WO2021203769A1 - 一种抗pd-1抗体在制备治疗肢端黑色素瘤的药物中的用途 - Google Patents

一种抗pd-1抗体在制备治疗肢端黑色素瘤的药物中的用途 Download PDF

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WO2021203769A1
WO2021203769A1 PCT/CN2021/000069 CN2021000069W WO2021203769A1 WO 2021203769 A1 WO2021203769 A1 WO 2021203769A1 CN 2021000069 W CN2021000069 W CN 2021000069W WO 2021203769 A1 WO2021203769 A1 WO 2021203769A1
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antibody
antigen
use according
pharmaceutically acceptable
acceptable salt
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PCT/CN2021/000069
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English (en)
French (fr)
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邹建军
郭军
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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 CN202180019855.7A priority Critical patent/CN115279405A/zh
Publication of WO2021203769A1 publication Critical patent/WO2021203769A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants

Definitions

  • the present disclosure relates to the use of an anti-PD-1 antibody or an antigen binding fragment thereof and a VEGFR inhibitor in the preparation of a medicine for treating acral melanoma.
  • anti-PD-1 anti-programmed death receptors
  • nivolumab and pembrolizumab anti-programmed death receptors
  • nivolumab is involved in different clinical subtypes of melanoma (such as acral melanoma, mucosal melanoma and skin melanoma)
  • ORR was 29.4%.
  • the ORR of the cutaneous melanoma group was 42.9%
  • the ORR of the mucosal melanoma group was 20.7%
  • the ORR of the acral melanoma group was 18.8%.
  • the ORR of the tumor group was 41.7%
  • the ORR of the mucosal melanoma group was 17.6%
  • the ORR of the acral melanoma group was only 7.7%.
  • the acral melanoma group exhibited poor ORR (7.7% Vs 17.6% Vs 41.7%). Therefore, there are still many uncertainties in the treatment of acral melanoma with PD-1 antibody monotherapy.
  • Apatinib is the world's first oral anti-angiogenic drug for advanced gastric cancer. It is highly selective for VEGFR-2 and has a strong anti-angiogenic effect.
  • the results showed that compared with placebo, apatinib alone can
  • the median overall survival was extended by 1.8 months, the median progression-free survival was extended by 0.8 months, and the adverse events were controllable.
  • the structural formula of apatinib is shown in formula (I).
  • PD-1 antibodies and VEGFR inhibitors are in clinical phase II/III, and the indications are malignant liver cancer (sorafenib and PD-1 antibody) Combination) and metastatic renal cell carcinoma (combination of sunitinib and PD-1 antibody).
  • Preliminary results show that the combined effect of the two drugs is better than that of single agent, but the combination of PD-1 antibody and VEGF inhibitor has Many uncertainties are worthy of in-depth study.
  • the disclosure provides a combination of an anti-PD-1 antibody and a VEGFR inhibitor in the preparation of a medicine for treating acral melanoma (melanoma).
  • the anti-PD-1 antibodies or antigen-binding fragments thereof are selected from: AMP-224, GLS-010, IBI-308, REGN-2810, PDR- 001, BGB-A317, Pidilizumab, PF-06801591, Genolimzumab, CA-170, MEDI-0680, JS-001, TSR-042, Cemiplimab, Camrelizumab, Pembrolizumab, Toripalimab, Sintilimab, Tislelizumab, LZM-009, AK-103 and Nivolumab.
  • the light chain variable region of the PD-1 antibody comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively.
  • the heavy chain variable region of the PD-1 antibody includes HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively.
  • the CDR sequences in the light/heavy chain of the PD-1 antibody or antigen-binding fragment are shown in the following table:
  • the PD-1 antibody is a humanized antibody.
  • the anti-PD-1 antibody or antigen-binding fragment thereof is an antibody fragment selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab') 2 fragments.
  • Immunoglobulins can be derived from any commonly known isotype, including but not limited to IgA, secreted IgA, IgG, and IgM.
  • the IgG subclass is also well known to those skilled in the art, including but not limited to IgG1, IgG2, IgG3, and IgG4.
  • Immunotype refers to the Ab class or subclass (for example, IgM or IgG1) encoded by the heavy chain constant region gene.
  • the anti-PD-1 antibody or antigen-binding fragment thereof described in this application comprises a heavy chain constant region of human IgG1, IgG2, IgG3 or IgG4 isotype, preferably comprising IgG1 or IgG4 isotype The constant region of the heavy chain.
  • the anti-PD-1 antibody or antigen-binding fragment thereof comprises a kappa or lambda light chain constant region.
  • the PD-1 antibody or antigen-binding fragment thereof comprises the light chain variable region shown in SEQ ID NO: 10 or a variant thereof, and the variant is preferably shown in SEQ ID NO: 10 There are 0-10 amino acid changes in the light chain variable region sequence, more preferably A43S amino acid changes; and the heavy chain variable region shown in SEQ ID NO: 9 or its variants, the variants are preferably in SEQ ID NO: 9 ID NO: There are 0-10 amino acid changes in the heavy chain variable region sequence shown in 9, more preferably G44R amino acid changes.
  • variable region sequences of the heavy and light chains of the aforementioned PD-1 antibody or its antigen-binding fragment are as follows:
  • the humanized antibody light chain sequence is the sequence shown in SEQ ID NO: 8 or a variant thereof; the variant preferably has 0-10 in the light chain variable region Amino acid change; more preferably A43S amino acid change.
  • the humanized antibody heavy chain sequence is the sequence 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 the G44R amino acid Variety.
  • the light chain sequence of the humanized antibody is the sequence shown in SEQ ID NO: 8
  • the heavy chain sequence is the sequence shown in SEQ ID NO: 7.
  • sequences of the heavy and light chains of the humanized antibody are as follows:
  • PD-1 programmed death 1
  • programmed death receptor 1 is an important immunosuppressive molecule.
  • Tumor cells use PD-L1 to bind to the PD-1 of T cells to "cheat" T cells, avoid the recognition of T cells, and continue to dominate the body.
  • the PD-L1/PD-1 antibody can help T cells uncover the hypocrisy of tumor cells and restore their recognition and killing of tumor cells.
  • the anti-PD-1 antibody or antigen-binding fragment thereof is Cemiplimab.
  • the anti-PD-1 antibody or antigen-binding fragment thereof is Toripalimab.
  • the anti-PD-1 antibody or antigen-binding fragment thereof is Sintilimab.
  • the anti-PD-1 antibody or antigen-binding fragment thereof is Tislelizumab.
  • VEGFR inhibitor is a VEGFR-2 inhibitor.
  • the VEGFR inhibitor is selected from apatinib, anlotinib, tafitinib, famitinib, sorafenib or a pharmaceutically acceptable salt thereof, preferably apatin Nepalese or its pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt of the present disclosure is selected from methanesulfonate, maleate, tartrate, succinate, acetate, difluoroacetate, fumarate, citrate, citrate , Benzenesulfonate, benzoate, naphthalenesulfonate, lactate, malate, hydrochloride, hydrobromide, sulfate, and phosphate.
  • the pharmaceutically acceptable salt of apatinib is selected from mesylate.
  • the pharmaceutically acceptable salt of Anlotinib is selected from hydrochloric acid.
  • the patients described in the present disclosure are selected from relapsed, inoperable or metastatic.
  • the recurring is recurring after surgery.
  • the patient is selected from those who have relapsed after surgery
  • the patient is selected from unresectable.
  • the aforementioned anti-PD-1 antibody and VEGFR inhibitor regimen further includes an alkylating agent.
