疫杀伤作用，调动机体免疫系统而清除体内肿瘤细胞。WO2015085847公开了一种新的抗PD-1抗体，目前PD-1抗体正处于临床试验阶段，已经显示出一定的抗肿瘤作用。
在一项法米替尼二线或二线以上标准化疗失败的晚期/转移性结直肠腺癌的多中心随机双盲安慰剂对照II期试验中，法米替尼组(25mg，1天/次，42天为一个周期)较安慰剂组可改善晚期/转移性结直肠癌患者无进展生存期(PFS)1.3个月(HR为0.596，P为0.0053)。客观缓解率(ORR)为2.2％，疾病控制率(DCR)为59.8％)，中位生存期(mOS)为7.5个月，安慰剂组为7.6个月，且不良事件可控。结构如下：
Figure PCTCN2019115608-appb-000002
目前已有多个PD-1抗体与VEGFR抑制剂(如舒尼替尼，索拉菲尼等)联合疗法正处于临床II/III期，适应症分别为恶性肝癌(索拉菲尼与PD-1抗体联用)和转移性肾细胞癌(舒尼替尼与PD-1抗体联用)，初步结果显示两种药物联用效 果均优于单药，但尚未见法米替尼与PD-1抗体联用的报告。
发明内容
本公开中提供了一种抗PD-1抗体或其抗原结合片段和法米替尼或其可药用盐联合在制备治疗肿瘤的药物中的用途。
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。
在一些实施方案中，所述人源化抗体包含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所示的轻链可变区有0-10的氨基酸变化，更优选A43S的氨基酸变化；所述人源化抗体包含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所示的重链可变区有0-10的氨基酸变化，更优选G44R的氨基酸变化。
前述的人源化抗体重、轻链可变区的序列如下所示：
重链可变区
Figure PCTCN2019115608-appb-000003
轻链可变区
Figure PCTCN2019115608-appb-000004
在另一些实施方案中，所述人源化抗体包含SEQ ID NO:8所示的轻链或其变体，所述变体优选在轻链可变区有0-10的氨基酸变化，更优选A43S的氨基酸变化；所述人源化抗体包含SEQ ID NO:7所示的重链或其变体，所述变体优选在重链可变区有0-10的氨基酸变化，更优选G44R的氨基酸变化。
在另一实施方案中，所述的人源化抗体含有如SEQ ID NO:8所示的轻链，和如SEQ ID NO:7所示的重链。
所述人源化抗体重、轻链的序列如下所示：
重链
Figure PCTCN2019115608-appb-000005
轻链
Figure PCTCN2019115608-appb-000006
本公开中所述联合抗PD-1抗体或其抗原结合片段和法米替尼或其可药用盐具有协同药效作用。
本公开中所述的用途，根据患者体重给药，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为0.1～10.0mg/kg，可以为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或任意两数值间任意值。
在可选实施方案中，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为10～300mg，可以为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或任意两数值间任意值，优选50～300mg，最优选200mg。
本公开中所述抗PD-1抗体或其抗原结合片段的给药频为一天一次、两天一次、三天一次、四天一次、五天一次、六天一次、一周一次、二周一次、三周一次、四周一次或一月一次，优选三周一次。
在可选实施方案中，本公开中所述抗PD-1抗体或其抗原结合片段给药剂量为50～300mg/2-3周一次，更优选为200mg/2-3周一次。
本公开中所述的用途，根据患者体重给药，所述法米替尼或其可药用盐在人类受试者中的施用剂量为0.1～10.0mg/kg，可以为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或任意两数值间任意值。
在可选实施方案中，所述法米替尼或其可药用盐在人类受试者中的施用剂量为0.1～100mg，可以为0.1mg、0.2mg、0.3mg、0.4mg、0.5mg、0.6mg、0.7mg、0.8mg、0.9mg、1.0mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、11mg、12mg、13mg、14mg、15mg、16mg、17mg、18mg、19mg、20mg、21mg、22mg、23mg、24mg、25mg、26mg、27mg、28mg、29mg、30mg、31mg、32mg、33mg、34mg、35mg、36mg、37mg、38mg、39mg、40mg或任意两数值间任意值，优选1～20mg。
本公开中所述的用途，其中，所述法米替尼或其可药用的给药频率为一天一次，两天一次，三天一次，四天一次，五天一次，六天一次，一周一次，每周给药三天、一天一次，每周给药四天、一天一次，每周给药五天、一天一次。
在可选实施方案中，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为10～300mg，所述法米替尼或其可药用盐在人类受试者中的施用剂量为0.1～100mg。
在可选实施方案中，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为10～300mg，2-3周一次，所述法米替尼或其可药用盐给药在人类受试者中的施用剂量为0.1～100mg，一天一次。
在可选实施方案中，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为50～300mg，所述法米替尼或其可药用盐在人类受试者中的施用剂量为1～20mg。
在可选实施方案中，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为50～300mg，2-3周一次，所述法米替尼或其可药用盐在人类受试者中的 施用剂量为1～20mg，一天一次。
在可选实施方案中，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为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为1～20mg。
在可选实施方案中，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为200mg，2-3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为1～20mg，一天一次。
在可选实施方案中，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为200mg，3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为1～20mg，一天一次。
另一方面，在可选实施方案中，本公开用途中，相比于单独施用同等剂量的法米替尼或其可药用盐，所述法米替尼或其可药用盐的AUC提高了至少15％(包括15％、16％、17％、18％、19％、20％、21％、22％、23％、24％、25％、26％、27％、28％、29％、30％或更高)，优选至少20％，最优至少25％。
在可选实施方案中，本公开用途中，相比于单独施用同等剂量的法米替尼或其可药用盐，所述法米替尼或其可药用盐的C max提高了至少15％(包括15％、16％、17％、18％、19％、20％、21％、22％、23％、24％、25％、26％、27％、28％、29％、30％或更高)，优选至少20％。
在本公开中优选的实施方案中，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。
本公开中提供上述抗PD-1抗体联合法米替尼或其可药用盐作为治疗制备治疗肿瘤的药物。
本公开中提供上述抗PD-1抗体联合法米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抗体引起或由法米替尼或其可药用盐引起。
在可选实施方案中，本公开用途中所述不良反应优选抗PD-1抗体的不良反应，最优选反应性毛细血管增生症。
在一些实施方案中，相比于单独施用同等剂量的抗PD-1抗体(如重、轻链的序列如本公开中SEQID NO：7和SEQID NO：8)，所述反应性毛细血管增生症 发生率不高于15％(包括15％、14.5％、14％、13.5％、13％、12.5％、12％、11.5％、11％、10.5％、10％、9.5％、9％、8.5％、8％、7.5％、7％、6.5％、6％、5.5％、5％、4％、4.5％、3.5％、3％、2.5％、2％、1.5％、1％或更低)，优选不高于2.5％。
本公开中提供上述抗PD-1抗体联合法米替尼或其可药用盐作为降低抗PD-1抗体单独施用剂量和/或法米替尼或其可药用盐单独施用剂量的药物。
在本公开中，提供了一种治疗肿瘤的办法，包括向患者施用上述抗PD-1抗体和法米替尼或其可药用盐。