  • the use further includes temozolomide or a pharmaceutically acceptable salt thereof.
  • the administration dose of the anti-PD-1 antibody or antigen-binding fragment thereof in a human subject is selected from 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/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,
  • the dose of the PD-1 antibody or antigen-binding fragment thereof in a human subject is 1-600 mg, preferably 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, 2.0 mg, 2.2mg, 2.4mg, 2.6mg, 2.8mg, 3.0mg, 3.2mg, 3.4mg, 3.6mg, 3.8mg, 4.0mg, 4.2mg, 4.4mg, 4.6mg, 4.8mg, 5.0mg, 5.2mg, 5.4mg, 5.6mg, 5.8mg, 6.0mg, 6.2mg, 6.4mg, 6.6mg, 6.8mg, 7.0mg, 7.2mg, 7.4mg, 7.6mg, 7.8mg, 8.0mg, 8.2mg, 8.4mg, 8.6mg , 8.8mg, 9.0mg, 9.2mg, 9.4mg, 9.6mg, 9.8mg, 10.0m
  • the frequency of administration of the anti-PD-1 antibody or antigen-binding fragment thereof described 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 days. Once a week, once every four weeks, or once a month.
  • the anti-PD-1 antibody or antigen-binding fragment thereof described in the present disclosure is administered in a human subject at a dose of 50-600 mg once every 2-3 weeks, more preferably 200 mg once every 2-3 weeks .
  • the dosage of the VEGFR inhibitor, such as apatinib or a pharmaceutically acceptable salt thereof, in a human subject is selected from 0.1-500 mg, and may be 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 12.5mg, 15mg, 17.5mg, 20mg, 22.5mg, 25mg, 30mg, 45mg, 50mg, 60mg, 70mg , 75mg, 80mg, 90mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 375mg, 400mg, 500mg, more preferably 0.25mg, 0.5mg, 1mg, 2mg, 3mg, 4mg, 10m
  • the frequency of administration of the VEGFR inhibitor such as apatinib 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, and weekly
  • the drug is administered three days, once a day, four days a week, once a day, and five days a week, once a day.
  • the dose of the PD-1 antibody or antigen-binding fragment thereof in a human subject is selected from 60 to 600 mg, intravenous infusion, once every to three weeks; VEGFR inhibitors such as methanesulfonic acid
  • the dosage of apatinib administered in human subjects is selected from 250 mg to 500 mg, orally, once every one to two days.
  • the dose of the PD-1 antibody or antigen-binding fragment thereof in a human subject is selected from 1-5 mg/kg, intravenous infusion, once every to three weeks; VEGFR inhibitors such as A
  • the dose of apatinib sulfonate administered in human subjects is selected from 250 mg to 500 mg, orally, once every one to two days.
  • the dose of the PD-1 antibody or antigen-binding fragment thereof in a human subject is selected from 200 mg, intravenous infusion, once every two weeks; VEGFR inhibitors such as apati mesylate
  • the administered dose of Nitraria in human subjects is selected from 250 mg, orally, once a day.
  • the administration dose of the PD-1 antibody or antigen-binding fragment thereof in a human subject is selected from 3 mg/kg, intravenous infusion, once every two weeks; VEGFR inhibitors such as amethylate
  • the administration dose of Patinib in human subjects is selected from 250 mg, orally, once a day.
  • the dose of the PD-1 antibody or antigen-binding fragment thereof in a human subject is selected from 200 mg, intravenous infusion, once every two weeks; VEGFR inhibitors such as apati mesylate
  • the administration dose of Nitraria in human subjects is selected from 375 mg, orally, once a day.
  • VEGFR inhibitor described in the present disclosure is taken after a meal, for example, taken within 30 minutes after a meal.
  • the dosage of the alkylating agent such as temozolomide in a human subject is selected from 50 mg/m 2 to 300 mg/m 2 , including 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,
  • the frequency of administration of alkylating agents such as temozolomide described 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, and once every four weeks Or once a month.
  • the alkylating agent such as temozolomide is administered in a human subject at a dose selected from 150 mg/m 2 or 200 mg/m 2 orally, once a day.
  • the alkylating agent such as temozolomide is administered in a human subject at a dose selected from 150 mg/m 2 or 200 mg/m 2 , orally, once a day for 5 days.
  • the alkylating agent such as temozolomide
  • a human subject at a dose selected from 150 mg/m 2 or 200 mg/m 2 orally, once a day for 5 days, and then the drug is stopped for 23 days .
  • the dosage of the PD-1 antibody or antigen-binding fragment thereof in a human subject is selected from 60 to 600 mg, intravenous infusion, once every to three weeks; VEGFR inhibitors such as A
  • the dosage of apatinib sulfonate in human subjects is selected from 250 mg to 500 mg, orally, once every one to two days;
  • the dosage of the alkylating agent such as temozolomide in human subjects is selected from 150 mg /m 2 or 200mg/m 2 , orally, once a day.
  • the dose of the PD-1 antibody or antigen-binding fragment thereof in a human subject is selected from 200 mg, intravenous infusion, once every two weeks; VEGFR inhibitors such as amethylate
  • the dosage of patinib in human subjects is selected from 250 mg, orally, once a day; the dosage of the alkylating agent such as temozolomide in human subjects is selected from 200 mg/m 2 , orally, daily Once, 5 days in total.
  • the present disclosure also provides a use of an anti-PD-1 antibody, a VEGFR inhibitor combined with temozolomide or a pharmaceutically acceptable salt thereof in the preparation of a medicine for treating melanoma.
  • the dose of the PD-1 antibody or antigen-binding fragment thereof in a human subject is selected from 60 to 600 mg; a VEGFR inhibitor such as apatinib mesylate is administered in a human subject
  • the dosage of the alkylating agent in human subjects is selected from 0.1 mg to 500 mg; the dosage of the alkylating agent in human subjects is selected from 50 mg/m 2 to 200 mg/m 2 .
  • the dosage of the PD-1 antibody or antigen-binding fragment thereof in a human subject is selected from 60 to 600 mg, intravenous infusion, once every to three weeks; VEGFR inhibitors such as A
  • the dosage of apatinib sulfonate in human subjects is selected from 0.1 to 500 mg, orally, once every one to two days;
  • the dosage of the alkylating agent such as temozolomide in human subjects is selected from 50 mg /m 2 to 200mg/m 2 , orally, once a day.
  • the dose of the PD-1 antibody or antigen-binding fragment thereof in a human subject is selected from 200 mg, intravenous infusion, once every two weeks; VEGFR inhibitors such as amethylate
  • the dosage of patinib in human subjects is selected from 250 mg, orally, once a day; the dosage of the alkylating agent such as temozolomide in human subjects is selected from 200 mg/m 2 , orally, daily One time, 5 days in total.
  • the present disclosure also provides the use of an anti-PD-1 antibody and a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of mucosal melanoma (mucosal melanoma), further comprising an alkane
  • the alkylating agent is preferably temozolomide or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides the above-mentioned anti-PD-1 antibody combined with a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof as a medicine for preparing and treating acral melanoma, and further comprises an alkylating agent, which is preferably Temozolomide or a pharmaceutically acceptable salt thereof.
  • the present disclosure also provides an anti-PD-1 antibody for treating melanoma (such as acral melanoma), wherein the anti-PD-1 antibody is administered in combination with a VEGFR inhibitor.
  • an alkylating agent is also included therein, and the alkylating agent is preferably temozolomide or a pharmaceutically acceptable salt thereof.
  • the present disclosure also provides a VEGFR inhibitor for treating melanoma (such as acral melanoma), wherein the VEGFR inhibitor is administered in combination with an anti-PD-1 antibody.