在本公开中，提供了一种降低抗PD-1抗体单独施用剂量和/或法米替尼或其可药用盐单独施用剂量的方法，包括向患者施用上述抗PD-1抗体联合法米替尼或其可药用盐。
在另一些实施方案中，与PD-1联合使用时，所述法米替尼或其可药用盐的给药剂量是其单独施用剂量的10％～100％(包括10％、15％、20％、30％、35％、40％、45％、50％、55％、60％、70％、75％、80％、90％、95％)，优选10％～75％，更优选75％、50％、25％、12.5％。
在另一些实施方案中，与法米替尼或其可药用盐联用时，抗PD-1抗体剂量是抗PD-1抗体单独施用剂量的10％～100％(包括10％、15％、20％、30％、35％、40％、45％、50％、55％、60％、70％、75％、80％、90％、95％)，优选10％～50％。
本公开还提供了一种降低抗PD-1抗体或其抗原结合片段、法米替尼或其可药用盐导致的不良反应的方法，包括向患者联合施用法米替尼或其可药用盐和前述的PD-1抗体，所述不良反应优选抗PD-1抗体的不良反应，最优选反应性毛细血管增生症。
在可选实施方案中，本公开所述不良反应优选抗PD-1抗体的不良反应，最优选反应性毛细血管增生症。
在一些实施方案中，相比于单独施用同等剂量的抗PD-1抗体(如重、轻链的序列如本公开中SEQID NO：7和SEQID NO：8)，所述反应性毛细血管增生症发生率不高于15％(包括15％、14.5％、14％、13.5％、13％、12.5％、12％、11.5％、11％、10.5％、10％、9.5％、9％、8.5％、8％、7.5％、7％、6.5％、6％、5.5％、5％、4％、4.5％、3.5％、3％、2.5％、2％、1.5％、1％或更低)，优选不高于2.5％。
本公开中还提供了一种药物套组，或者一种药物包装盒，或者药物组合，其中含有法米替尼或其可药用盐，和PD-1抗体。
本公开中还提供了一种抗PD-L1抗体或抗CTAL-4抗体，和法米替尼或其可药用盐联合在制备治疗肿瘤的药物中的用途。
在可选实施方案中，根据患者体重给药，所述抗PD-L1抗体或其抗原结合片段或抗CTAL-4抗体或其抗原结合在人类受试者中的施用剂量为0.1～10.0mg/kg，可以为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。
在另一可选实施方案中，其中所述PD-L1抗体或其抗原结合片段或抗CTAL-4抗体或其抗原结合片段在人类受试者中的施用剂量为50～700mg，可以为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、605mg、610mg、615mg、620mg、625mg、630mg、635mg、640mg、645mg、650mg、655mg、660mg、665mg、670mg、675mg、680mg、685mg、690mg、695mg、700mg，优选50～600mg，最优选200mg。
本公开中所述抗PD-L1抗体或其抗原结合片段或抗CTAL-4抗体或其抗原结合片段的给药频为一天一次、两天一次、三天一次、四天一次、五天一次、六天一次、一周一次、二周一次、三周一次、四周一次或一月一次。
在可选实施方案中，本公开中所述抗PD-L1抗体或其抗原结合片段或抗CTAL-4抗体或其抗原结合片段在人类受试者中的施用剂量为50～600mg/2-3周一次，更优选为200mg/2-3周一次。
在可选实施方案中，所述抗PD-L1抗体或其抗原结合片段或抗CTAL-4抗体或其抗原结合片段在人类受试者中的施用剂量为50～700mg，2-3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为为0.1～100mg，一天一次。
在可选实施方案中，所述抗PD-L1抗体或其抗原结合片段或抗CTAL-4抗体或其抗原结合片段在人类受试者中的施用剂量为50～600mg，所述法米替尼或其可药用盐在人类受试者中的施用剂量为1～20mg。
在可选实施方案中，所述抗PD-L1抗体或其抗原结合片段或抗CTAL-4抗体或其抗原结合片段在人类受试者中的施用剂量为50～600mg，2-3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为1～20mg，一天一次。
在可选实施方案中，所述抗PD-L1抗体或其抗原结合片段或抗CTAL-4抗体或其抗原结合片段在人类受试者中的施用剂量为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为1～20mg。