  • a VEGFR inhibitor for treating melanoma (such as acral melanoma)
  • the VEGFR inhibitor is administered in combination with an anti-PD-1 antibody.
  • an alkylating agent is also included therein, and the alkylating agent is preferably temozolomide or a pharmaceutically acceptable salt thereof.
  • the present disclosure also provides an alkylation inhibitor such as temozolomide or a pharmaceutically acceptable salt thereof for the treatment of melanoma (such as acral melanoma), wherein the alkylation inhibitor is an inhibitor of anti-PD-1 antibody and VEGFR Agent combination application.
  • the present disclosure provides the above-mentioned anti-PD-1 antibody combined with a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof as a medicine for reducing adverse drug reactions.
  • the adverse drug reaction is selected from an anti-PD-1 antibody or a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides the above-mentioned anti-PD-1 antibodies and VEGFR inhibitors such as apatinib or a pharmaceutically acceptable salt thereof in combination with temozolomide or a pharmaceutically acceptable salt thereof as drugs for reducing adverse drug reactions.
  • the adverse drug reaction is selected from an anti-PD-1 antibody or a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof, or temozolomide or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides the above-mentioned anti-PD-1 antibody in combination with a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof as a single dose reduction of the anti-PD-1 antibody and/or a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof
  • a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof
  • the salt is administered alone in the dose of the drug.
  • the present disclosure provides a method for treating acral melanoma, which comprises administering to a patient an effective amount of the above-mentioned anti-PD-1 antibody and a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof, and further administering an effective dose to the patient
  • the alkylating agent such as temozolomide or its pharmaceutically acceptable salt.
  • the present disclosure also provides a combination for treating acral melanoma.
  • the combination contains an anti-PD-1 antibody and a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof.
  • the aforementioned combination further comprises an alkylating agent such as temozolomide or a pharmaceutically acceptable salt thereof.
  • the present disclosure also provides an anti-PD-1 antibody, a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof, and an alkylating agent such as temozolomide or a pharmaceutically acceptable salt thereof for the treatment of melanoma
  • a combination of salt contains an effective dose of anti-PD-1 antibody, VEGFR inhibitor or alkylating agent.
  • melanoma includes mucosal melanoma or acral melanoma.
  • the present disclosure also provides a method for reducing the dose of anti-PD-1 antibody alone and/or the dose of VEGFR inhibitor, such as apatinib or a pharmaceutically acceptable salt thereof, comprising administering the above-mentioned anti-PD-1 antibody in combination to a patient A VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof, and an effective dose of an alkylating agent is further administered to the patient, and the alkylating agent is preferably temozolomide or a pharmaceutically acceptable salt thereof.
  • VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof
  • the dose of the VEGFR inhibitor such as apatinib or its pharmaceutically acceptable salt is 10%-100%, preferably 10%- 100% of the dose administered alone. 75%, more preferably 75%, 50%, 25%, 12.5%.
  • the administration dose of the alkylating agent such as temozolomide or its pharmaceutically acceptable salt is 10% to 100%, preferably 10% to 75% of the dose administered alone. , More preferably 75%, 50%, 25%, 12.5%.
  • the dose of anti-PD-1 antibody when combined with a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof, is 10%-100%, preferably 10%- 100% of the dose of anti-PD-1 antibody administered alone. 50%.
  • the dosage of the alkylating agent such as temozolomide or a pharmaceutically acceptable salt thereof when used in combination with a VEGFR inhibitor, is 10% to 100%, preferably 10% to 75%, of the dose administered alone. , More preferably 75%, 50%, 25%, 12.5%.
  • the PD-1 antibody when used in combination with a VEGFR inhibitor such as apatinib or its pharmaceutically acceptable salt or/and an alkylating agent such as temozolomide or its pharmaceutically acceptable salt, it can reduce the risk of PD-1 antibody and/or immune-mediated adverse drug reactions; preferably, the adverse reactions are selected from vascular-related adverse reactions, glandular hypofunction, skin adverse reactions, respiratory system adverse reactions, liver-related adverse reactions, endocrine Related adverse reactions, digestive system adverse reactions, kidney-related adverse reactions, fatigue, fever; the preferred blood vessel-related adverse reactions are selected from hemangioma, vasculitis, lymphangioma, and the glandular function is selected from hypothyroidism, thyroid Hypoparathyroidism, pancreatic hypofunction, and prostate hypofunction; the skin adverse reaction is selected from pruritus, urticaria, rash, toxic epidermal necrosis; the respiratory system adverse reaction is selected from pneumonia, bronchitis, chronic obstructive pulmonary
  • the present disclosure also provides a pharmaceutical combination, which contains a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof, and an anti-PD-1 antibody or an antigen-binding fragment thereof, and further includes an alkylating agent, the alkyl
  • the chemical agent is selected from temozolomide or a pharmaceutically acceptable salt thereof.
  • 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 or a lyophilized powder injection, which contains the PD-1 antibody, a buffer, a stabilizer, and optionally a surfactant.
  • the buffer can be selected from one or more of acetate, citrate, succinate, and phosphate.
  • the stabilizer may be selected from sugars or amino acids, preferably disaccharides such as sucrose, lactose, trehalose, maltose.
  • the surfactant is selected from polyoxyethylene hydrogenated castor oil, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, preferably the polyoxyethylene sorbitan fatty acid ester is polysorbate 20, 40, 60 or 80 , Polysorbate 20 is most preferred.
  • the most preferred injectable form of PD-1 antibody contains PD-1 antibody, acetate buffer, trehalose and polysorbate 20.
  • the combination scheme of the present disclosure optionally further includes other components, including but not limited to other anti-tumor drugs and the like.
  • “combination” is a mode of administration, which means that at least one dose of VEGFR inhibitor, such as apatinib or a pharmaceutically acceptable salt thereof, and at least one dose of PD-1 antibody are administered within a certain period of time Or its antigen-binding fragments, both of which exhibit pharmacological effects.
  • the time limit may be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours, more preferably within 12 hours.
  • VEGFR inhibitors such as apatinib or a pharmaceutically acceptable salt thereof and PD-1 antibody or an antigen-binding fragment thereof can be administered simultaneously or sequentially.
  • This period includes treatments in which a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof and a PD-1 antibody or an antigen-binding fragment thereof are administered by the same route of administration or different routes of administration.
  • the administration mode of the combination described in the present application is selected from simultaneous administration, independent formulation and co-administration, or independent formulation and sequential administration.
  • the “combination” of the present disclosure refers to the administration of three different kinds of drugs such as VEGFR inhibitors, PD-1 antibodies, and alkylating agents such as temozolomide within a certain period of time, and the period of time is as described above Described.
  • the "effective amount” or “effective dose” in the present disclosure includes an amount sufficient to improve or prevent the symptoms or conditions of a medical disorder.
  • An effective amount also means an amount sufficient to allow or facilitate diagnosis.
  • the effective amount for a particular patient or veterinary subject can vary depending on factors such as the condition to be treated, the patient's general health, the method of administration and dosage, and the severity of side effects.
  • the effective amount can be the maximum dose or dosing schedule that avoids significant side effects or toxic effects.
  • humanized antibody also known as CDR-grafted antibody, refers to the transplantation of mouse CDR sequences into the human antibody variable region framework, that is, different types of human germlines The antibody produced in the antibody framework sequence. It can overcome the strong variable antibody response induced by the chimeric antibody due to the large amount of mouse protein components.
  • framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences.
  • the germline DNA sequences of the human heavy chain and light chain variable region genes can be found in the "VBase" human germline sequence database (available on the Internet www.mrccpe.com.ac.uk/vbase), as well as in Kabat, EA, etc. People, 1991 Sequences of Proteins of Immunological Interest, found in the 5th edition.
  • the CDR sequence of the humanized PD-1 antibody is selected from SEQ ID NO: 1, 2, 3, 4, 5, 6.
  • antigen-binding fragment refers to Fab fragments, Fab' fragments, F(ab')2 fragments, and Fv fragments that bind to human PD-1, sFv fragments that have antigen binding activity; One or more CDR regions in SEQ ID NO: 1 to SEQ ID NO: 6.
  • the Fv fragment contains the variable region of the heavy chain of the antibody and the variable region of the light chain, but does not have the constant region, and has the smallest antibody fragment with all antigen binding sites.
  • an Fv antibody also contains a polypeptide linker between the VH and VL domains, and can form the structure required for antigen binding.
  • Different linkers can also be used to connect the variable regions of two antibodies into a polypeptide chain, which is called single chain antibody or single chain Fv (sFv).
  • binding to PD-1 in this application refers to the ability to interact with human PD-1.
  • antigen-binding site in the present application refers to a discrete three-dimensional site on the antigen that is recognized by the antibody or antigen-binding fragment of the present application.
  • PFS Progression-free survival
  • OS Overall survival
  • Objective response rate refers to the proportion of patients whose tumors have shrunk to a certain level and maintained for a certain period of time, including CR and PR cases.
  • the solid tumor remission assessment standard (RECIST 1.1 standard) was used to assess the objective tumor remission. Subjects must be accompanied by measurable tumor lesions at baseline.
  • the efficacy evaluation criteria are divided into complete remission (CR), partial remission (PR), stable (SD), and progress (PD) according to the RECIST 1.1 standard.
  • DCR Disease Control Rate
  • CR Complete remission
  • Partial remission The sum of the diameters of the target lesions is reduced by at least 30% from the baseline level.
  • PD Disease progression: Take the minimum value of the sum of the diameters of all target lesions measured during the entire experimental study as the reference, and the relative increase in diameter and relative increase of at least 20% (if the baseline measurement value is the smallest, the baseline value is used as the reference); In addition, the absolute value of the diameter sum must be increased by at least 5mm (the appearance of one or more new lesions is also regarded as disease progression).
  • Stable disease The degree of reduction of the target lesion did not reach the PR, and the degree of increase did not reach the PD level, which is somewhere in between. The minimum sum of the diameters can be used as a reference during the study.
  • Example 1 Anti-PD-1 antibody combined with apatinib mesylate in the treatment of acral melanoma
  • Compound A PD-1 antibody is prepared according to the method in patent application WO2017054646A, and the heavy and light chain sequences are as shown in SEQ ID NO: 7 and SEQ ID NO: 8 in this disclosure. 200 mg/bottle, 20 mg/ml for use.
  • Compound B Apatinib mesylate, which can be prepared according to the method in patent application WO2010031266A1.
  • Inclusion criteria (1) confirmed by histopathology, patients with recurrence, unresectable or metastatic acral melanoma after surgery; (2) 3. Have not received any systemic anti-tumor drug treatment in the past
  • PD-1 antibody a fixed dose of 200 mg, intravenous infusion (no preventive medication required), or 3 mg/kg for subjects with a body weight of less than 50 kg at baseline, once every 2 weeks, a cycle of 4 weeks;
  • Apatinib 250mg/tablet, orally, once a day, one tablet at a time, administered after meals.
  • Example 2 Anti-PD-1 antibody combined with apatinib mesylate in the treatment of acral melanoma
  • Compound A PD-1 antibody is prepared according to the method in patent application WO2017054646A, and the heavy and light chain sequences are as shown in SEQ ID NO: 7 and SEQ ID NO: 8 in this disclosure. 200 mg/bottle, 20 mg/ml for use.