在可选实施方案中，所述抗PD-L1抗体或其抗原结合片段或抗CTAL-4抗体或其抗原结合片段在人类受试者中的施用剂量为200mg，2-3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为1～20mg，一天一次。
在本公开中优选的实施方案中，所述的PD-L1抗体或抗CTAL-4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-L1抗体或抗CTAL-4抗体配制成可注射的形式。
本公开中提供上述抗PD-L1抗体或抗CTAL-4抗体联合法米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-L1抗体或抗CTAL-4抗体引起或由法米替尼或其可药用盐引起。
本公开中提供上述抗PD-L1抗体联合法米替尼或其可药用盐作为降低抗PD-L1抗体单独施用剂量和/或法米替尼或其可药用盐单独施用剂量的药物。
本公开中提供上述抗CTAL-4抗体联合法米替尼或其可药用盐作为降低抗CTAL-4抗体单独施用剂量和/或法米替尼或其可药用盐单独施用剂量的药物。
在本公开中，提供了一种治疗肿瘤的办法，包括向患者施用上述抗PD-L1抗体或抗CTAL-4抗体和法米替尼或其可药用盐。
在本公开中，提供了一种降低抗PD-L1抗体单独施用剂量和/或法米替尼或其可药用盐单独施用剂量的方法，包括向患者施用上述抗PD-L1抗体联合法米替尼或其可药用盐。
在本公开中，提供了一种降低抗CTAL-4抗体单独施用剂量和/或法米替尼或其可药用盐单独施用剂量的方法，包括向患者施用上述抗CTAL-4抗体联合法米替尼或其可药用盐。
在可选实施方案中，与PD-L1联合使用时，所述法米替尼或其可药用盐的给药剂量是其单独施用剂量的10％～100％(包括10％、15％、20％、30％、35％、40％、45％、50％、55％、60％、70％、75％、80％、90％、95％)，优选10％～75％，更优选75％、50％、25％、12.5％。
在可选实施方案中，与法米替尼或其可药用盐联用时，抗PD-L1抗体剂量是抗PD-L1抗体单独施用剂量的10％～100％(包括10％、15％、20％、30％、35％、40％、45％、50％、55％、60％、70％、75％、80％、90％、95％)，优选10％～50％。
在可选实施方案中，与抗CTAL-4抗体联合使用时，所述法米替尼或其可药用盐的给药剂量是其单独施用剂量的10％～100％，优选10％～75％，更优选75％、50％、25％、12.5％。
在可选实施方案中，与法米替尼或其可药用盐联用时，抗CTAL-4抗体剂量是抗CTAL-4抗体单独施用剂量的10％～100％，优选10％～50％。
本公开中还提供了一种药物套组，或者一种药物包装盒，其中含有法米替尼或其可药用盐，和PD-L1抗体或CTAL-4抗体。
在本公开中的用途中，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、肠癌(如直肠癌、结直肠癌)、肾癌(如肾细胞癌)、肝癌(如原发性肝癌、肝细胞癌、胆管细胞癌、转移性肝癌、继发性肝癌)、黑素瘤(如转移性黑色瘤)、非小细胞肺癌、尿路上皮癌(如膀胱癌、输尿管、尿道癌)、宫颈癌、卵巢癌(如复发性卵巢癌)、子宫内膜癌、成淋巴细胞T细胞白血病、慢性髓细胞性白血病、甲状腺癌、慢性淋巴细胞白血病、毛细胞白血病、急性成淋巴细胞性白血病、急性髓细胞白血病(AML)、慢性中性粒细胞白血病、急性成淋巴细胞T细胞白血病、免疫母细胞大细胞白血病、套细胞白血病、多发性骨髓瘤巨核母细胞白血病、急性巨核细胞白血病、早幼粒细胞白血病、红白血病、恶性淋巴瘤、多发性骨髓瘤、浆细胞瘤、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、骨髓增生异常综合征(MDS)。
在可选实施方案中，本公开用途中肿瘤为非小细胞肺癌、甲状腺癌、乳腺癌(如三阴性乳腺癌)、黑素瘤(如转移性黑色瘤)、肾癌、尿路上皮癌(如膀胱癌、输尿管、尿道癌)、宫颈癌、甲状腺癌、卵巢癌(如复发性卵巢癌)、子宫内膜癌、肠癌或肝癌。
在优选实施方案中，所述肿瘤患者为接受过铂类药物治疗的。例如接受铂类药物治疗失败或者不可耐受的患者，或者接受铂治疗方案治疗期间或治疗结束后<6个月进展或复发。
在一些实施方案中，本公开用途中所述肿瘤为肾癌(肾细胞癌)。优选地，为组织或细胞学确诊的晚期肾透明细胞癌(混合型肿瘤，如肾透明细胞癌)。
在优选实施方案中，本公开用途中所述肾细胞癌患者为既往经过白细胞介素-2和/或抗血管新生靶向药治疗、治疗失败的。