  • Compound B Apatinib mesylate, which can be prepared according to the method in patent application WO2010031266A1.
  • Compound C Temozolomide, Temozolomide for injection (powder injection, Shanghai Hengrui) or Temozolomide capsules (Mersk)
  • Inclusion criteria (1) confirmed by histopathology, patients with recurrence, unresectable or metastatic melanoma (including extremities) after surgery; (2) 3. Have not received any systemic anti-tumor drug treatment in the past.
  • PD-1 antibody a fixed dose of 200 mg, intravenous infusion (no preventive medication required), or 3 mg/kg for subjects with a body weight of less than 50 kg at baseline, once every 2 weeks, a cycle of 4 weeks;
  • Apatinib 250mg/tablet, orally, once a day, one tablet at a time, administered after meals, every 28 days as a cycle;
  • Temozolomide 200mg/m 2 , orally or intravenously, once a day for 5 consecutive days, a cycle every 28 days.

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Abstract

提供一种抗PD-1抗体与阿帕替尼在制备治疗肢端黑色素瘤的药物中的用途，该方案对肢端黑色素瘤疾病控制率达72.2％，对疾病客观缓解率为22.2％。还提供了一种抗PD-1抗体、阿帕替尼和替莫唑胺在制备治疗黑色素瘤的药物中的用途。

Description

一种抗PD-1抗体在制备治疗肢端黑色素瘤的药物中的用途 技术领域
本公开涉及一种抗PD-1抗体或其抗原结合片段和VEGFR抑制剂联合在制备治疗肢端黑色素瘤的药物中的用途。
背景技术
早期临床试验显示特异性结合抗程序性死亡受体(抗PD-1)，如nivolumab和pembrolizumab，可使晚期黑色素瘤患者预后得到显著改善(N Engl J Med 2015；372：320-30和N Engl J Med 2015；372：2521-32)。然而大多数此类研究主要基于抗PD-1药物在高加索人群中的药效数据进行分析，黑色素瘤临床亚型在人群中差异较大，且抗PD-1药物对疾病的不同亚型响应也有所不同。
A.N.Shoushtari等人(Cancer.2016，122(21)：3354.doi：10.1002/cncr.30259)研究了抗PD-1抗体pembrolizumab对肢端黑色素瘤和粘膜黑色素瘤的疗效，他们发现肢端黑色素瘤组的ORR为32％，粘膜黑色素瘤组的ORR为23％，其结果与早期临床研究数据相当。
T.Maeda等人(Br J Dermatol.2018 Nov 17.doi：10.1111/bjd.17434)报道纳武单抗在不同临床亚型的黑色素瘤(如肢端黑色素瘤、粘膜黑色素瘤和皮肤黑色素瘤)亚洲患者的临床研究数据，在68例患者中，ORR为29.4％，其中2例患者为完成反应，18例患者为部分反应，11例为疾病稳定，37例患者为疾病进展，在细分三种临床亚型中，皮肤黑色素瘤组的ORR为42.9％，粘膜黑色素瘤组的ORR为20.7％，肢端黑色素瘤组的ORR为18.8％，进一步细分转移性与非转移性的，皮肤黑色素瘤组的ORR为41.7％，粘膜黑色素瘤组的ORR为17.6％，肢端黑色素瘤组的ORR只有7.7％。不论是否细分转移性的，肢端黑色素瘤组均展现差的ORR(7.7％Vs 17.6％Vs 41.7％)。故PD-1抗体单药用于肢端黑色素瘤的治疗仍存在诸多不确定性。
联合使用一种以上靶点各异又相互关联的抗肿瘤药物，充分发挥各组分优势，既能提高单药的抗肿瘤活性又可降低药物毒性，是一种被普遍接受的抗肿瘤疗法。
阿帕替尼是全球首个晚期胃癌的口服抗血管生成药物，对VEGFR-2具有高度选择性，强效抗血管生成。在一项关于阿帕替尼二线以后治疗转移性胃/胃食管结合部癌患者的多中心随机双盲安慰剂对照III期试验中，结果显示与安慰剂相比，阿帕替尼单药能将中位总生存期延长1.8个月，中位无进展生存期延长0.8个月，且不良事件可控。阿帕替尼的结构式如式(I)所示。
Figure PCTCN2021000069-appb-000001
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)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PD-1抗体与VEGF抑制剂联用具有很多不确定性，值得深入研究，同时尚未见VEGFR抑制剂与PD-1抗体联于治疗肢端黑色素瘤的报告。另一方面，PD-1抗体、VEGF抑制剂与烷基化剂如替莫唑胺三药联用是否取得更为优异联合用药的药效也是不能确定性，值得深入研究。
发明内容
本公开(the disclosure)提供了一种抗PD-1抗体和VEGFR抑制剂联合在制备治疗肢端黑色素瘤(黑素瘤)的药物中的用途。
PD-1抗体是已知的，在一些可选实施方案中，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、Cemiplimab、Camrelizumab、Pembrolizumab、Toripalimab、Sintilimab、Tislelizumab、LZM-009、AK-103和Nivolumab。
在一些实施方案中，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。
在一些实施方案中，所述PD-1抗体或抗原结合片段轻/重链中CDR序列如下表所示：
名称 序列 编号
HCDR1 SYMMS SEQID NO：1
HCDR2 TISGGGANTYYPDSVKG SEQID NO：2
HCDR3 QLYYFDY SEQID NO：3
LCDR1 LASQTIGTWLT SEQID NO：4
LCDR2 TATSLAD SEQID NO：5
LCDR3 QQVYSIPWT SEQID NO：6
在可选实施方案中，所述的PD-1抗体为人源化抗体。
在一些可选实施方案中，所述抗PD-1抗体或其抗原结合片段选自由Fab，Fab’-SH，Fv，scFv，和(Fab’)2片段组成的组的抗体片段。
免疫球蛋白可以来源于任何通常已知的同种型，包括但不限于IgA、分泌型IgA、IgG和IgM。IgG亚类也是本领域技术人员众所周知的，包括但不限于IgG1、IgG2、IgG3和IgG4。“同种型”是指由重链恒定区基因编码的Ab种类或亚类(例如，IgM或IgG1)。在一些可选实施方案中，本申请中所述抗PD-1抗体或其抗原结合片段包含人源IgG1、IgG2、IgG3或IgG4同种型的重链恒定区，优选包含IgG1或IgG4同种型的重链恒定区。
在另一些可选实施方案中，所述抗PD-1抗体或其抗原结合片段包含κ或λ的轻链恒定区。
在一些实施方案中，所述PD-1抗体或其抗原结合片段包含如SEQ ID NO：10所示的轻链可变区或其变体，所述变体优选在SEQ ID NO：10所示的轻链可变区序列上有0-10的氨基酸变化，更优选A43S的氨基酸变化；和如SEQ ID NO：9所示的重链可变区或其变体，所述变体优选在SEQ ID NO：9所示的重链可变区序列上有0-10的氨基酸变化，更优选G44R的氨基酸变化。
前述PD-1抗体或其抗原结合片段重、轻链的可变区序列如下所示：
重链可变区
Figure PCTCN2021000069-appb-000002
轻链可变区
Figure PCTCN2021000069-appb-000003
在可选实施方案中，所述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。
在一些实施方案中，所述人源化抗体的轻链序列为如SEQ ID NO：8所示的序列，重链序列为如SEQ ID NO：7所示的序列。
所述人源化抗体重、轻链的序列如下所示：
重链
Figure PCTCN2021000069-appb-000004
Figure PCTCN2021000069-appb-000005
轻链
Figure PCTCN2021000069-appb-000006
另一方面，PD-1(programmed death 1)，即程序性死亡受体1，是一种重要的免疫抑制分子。当PD-1的开关打开，就会启动一系列反应，抑制T细胞活性。肿瘤细胞借助PD-L1与T细胞的PD-1结合，“欺骗”T细胞，逃避T细胞的识别，继续在体内横行霸道。而PD-L1/PD-1抗体则可以帮助T细胞揭开肿瘤细胞伪善的面纱，恢复其对肿瘤细胞识别和杀伤。在一些可选联用实施方案中，所述抗PD-1抗体或其抗原结合片段为Cemiplimab。在一些可选联用实施方案中，所述抗PD-1抗体或其抗原结合片段为Toripalimab。在一些可选联用实施方案中，所述抗PD-1抗体或其抗原结合片段为Sintilimab。在一些可选联用实施方案中，所述抗PD-1抗体或其抗原结合片段为Tislelizumab。
抗体通用名 CAS号 参考文献
Camrelizumab 1798286-48-2 WO2017054646
Nivolumab 946414-94-4 WO2006121168
Pembrolizumab 1374853-91-4 WO2008156712
Cemiplimab 1801342-60-8 WO2015112800
Toripalimab 1924598-82-2 WO2014206107
Sintilimab 2072873-06-2 WO2017024465
Tislelizumab 1858168-59-8 WO2015035606
另一方面，在一些实施方案中，其中所述VEGFR抑制剂是VEGFR-2抑制剂。
在一些实施方案中，其中所述的VEGFR抑制剂选自阿帕替尼、安罗替尼、他菲替尼、法米替尼、索拉非尼或其可药用盐，优选阿帕替尼或其可药用盐。
本公开所述可药用盐选自甲磺酸盐、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。在一些实施方案中，所述阿帕替尼可药用盐选自甲磺酸盐。在一些实施方案中，所述安罗替尼可药用盐选自盐酸。本公开所述联合抗PD-1抗体和VEGFR抑制剂具有协同 药效作用。
进一步地，本公开中所述患者选自复发的，不能手术切除的或转移性的。
在一些实施方案中，所述复发的为手术后复发的。
在可选实施方案中，所述患者选自手术后复发的
在可选实施方案中，所述患者选自不能手术切除的。
另一方面，前述抗PD-1抗体与VEGFR抑制剂方案中还进一步包含烷基化剂。
在一些实施方案中，所述用途还进一步包括替莫唑胺或其可药用盐。
在一些实施方案中，所述抗PD-1抗体或其抗原结合片段在人类受试者中的施用剂量(按患者体重给药)选自0.1mg/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，优选3mg/kg。
在另一选实施方案中，所述PD-1抗体或其抗原结合片段在人类受试者中的施用剂量为1～600mg，优选1.0mg、1.2mg、1.4mg、1.6mg、1.8mg、2.0mg、2.2mg、2.4mg、2.6mg、2.8mg、3.0mg、3.2mg、3.4mg、3.6mg、3.8mg、4.0mg、4.2mg、4.4mg、4.6mg、4.8mg、5.0mg、5.2mg、5.4mg、5.6mg、5.8mg、6.0mg、6.2mg、6.4mg、6.6mg、6.8mg、7.0mg、7.2mg、7.4mg、7.6mg、7.8mg、8.0mg、8.2mg、8.4mg、8.6mg、8.8mg、9.0mg、9.2mg、9.4mg、9.6mg、9.8mg、10.0mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、145mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、195mg、200mg、205mg、210mg、215mg、220mg、225mg、230mg、235mg、240mg、245mg、250mg、255mg、260mg、265mg、270mg、275mg、280mg、285mg、290mg、295mg、300mg、305mg、310mg、315mg、320mg、325mg、330mg、335mg、340mg、345mg、350mg、355mg、360mg、365mg、370mg、375mg、380mg、385mg、390mg、395mg、400mg、405mg、410mg、415mg、420mg、425mg、430mg、435mg、440mg、445mg、450mg、455mg、460mg、465mg、470mg、475mg、480mg、485mg、490mg、495mg、500mg、505mg、510mg、515mg、520mg、525mg、530mg、535mg、540mg、545mg、550mg、555mg、560mg、565mg、570mg、575mg、580mg、585mg、590mg、595mg、600mg或任意两数值间任意值，优选200mg。
本公开所述抗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。
在一些实施方案中，本公开所述抗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50～600mg/2-3周一次，更优选为200mg/2-3周一次。
在另一些实施方案中，所述VEGFR抑制剂如阿帕替尼或其可药用盐在人类受试者中的施用剂量选自0.1-500mg，可以为0.1mg、0.25mg、0.5mg、0.75mg、1mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、11mg、12mg、12.5mg、15mg、17.5mg、20mg、22.5mg、25mg、30mg、45mg、50mg、60mg、70mg、75mg、80mg、90mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、375mg、400mg、500mg，更优选0.25mg、0.5mg、1mg、2mg、3mg、4mg、10mg、15mg、20mg、30mg、45mg、50mg、60mg、75mg、100mg、125mg、150mg、175mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg、400mg、425mg、450mg、475mg、500mg或任意两数值间任意值，优选250mg或375mg。
本公开所述的用途，所述VEGFR抑制剂如阿帕替尼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。
在一些实施方案中，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选自60至600mg，静脉输注，每一至三周一次；VEGFR抑制剂如甲磺酸阿帕替尼在人类受试者中的施用剂量选自250mg至500mg，口服，每一到两日一次。
在一些实施方案中，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选自1-5mg/kg，静脉输注，每一至三周一次；VEGFR抑制剂如甲磺酸阿帕替尼在人类受试者中的施用剂量选自250mg至500mg，口服，每一到两日一次。
在一些实施方案中，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选自200mg，静脉输注，每两周一次；VEGFR抑制剂如甲磺酸阿帕替尼在人类受试者中的施用剂量选自250mg，口服，每日一次。
在一些实施方案中，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选自3mg/kg，静脉输注，每两周一次；VEGFR抑制剂如甲磺酸阿帕替尼在人类受试者中的施用剂量选自250mg，口服，每日一次。
在一些实施方案中，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选自200mg，静脉输注，每两周一次；VEGFR抑制剂如甲磺酸阿帕替尼在人类受试者中的施用剂量选自375mg，口服，每日一次。
进一步地，本公开所述VEGFR抑制剂为餐后用药，譬如餐后30分钟内服药。
另一方面，在另一选实施方案中，所述烷基化剂如替莫唑胺在人类受试者中的施用剂量(按体表面积给药)选自50mg/m 2～300mg/m 2，包括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150mg/m 2或200mg/m 2。
本公开所述烷基化剂如替莫唑胺给药频为一天一次、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。
在一些实施方案中，所述烷基化剂如替莫唑胺在人类受试者中的施用剂量选自150mg/m 2或200mg/m 2，口服，每日一次。
在一些实施方案中，所述烷基化剂如替莫唑胺在人类受试者中的施用剂量选自150mg/m 2或200mg/m 2，口服，每日一次，共5天。
在一些实施方案中，所述烷基化剂如替莫唑胺在人类受试者中的施用剂量选自150mg/m 2或200mg/m 2，口服，每日一次，共5天，然后停药23天。
在另一些实施方案中，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选自60至600mg，静脉输注，每一至三周一次；VEGFR抑制剂如甲磺酸阿帕替尼在人类受试者中的施用剂量选自250mg至500mg，口服，每一到两日一次；所述烷基化剂如替莫唑胺在人类受试者中的施用剂量选自150mg/m 2或200mg/m 2，口服，每日一次。
在另一些实施方案中，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选自200mg，静脉输注，每两周一次；VEGFR抑制剂如甲磺酸阿帕替尼在人类受试者中的施用剂量选自250mg，口服，每日一次；所述烷基化剂如替莫唑胺在人类受试者中的施用剂量选自200mg/m 2，口服，每日一次，共5天。
本公开另一方面还提供一种抗PD-1抗体、VEGFR抑制剂联合替莫唑胺或其可药用盐在制备治疗黑素瘤的药物中的用途。
在一些实施方案中，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选自60至600mg；VEGFR抑制剂如甲磺酸阿帕替尼在人类受试者中的施用剂量选自0.1mg至500mg；所述烷基化剂如替莫唑胺在人类受试者中的施用剂量选自50mg/m 2至200mg/m 2。