在一些实施方案中，本公开用途中所述肿瘤为尿路上皮癌(如膀胱癌、输尿管、尿道癌)。优选地，为组织或细胞学确诊的无法根治的尿路上皮癌(如包括肾盂癌、输尿管癌、膀胱癌及尿道癌，混合型癌如组织学类型为移行细胞癌亚型)。
在优选实施方案中，本公开用途中所述尿路上皮癌患者为接受过铂类药物治疗的。例如，接受接受铂类药物治疗失败或者不可耐受的患者，或者接受铂治疗方案治疗期间或治疗结束后进展或复发。
在一些实施方案中，本公开用途中所述肿瘤为宫颈癌。优选地，为组织或细胞学确认的晚期宫颈鳞状细胞癌。
在优选实施方案中，所述宫颈癌患者为既往经过≥1线系统治疗失败的。
在另一些实施方案中，本公开用途中所述肿瘤为卵巢癌，优选地，为复发性卵巢癌，进一步地，为组织病理学确诊的复发性卵巢上皮癌、输卵管癌或原发性腹膜癌。
在优选实施方案中，所述复发性卵巢癌患者为接受过铂类药物治疗的。例如接受铂类药物治疗失败或者不可耐受的患者，或者接受铂治疗方案治疗期间或治疗结束(完成4程及以上治疗)后<6个月进展或复发。
在另一些实施方案中个，本公开用途中所述肿瘤为子宫内膜癌，优选地，为组织病理学确诊的子宫内膜癌。在优选实施方案中，所述子宫内膜癌患者为接受过铂类药物治疗的。例如，例如接受铂类药物治疗失败或者不可耐受的患者，或者接受铂治疗方案治疗期间或治疗结束(完成4程及以上治疗)后<6个月进展或复发。
本公开中还提供了一种法米替尼或其可药用盐在制备治疗受益于抑制TYRO3和/或AXL和/或MER的病症的药物中的用途。
本公开中还提供了一种法米替尼或其可药用盐治疗受益于抑制TYRO3和/或AXL和/或MER的病症的方法，包括向患者施用上述法米替尼或其可药用盐。进一步地，在可选实施方案中，所述法米替尼或其可药用盐是可单用或联用。
进一步地，在可选实施方案中，所述法米替尼或其可药用盐是可以单独施用或联合施用的。
本公开中所述受益于抑制TYRO3(Tyro3 tyrosine kinase receptor inhibitor)和/或AXL(Axl tyrosine kinase receptor inhibitor)和/或MER(Mer tyrosine kinase receptor inhibitor)的病症示例包括但不限于：成淋巴细胞T细胞白血病、慢性髓细胞性白血病、慢性淋巴细胞白血病、毛细胞白血病、急性成淋巴细胞性白血病、急性髓细胞白血病(AML)、慢性中性粒细胞白血病、急性成淋巴细胞T细胞白血病、免疫母细胞大细胞白血病、套细胞白血病、多发性骨髓瘤巨核母细胞白血病、急性巨核细胞白血病、早幼粒细胞白血病、红白血病、恶性淋巴瘤、多发性骨髓瘤、浆细胞瘤、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，骨髓增生异常综合征(MDS)、血栓性病症(如心肌梗死、缺血性脑梗塞、外周血管病、静脉血栓栓塞等)，等等。
本公开中所述法米替尼可药用的盐选自但不限于甲磺酸盐、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，优选苹果酸盐。
在一些所述方案中，本公开中法米替尼可药用的盐在人类受试者中的施用剂量以自由碱形式计算。
如无相反解释，本公开中术语具有如下含义：
本公开关于“AUC”是指药代动力学血药浓度曲线对时间轴所包围的面积，该参数是评价药物吸收程度的重要指标，反映药物在体内的暴露特性。由于药动学研究中血药浓度只能观察至某时间点t，因此AUC有两种表示方式:AUC(0-t)和AUC(0-∞)，前者根据梯形面积法得到，后者计算式:AUC(0-∞)＝AUC(0-t)+末端 点浓度/末端消除速率。本申请中所述的AUC是指单次给药或多次给药达到稳态后患者的平均AUC0-24，优选多次给药达到稳态后患者的平均AUC0-24(即AUCss)。
本公开关于“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法米替尼或可药用盐，和少一种剂量的抗PD-1抗体或其抗原结合片段，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。可以同时或依次给予法米替尼或可药用盐和抗PD-1抗体或其抗原结合片段。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法米替尼或可药用盐和抗PD-1抗体或其抗原结合片段。本公开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。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)。
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。
“mpk”：毫克/每公斤。
本公开中所用试剂、生物样品或活性物可通过商业途径获得，如所用人PD-1转基因小鼠，4-5周龄，可从英国Cephrim Biosciences,Inc公司购买。
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：
以人PD-1转基因小鼠为受试动物，评价PD-1抗体和法米替尼联用后对转入PD-L1基因的小鼠结肠癌细胞MC-38(PD-L1)移植瘤C57人PD-1转基因小鼠的疗效。
化合物A：PD-1抗体，其重、轻链的序列如本公开中SEQID NO：7和SEQID NO：8。200mg/每瓶，配成20mg/ml备用。
化合物B：苹果酸法米替尼，可按照专利申请WO2007085188中的方法制备。
试验方案：
在7天时将MC38细胞(5x105)接种于40只人PD-1转基因小鼠(包括雌雄2种性别)右肋部皮下，待小鼠平均肿瘤体积达到100mm 3左右时，选取32只，随机分成4组，每组8只。分组后根据方案分别给予溶媒对照、腹腔注射化合物A、口服灌胃化合物及两者联合用药。每周两次测瘤体积，称体重，记录数据。
Figure PCTCN2019115608-appb-000007
本次实验结果显示，PD-1抗体(3mpk)与苹果酸法米替尼(10mpk)联用组的药效是优于PD-1抗体、苹果酸法米替尼单用的药效。给药各组小鼠体重正常，显示药物无明显毒副作用。
实施例2：苹果酸法米替尼对体外TYRO3、AXL、MER激酶活性的影响
(1)IC50Profiler TM实验步骤
Figure PCTCN2019115608-appb-000008
Figure PCTCN2019115608-appb-000009
注：MOPS，3-(N-玛琳代)丙磺酸
将适量激酶、多肽底物，分别和不同浓度的苹果酸法米替尼(1nM、3nM、10nM、30nM、100nM、300nM、1μM、3μM、10μM)混匀，在室温下孵育60min。加入醋酸镁和[gamma-33P]-ATP启动激酶催化反应，室温下反应40分钟。反应结束后加入3％的磷酸溶液终止反应。取反应混合物10μL，加入到P30滤膜中过滤，75mM的磷酸缓冲液清膜3次，用甲醇洗一次，去除游离的[gamma-33P]-ATP并固定蛋白，将膜烘干，液闪仪计数，测定多肽底物是的33P的量。
(2)试验结果
根据浓度-抑制曲线，拟合后得到的IC50值见表1
表1
Figure PCTCN2019115608-appb-000010
实施例3：
1、受试抗体和化合物
化合物A：其重、轻链的序列如本公开中SEQID NO：7和SEQID NO：8。200mg/每瓶，配成20mg/ml备用；
化合物B：苹果酸法米替尼，可按照专利申请WO2007085188中的方法制备。
2、入组标准：晚期肾癌、尿路上皮癌、宫颈癌、复发性卵巢癌及子宫内膜癌患者
(1)针对肾细胞癌：组织或细胞学确诊的晚期肾透明细胞癌(混合型肿瘤，如肾透明细胞癌占主要成分可以入组)；原发灶经过手术切除，且既往经过白细胞介素-2和/或抗血管新生靶向药治疗、治疗失败；
(2)针对尿路上皮癌：组织或细胞学确诊的无法根治的尿路上皮癌，包括肾盂癌、输尿管癌、膀胱癌及尿道癌，混合型癌要求主要的组织学类型为移行细胞癌亚型；既往经过含铂类方案治疗进展或复发，且既往系统治疗方案数不超过2个。
(3)针对宫颈癌：组织或细胞学确认的晚期宫颈鳞状细胞癌；既往经过≥1线系统治疗失败；
(4)针对复发性卵巢癌：组织病理学确诊的复发性卵巢上皮癌、输卵管癌或原发性腹膜癌，既往经过以铂类为基础的方案治疗，且最后一次含铂治疗方案治疗期间或治疗结束(完成4程及以上治疗)后<6个月进展或复发；
(5)针对子宫内膜癌：组织病理学确诊的子宫内膜癌，既往至少经过以铂类为基础的方案治疗，治疗结束后或治疗期间，疾病复发或进展。
3、给药方案：
化合物A：静脉注射，200mg，3周给药1次，每3周1周期；化合物B：20mg或15mg，口服，一日一次。
4、安全性数据
化合物A与化合物B联用时，未观察到研究药物相关死亡。虽然3级及以上不良事件发生率为60％，但都可控。毒性反应多为与化合物B用药相关的毒性，可通过纠正治疗，暂停化合物B给药得到有效控制。研究者判断的免疫相关不良事件发生率低(13.8％)且基本上都是较低级别的不良事件，仅1例为3级急性肠炎，其他均为2级及以下不良事件。另外，两药联用，仅2例(2.5％)受试者发生反应性皮肤毛细血管增生症，显著低于化合物A单药治疗实体瘤的发生率(54.3％)，提示联合化合物B或可降低化合物A的不良反应。总体严重不良事件发生率不高，仅2例(2.5％)受试者因SAE退出治疗。为此，化合物A与化合物B联合给药用于泌尿系统肿瘤和妇科肿瘤的安全性良好。