在另一些实施方案中，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选自60至600mg，静脉输注，每一至三周一次；VEGFR抑制剂如甲磺酸阿帕替尼在人类受试者中的施用剂量选自0.1至500mg，口服，每一到两日一次；所述烷基化剂如替莫唑胺在人类受试者中的施用剂量选自50mg/m 2至200mg/m 2，口服，每日一次。
在另一些实施方案中，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选自200mg，静脉输注，每两周一次；VEGFR抑制剂如甲磺酸阿帕 替尼在人类受试者中的施用剂量选自250mg，口服，每日一次；所述烷基化剂如替莫唑胺在人类受试者中的施用剂量选自200mg/m 2，口服，每日一次，共5天。
本公开还提供了一种抗PD-1抗体和VEGFR抑制剂如阿帕替尼或其可药用盐联合在制备治疗粘膜黑色素瘤(粘膜型黑色素瘤)的药物中的用途，还进一步包含烷基化剂，所述烷基化剂优选替莫唑胺或其可药用盐。
本公开提供上述抗PD-1抗体联合VEGFR抑制剂如阿帕替尼或其可药用盐作为治疗制备治疗肢端黑色素瘤的药物，还进一步包含烷基化剂，所述烷基化剂优选替莫唑胺或其可药用盐。
本公开还提供一种用于治疗黑色素瘤(如肢端黑色素瘤)的抗PD-1抗体，其中抗PD-1抗体与VEGFR抑制剂组合施用。在一些实施方案中，其中还包括烷基化剂，所述烷基化剂优选替莫唑胺或其可药用盐。
另外，本公开还提供一种用于治疗黑色素瘤(如肢端黑色素瘤)的VEGFR抑制剂，其中VEGFR抑制剂与抗PD-1抗体组合施用。在一些实施方案中，其中还包括烷基化剂，所述烷基化剂优选替莫唑胺或其可药用盐。
本公开还提供一种用于治疗黑色素瘤(如肢端黑色素瘤)的烷基化抑制剂如替莫唑胺或其可药用盐，其中所述烷基化抑制剂与抗PD-1抗体和VEGFR抑制剂组合施用。本公开提供上述抗PD-1抗体联合VEGFR抑制剂如阿帕替尼或其可药用盐作为减少药物不良反应的药物。在一些实施方案中，所述的药物不良反应选自由抗PD-1抗体引起或由VEGFR抑制剂如阿帕替尼或其可药用盐引起。
另一方面，本公开提供上述抗PD-1抗体、VEGFR抑制剂如阿帕替尼或其可药用盐联合替莫唑胺或其可药用盐作为减少药物不良反应的药物。在一些实施方案中，所述的药物不良反应选自由抗PD-1抗体引起或由VEGFR抑制剂如阿帕替尼或其可药用盐，或者由替莫唑胺或其可药用盐引起。
本公开提供上述抗PD-1抗体联合VEGFR抑制剂如阿帕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VEGFR抑制剂如阿帕替尼或其可药用盐单独施用剂量的药物。
本公开提供了一种治疗肢端黑色素瘤的办法，包括向患者施用有效量的上述抗PD-1抗体和VEGFR抑制剂如阿帕替尼或其可药用盐，还进一步向患者施用有效剂量的烷基化剂如替莫唑胺或其可药用盐。
本公开还提供一种用于治疗治疗肢端黑色素瘤的组合。在一些实施方案中，该组合中含有抗PD-1抗体和VEGFR抑制剂如阿帕替尼或其可药用盐的。在另一些实施方案中，前述组合还包含烷基化剂如替莫唑胺或其可药用盐。
另一方面，本公开还提供一种用于治疗黑色素瘤的、含有抗PD-1抗体、VEGFR抑制剂如阿帕替尼或其可药用盐的和烷基化剂如替莫唑胺或其可药用盐的组合。该组合中含有有效剂量的抗PD-1抗体、VEGFR抑制剂或烷基化剂。在一些实施方案中，黑色素瘤包括粘膜型黑色素瘤或肢端黑色素瘤。
本公开还提供了一种降低抗PD-1抗体单独施用剂量和/或VEGFR抑制剂如阿帕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VEGFR抑制剂如阿帕替尼或其可药用盐，还进一步向患者施用有效剂量的烷基化剂，所述烷基化剂优选替莫唑胺或其可药用盐。
在一些实施方案中，与PD-1联合使用时，所述VEGFR抑制剂如阿帕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％。在一些实施方案中，与PD-1联合使用时，所述烷基化剂如替莫唑胺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％。
在一些实施方案中，与VEGFR抑制剂如阿帕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％，优选10％～50％。在一些实施方案中，与VEGFR抑制剂联合使用时，所述烷基化剂如替莫唑胺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％。
在本公开实施方案中，当PD-1抗体与VEGFR抑制剂如阿帕替尼或其可药用盐或/和烷基化剂如替莫唑胺或其可药用盐联合使用时，可减少由抗PD-1抗体和/或免疫介导的药物不良反应；优选地，所述的不良反应选自血管相关不良反应、腺体机能减退、皮肤不良反应、呼吸系统不良反应、肝脏相关不良反应、内分泌相关不良反应、消化系统不良反应、肾脏相关不良反应、疲劳、发热；所述优选血管相关不良反应选自血管瘤、血管炎、淋巴管瘤、所述腺体功能减退选自甲状腺机能减退、甲状旁腺功能减退、胰腺功能减退、前列腺功能减退；所述皮肤不良反应选自瘙痒症、荨麻疹、皮疹、毒性表皮坏死症；所述呼吸系统不良反应选自肺炎、支气管炎、慢性阻塞性肺病、肺纤维化；所述肝脏相关不良反应选自肝炎、肝功能异常；所述内分泌相关不良反应选自I型糖尿病、II型糖尿病、低血糖症；肾脏相关不良反应选自肾炎、肾衰竭；所述消化系统不良反应选自腹泻、恶心、呕吐、肠炎、便秘；更优选的，所述药物不良反应选自血管瘤、甲状腺机能减退、甲状旁腺功能减退、瘙痒症、肺炎、肝炎、肝功能异常、I型糖尿病、肾炎、肾衰竭。
本公开还提供了一种药物组合，其中含有VEGFR抑制剂如阿帕替尼或其可药用盐，和抗PD-1抗体或其抗原结合片段，进一步包括烷基化剂，所述烷基化剂选自替莫唑胺或其可药用盐。
在本公开实施方案中，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。
本公开联合方案任选的还包含其他组分，所述其他组分包括但不限于其他抗肿瘤药等。
如无相反解释，本公开中术语具有如下含义：
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VEGFR抑制剂如阿帕替尼或其可药用盐和至少一种剂量的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，更优选12小时以内。可以同时或依次给予VEGFR抑制剂如阿帕替尼或其可药用盐和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VEGFR抑制剂如阿帕替尼或其可药用盐和PD-1抗体或其抗原结合片段。本申请所述联合的给药方式选自同时给药、独立地配制并共给药或独立地配制并相继给药。在另一些实施方案中，本公开“联合”是指在一定时间期限内给予三种不同种的药物如VEGFR抑制剂、PD-1抗体以及烷基化剂如替莫唑胺，所述的时间期限如前述所描述。
本公开中所述“有效量”或“有效剂量”包含足以改善或预防医学病症的症状或病症的量。有效量还意指足以允许或促进诊断的量。用于特定患者或兽医学受试者的有效量可依据以下因素而变化：如待治疗的病症、患者的总体健康情况、给药的方法途径和剂量以及副作用严重性。有效量可以是避免显著副作用或毒性作用的最大剂量或给药方案。
术语“人源化抗体(humanized antibody)”，也称为CDR移植抗体(CDR-grafted antibody)，是指将小鼠的CDR序列移植到人的抗体可变区框架，即不同类型的人种系抗体构架序列中产生的抗体。可以克服嵌合抗体由于携带大量小鼠蛋白成分，从而诱导的强烈的抗体可变抗体反应。此类构架序列可以从包括种系抗体基因序列的公共DNA数据库或公开的参考文献获得。如人重链和轻链可变区基因的种系DNA序列可以在“VBase”人种系序列数据库(在因特网www.mrccpe.com.ac.uk/vbase可获得)，以及在Kabat，E.A.等人，1991 Sequences of Proteins of Immunological Interest，第5版中找到。在本申请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；包含本申请所述抗体的选自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)。本申请的术语“与PD-1结合”，指能与人PD-1相互作用。本申请的术语“抗原结合位点”指抗原上不连续的，由本申请抗体或抗原结合片段识别的三维空间位点。
无进展生存期(PFS)：从随机开始到首次记录肿瘤客观进展日期或到任何原因导致死亡的时间，以先出现者为准。
总生存期(OS)指从随机期至任何原因导致死亡的期。末次随访时仍存活的受试者，其OS以末次随访时间计为数据删失。失访的受试者，其OS以失访前末次证实存活时间计为数据删失。数据删失的OS定义为从随机分组到删失的时间。
客观缓解率(Objective response rate，ORR)指肿瘤缩小达到一定并且保持一定时间的病人的比例，包含了CR和PR的病例。采用实体瘤缓解评估标准(RECIST 1.1标准)来评定肿瘤客观缓解。受试者在基线时必须伴有可测量的肿瘤病灶，疗效评定标准根据RECIST 1.1标准分为完全缓解(CR)、部分缓解(PR)、稳定(SD)、进展(PD)。
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。
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：抗PD-1抗体联合甲磺酸阿帕替尼治疗肢端黑色素瘤的研究