5、有效性
80例受试者中75例进行了至少一次疗效评价，5例因首次疗评前已出组或死亡导致无法评估。
肾癌队列25例受试者中23例进行了疗效评价，12例受试者表现为部分缓解(PR)，9例受试者表现为疾病稳定(SD)，2例为疾病进展(PD)，客观缓解率(ORR)为52.2％，疾病控制率(DCR)为91.3％，优于化合物B 25mg、qd、单药治疗肾癌的ORR(36％)。
尿路上皮癌队列10例受试者中9例进行了疗效评价，3例受试者表现为部分缓解(PR)，3例受试者表现为疾病稳定(SD)，3例为疾病进展(PD)，客观缓解率(ORR)为33.3％，疾病控制率(DCR)为66.7％。
卵巢癌队列24例受试者均进行了疗效评价，8例受试者表现为部分缓解(PR)，10例受试者表现为疾病稳定(SD)，7例为疾病进展(PD)，客观缓解率(ORR) 为33.3％，疾病控制率(DCR)为75％。
子宫内膜癌队列5例受试者中4例进行了疗效评价，2例受试者表现为部分缓解(PR)，1例受试者表现为疾病稳定(SD)，1例为疾病进展(PD)，客观缓解率(ORR)为50％，疾病控制率(DCR)为75％。
宫颈癌队列16例受试者中15例进行了疗效评价，8例受试者表现为部分缓解(PR)，5例受试者表现为疾病稳定(SD)，2例为疾病进展(PD)，客观缓解率(ORR)为53.3％，疾病控制率(DCR)为86.7％。
总体上，80例受试者中75例进行了至少一次疗效评价，33例受试者表现为部分缓解(PR)，27例受试者表现为疾病稳定(SD)，15例为疾病进展(PD)，客观缓解率(ORR)为44.0％，疾病控制率(DCR)为80.0％。
6、药代动力学
在12例参加药代动力学研究的受试者中，采集了9例受试者PK血。
结果显示，化合物A与化合物B联用下的化合物B的暴露量较化合物B单用有所增加，化合物B的PK参数(包括Css,min，Css,max，AUCss)优于单药。
表2化合物B的药代动力学参数
Figure PCTCN2019115608-appb-000011
注：Mean±SD平均值±标准偏差；Geomean几何平均
7、小结
化合物A与化合物B联合给药，耐受性良好、毒性可控、可耐受，同时联合给药能够有效降低化合物A常见的不良反应——反应性毛细血管增生症的发生，疗效较好。

Claims (17)

  1. 一种抗PD-1抗体或其抗原结合片段和法米替尼或其可药用盐联合在制备治疗肿瘤的药物中的用途。
  2. 根据权利要求1所述的用途，其中所述的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。
  3. 根据权利要求2所述的用途，其中所述的PD-1抗体为人源化抗体。
  4. 根据权利要求3所述的用途，其中所述人源化抗体包含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所示的重链可变区有0-10的氨基酸变化，更优选为G44R的氨基酸变化。
  5. 根据权利要求3所述的用途，其中所述人源化抗体包含SEQ ID NO:8所示的轻链或其变体，所述变体优选在轻链可变区有0-10的氨基酸变化，更优选A43S的氨基酸变化；所述人源化抗体包含SEQ ID NO:7所示的重链或其变体，所述变体优选在重链可变区有0-10的氨基酸变化，更优选G44R的氨基酸变化。
  6. 根据权利要求5所述的用途，其中所述人源化抗体包含如SEQ ID NO:8所示的轻链，和如SEQ ID NO:7所示的重链。
  7. 根据权利要求1所述的用途，其中所述肿瘤选自乳腺癌、肺癌、肝癌、胃癌、肠癌、肾癌、尿路上皮癌、宫颈癌、卵巢癌、子宫内膜癌、黑素瘤、非小细胞肺癌、甲状腺癌，优选非小细胞肺癌、乳腺癌、黑素瘤、肝癌、尿路上皮癌、宫颈癌、卵巢癌、甲状腺癌、子宫内膜癌或肾癌。
  8. 根据权利要求1-7任一项所述的用途，相比于单独施用同等剂量的法米替尼或其可药用盐，所述法米替尼或其可药用盐的AUC提高了至少15％，优选至少20％，最优至少25％。
  9. 根据权利要求1-8任一项所述的用途，相比于单独施用同等剂量的法米替尼或其可药用盐，所述法米替尼或其可药用盐的C max提高了至少15％，优选至少 20％。
  10. 根据权利要求1所述的用途，其中所述的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10～300mg，2-3周一次。
  11. 根据权利要求1所述的用途，其中所述的法米替尼或其可药用盐在人类受试者中的施用剂量为0.1～100mg、一天一次，优选为1～20mg、一天一次。
  12. 根据权利要求1-11任一项所述的用途，其中所述的法米替尼可药用盐选自苹果酸盐。
  13. 根据权利要求7所述的用途，其中相比于单独施用同等剂量的权利要求2-6任一项抗PD-1抗体，所述反应性毛细血管增生症发生率不高于15％。
  14. 一种降低抗PD-1抗体或其抗原结合片段、法米替尼或其可药用盐导致的不良反应的方法，包括向患者联合施用法米替尼或其可药用盐和权利要求2-6任一项所述的PD-1抗体，所述不良反应优选抗PD-1抗体的不良反应，最优选反应性毛细血管增生症。
  15. 根据权利要求14所述的方法，其中所述反应性毛细血管增生症发生率不高于15％。
  16. 一种减少PD-1抗体或其抗原结合片段、法米替尼或其可药用盐单独施用剂量的方法，包括向患者联合施用法米替尼或其可药用盐和权利要求2-6任一项所述的PD-1抗体。
  17. 一种药物包装盒，其中含有法米替尼或其可药用盐，和权利要求2-6任意一项所述的PD-1抗体或其抗原结合片段。
PCT/CN2019/115608 2018-11-06 2019-11-05 一种抗pd-1抗体和法米替尼联合在制备治疗肿瘤的药物中的用途 WO2020093993A1 (zh)

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US17/288,894 US20220251203A1 (en) 2018-11-06 2019-11-05 Use of anti-pd-1 antibody in combination with famitinib in preparation of drug for treating tumors
EP19881012.9A EP3878468A4 (en) 2018-11-06 2019-11-05 USE OF ANTI-PD-1 ANTIBODIES IN COMBINATION WITH FAMITINIB FOR THE MANUFACTURE OF A MEDICATION FOR THE TREATMENT OF TUMORS
MX2021004812A MX2021004812A (es) 2018-11-06 2019-11-05 Uso de anticuerpo anti-pd-1 en combinacion con famitinib en la preparacion de farmacos para el tratamiento de tumores.
AU2019375808A AU2019375808A1 (en) 2018-11-06 2019-11-05 Use of anti-PD-1 antibody in combination with famitinib in preparation of drug for treating tumors
KR1020217014341A KR20210089168A (ko) 2018-11-06 2019-11-05 종양 치료용 약물의 제조에서 파미티닙과 조합된 항-pd-1 항체의 용도
CN202311363969.0A CN117298270A (zh) 2018-11-06 2019-11-05 一种抗pd-1抗体和法米替尼联合在制备治疗肿瘤的药物中的用途
CN201980049882.1A CN112543646B (zh) 2018-11-06 2019-11-05 一种抗pd-1抗体和法米替尼联合在制备治疗肿瘤的药物中的用途
CA3117819A CA3117819A1 (en) 2018-11-06 2019-11-05 Use of anti-pd-1 antibody in combination with famitinib in preparation of drug for treating tumors
JP2021522987A JP2022512822A (ja) 2018-11-06 2019-11-05 腫瘍を治療するための薬物の調製におけるファミチニブと組み合わせた抗ｐｄ－１抗体の使用
BR112021007836-3A BR112021007836A2 (pt) 2018-11-06 2019-11-05 uso de anticorpo anti-pd-1 em combinação com famitinibe na preparação de medicamentos para o tratamento de tumores

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