化合物A：PD-1抗体按照专利申请WO2017054646A中的方法制备，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：甲磺酸阿帕替尼，可按照专利申请WO2010031266A1中的方法制备。
入组标准：(1)经病理组织学证实，手术后复发、不能手术切除或转移性肢端黑色素瘤患者；(2)3.既往未接受过任何系统抗肿瘤药物治疗
给药方法：
PD-1抗体：固定剂量200mg，静脉输注(无需预防用药)，或针对基线期体重＜50kg的受试者，采用3mg/kg，每2周一次，4周一个周期；
阿帕替尼：250mg/片，口服，每日一次，一次一片，餐后给药。
结论：
共计入组20例受试者，可评价18例受试者中，4例患者靶病灶直径之和比基线水平减少至少30％，9例受试者表现为疾病稳定(SD)，5例患者表现为疾病进展，整体疾病控制率72.2％，疾病缓解率22.2％，而单药PD-1疾病缓解率为15％，明显改善患者用药安全性、有效性。
实施例2：抗PD-1抗体联合甲磺酸阿帕替尼治疗肢端黑色素瘤的研究
化合物A：PD-1抗体按照专利申请WO2017054646A中的方法制备，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：甲磺酸阿帕替尼，可按照专利申请WO2010031266A1中的方法制备。
化合物C：替莫唑胺，注射用替莫唑胺(粉针，上海恒瑞)或替莫唑胺胶囊(默沙东)
入组标准：(1)经病理组织学证实，手术后复发、不能手术切除或转移性黑色素瘤患者(包括肢端的)；(2)3.既往未接受过任何系统抗肿瘤药物治疗。
给药方法：
PD-1抗体：固定剂量200mg，静脉输注(无需预防用药)，或针对基线期体重＜50kg的受试者，采用3mg/kg，每2周一次，4周一个周期；
阿帕替尼：250mg/片，口服，每日一次，一次一片，餐后给药，每28天为一个周期；
替莫唑胺：200mg/m 2，口服或静脉注射，每日一次，连续给药5天，每28天一周期。
结论：
可评价23例受试者中，1例患者所有靶病灶消失，无新病灶出现，且肿瘤标志物正常(CR)，11例患者靶病灶直径之和比基线水平减少至少30％(PR)，10例患者表现为疾病稳定(SD)，1例患者出组，疾病控制率96.65％(22例)，客观缓解率52.17％(12例)。相比于其他治疗方式，如两药(ORR22.2％，DCR72.2％)或单药PD-1(15％)有明显优势的。

Claims (20)

  1. 一种抗PD-1抗体和VEGFR抑制剂联合在制备治疗肢端黑色素瘤的药物中的用途。
  2. 如权利要求1所述的用途，其中所述的VEGFR抑制剂选自阿帕替尼、安罗替尼、他菲替尼、法米替尼、索拉非尼或其可药用盐，优选阿帕替尼或其可药用盐。
  3. 如权利要求1或2所述的用途，其中所述的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、Cemiplimab、Camrelizumab、Pembrolizumab、Toripalimab、Sintilimab、Tislelizumab、LZM-009、AK-103和Nivolumab。
  4. 如权利要求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。
  5. 如权利要求4所述的用途，其中所述的PD-1抗体选自人源化抗体或其抗原结合片段。
  6. 如权利要求4或5所述的用途，其中所述抗PD-1抗体或其抗原结合片段包含人源IgG1、IgG2、IgG3或IgG4同种型的重链恒定区，优选包含IgG1或IgG4同种型的重链恒定区。
  7. 权利要求4-6任一项所述的用途，其中所述抗PD-1抗体或其抗原结合片段包含κ或λ的轻链恒定区。
  8. 如权利要求4-6任一项所述的用途，其中所述人源化抗体的轻链可变区序列为如SEQ ID NO：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；重链可变区序列为如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。
  9. 如权利要求4-6任一项所述的用途，其中所述PD-1抗体或其抗原结合片段 包含SEQ ID NO：8所示轻链，和如SEQ ID NO：7所示重链。
  10. 如权利要求1-9任一项所述的用途，其中所述患者选自复发的，不能手术切除的或转移性的，所述复发的优选手术后复发的。
  11. 如权利要求1-10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，例如3mg/kg。
  12. 如权利要求1-10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，例如200mg。
  13. 如权利要求1-12任一项所述的用途，其中所述的VEGFR抑制剂剂量选自0.1-500mg，例如250mg或375mg。
  14. 如权利要求1-13任一项所述的用途，其中还进一步包含烷基化剂，所述烷基化剂优选替莫唑胺或其可药用盐。
  15. 如权利要求14所述的用途，其中所述的替莫唑胺剂量选自50mg/m 2～300mg/m 2，例如150mg/m 2或200mg/m 2。
  16. 如权利要求2-15任一项所述的用途，其中所述阿帕替尼可药用盐选自甲磺酸盐、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、硫酸盐和磷酸盐，优选甲磺酸盐。
  17. 一种抗PD-1抗体、VEGFR抑制剂联合替莫唑胺或其可药用盐在制备治疗黑素瘤的药物中的用途。
  18. 一种用于治疗黑色素瘤的抗PD-1抗体，其中抗PD-1抗体与VEGFR抑制剂组合施用，进一步还包括烷基化剂，所述烷基化剂优选替莫唑胺或其可药用盐。
  19. 一种用于治疗黑色素瘤的VEGFR抑制剂，其中所述VEGFR抑制剂与抗PD-1抗体组合施用，进一步还包括烷基化剂，所述烷基化剂优选替莫唑胺或其可药用盐。
  20. 一种药物组合，其包含有效治疗量的PD-1抗体或其抗原结合片段和VEGFR抑制剂，进一步包括烷基化剂，所述烷基化剂优选替莫唑胺或其可药用盐。
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101676267A (zh) * 2008-09-16 2010-03-24 江苏恒瑞医药股份有限公司 N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺的盐
CN105026428A (zh) * 2013-12-12 2015-11-04 上海恒瑞医药有限公司 PD-l抗体、其抗原结合片段及其医药用途
CN106963948A (zh) * 2017-05-12 2017-07-21 顾艳宏 阿帕替尼与Anti‑PD‑1抗体联用在制备结肠癌药物中的应用
CN106999591A (zh) * 2015-09-28 2017-08-01 江苏恒瑞医药股份有限公司 一种抗pd‑1抗体制剂及其在医药上的应用
CN108079292A (zh) * 2016-11-23 2018-05-29 苏州盛迪亚生物医药有限公司 一种抗pd-1抗体在制备治疗肝癌的药物中的用途
CN108601831A (zh) * 2016-10-10 2018-09-28 苏州盛迪亚生物医药有限公司 一种抗pd-1抗体和vegfr抑制剂联合在制备治疗癌症的药物中的用途

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109893654B (zh) * 2017-12-11 2021-07-27 江苏恒瑞医药股份有限公司 Vegfr抑制剂治疗肿瘤的方法
CN110882385B (zh) * 2018-09-07 2021-07-09 上海君实生物医药科技股份有限公司 抗pd-1抗体在治疗肿瘤中的用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101676267A (zh) * 2008-09-16 2010-03-24 江苏恒瑞医药股份有限公司 N-[4-(1-氰基环戊基)苯基]-2-(4-吡啶甲基)氨基-3-吡啶甲酰胺的盐
CN105026428A (zh) * 2013-12-12 2015-11-04 上海恒瑞医药有限公司 PD-l抗体、其抗原结合片段及其医药用途
CN106999591A (zh) * 2015-09-28 2017-08-01 江苏恒瑞医药股份有限公司 一种抗pd‑1抗体制剂及其在医药上的应用
CN108601831A (zh) * 2016-10-10 2018-09-28 苏州盛迪亚生物医药有限公司 一种抗pd-1抗体和vegfr抑制剂联合在制备治疗癌症的药物中的用途
CN108079292A (zh) * 2016-11-23 2018-05-29 苏州盛迪亚生物医药有限公司 一种抗pd-1抗体在制备治疗肝癌的药物中的用途
CN106963948A (zh) * 2017-05-12 2017-07-21 顾艳宏 阿帕替尼与Anti‑PD‑1抗体联用在制备结肠癌药物中的应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SHOUSHTARI, A. N. ET AL.: "Efficacy of anti-PD-1 agents in acral and mucosal melanoma", CANCER, vol. 122, no. 21, 15 November 2016 (2016-11-15), XP071097357, ISSN: 0008-543X, DOI: 10.1002/cncr.30259 *

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