WO2020119757A1 - Cdk4/6抑制剂联合免疫治疗在制备治疗淋巴瘤的药物中的用途 - Google Patents

Cdk4/6抑制剂联合免疫治疗在制备治疗淋巴瘤的药物中的用途 Download PDF

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WO2020119757A1
WO2020119757A1 PCT/CN2019/124831 CN2019124831W WO2020119757A1 WO 2020119757 A1 WO2020119757 A1 WO 2020119757A1 CN 2019124831 W CN2019124831 W CN 2019124831W WO 2020119757 A1 WO2020119757 A1 WO 2020119757A1
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antibody
antigen
binding fragment
pharmaceutically acceptable
acceptable salt
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PCT/CN2019/124831
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English (en)
French (fr)
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江瑶
王泉人
李华军
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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 CN201980072280.8A priority Critical patent/CN112955148B/zh
Publication of WO2020119757A1 publication Critical patent/WO2020119757A1/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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants

Definitions

  • the present disclosure belongs to the field of pharmacy, and relates to the use of a CDK4/6 inhibitor combined immunotherapy in the preparation of a medicament for treating lymphoma.
  • tumor immunotherapy represented by anti-PD-1/PD-L1 monoclonal antibodies represents the research direction of tumor therapy.
  • the immune checkpoint inhibitory receptors of programmed cell death protein-1 (PD-1) are mainly expressed in activated T cells.
  • the PD-1 signal cascade negatively regulates T cell receptor activation and also reduces T cell proliferation and function.
  • the final result is T cell depletion.
  • PD-1 expression was significantly up-regulated.
  • cytokines such as IFN- ⁇ and IFN- ⁇ appear in the tumor microenvironment
  • the expression of PD-1 ligand (PD-L1) in tumor cells and tumor-related immune cells also increases significantly.
  • PD-1 monoclonal antibodies such as nivolumab and pembrolizumab, have the ability to bind to PD-1, thereby disrupting the interaction between PD-1 protein and its ligands (PD-L1 and PD-L2) and preventing T Inhibitory signal in the cell microenvironment.
  • PD-1 monoclonal antibodies are now approved for the treatment of various cancers, including squamous cell carcinoma of the bladder, lung, head and neck, and are approved for the treatment of melanoma in the United States, Europe and other regions.
  • anti-PD-1 monoclonal antibodies to achieve PD-1 blockade has proved to be effective for relapsed/refractory classic Hodgkin lymphoma, and also shows certain efficacy for non-Hodgkin lymphoma.
  • In a phase 1 study with anti-PD-1 antibodies to treat relapsed T-cell lymphoma clinical remission was also observed. Previous studies have shown that EBV infection may enhance the expression of PD-L1 in tumor cells.
  • EBV-related non-Hodgkin lymphomas such as mature T cells and NK cell lymphomas express high levels of PD-L1, indicating that EBV-related mature T Cell and NK cell lymphomas may be more susceptible to PD-1 blockade.
  • many patients with non-Hodgkin's lymphoma have not obtained good results with anti-PD-l/PD-Ll monoclonal antibody alone, so it is still necessary to continue to find a combination drug that enhances the anti-PD-l/PD-Ll monoclonal antibody.
  • CDK4/6 inhibitors are abemaciclib, ribociclib or palbociclib.
  • W02014183520 provides a potent CDK4/6 inhibitor with the structure shown in formula I.
  • WO2016124067 discloses the hydroxyethyl group of CDK4/6 inhibitor formula I compounds Sulfonate,
  • the present disclosure provides the use of a compound represented by formula I or a pharmaceutically acceptable salt thereof in combination with an anti-PD-1 antibody or antigen-binding fragment thereof in the preparation of a medicament for treating gold lymphoma,
  • the anti-PD-1 antibody or antigen-binding fragment thereof described in the present disclosure is selected from AMP-224, GLS-010, IBI-308, REGN-2810, PDR-001, BGB-A317, Pidilizumab, PF -06801591, Genolimzumab, CA-170, MEDI-0680, JS-001, TSR-042, Camrelizumab, Pembrolizumab, LZM-009, AK-103 and Nivolumab.
  • the light chain variable region of the anti-PD-1 antibody or antigen-binding fragment thereof includes LCDR1 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively.
  • LCDR2 and LCDR3; the heavy chain variable region contains HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively.
  • each CDR sequence of the PD-1 antibody or antigen-binding fragment thereof is shown in the following table:
  • the anti-PD-1 antibody or antigen-binding fragment thereof is selected from humanized antibodies or fragments thereof.
  • the anti-PD-1 antibody or antigen-binding fragment thereof described in the present disclosure is an antibody fragment selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab') 2 fragments.
  • immunoglobulin can be derived from any commonly known isotype, including but not limited to IgA, secreted IgA, IgG and IgM.
  • IgG subclasses are also well known to those skilled in the art, including but not limited to IgG1, IgG2, IgG3 and IgG4.
  • immunotype refers to the Ab species or subclass (eg, IgM or IgG1) encoded by the heavy chain constant region gene.
  • the anti-PD-1 antibody or antigen-binding fragment thereof described in the present disclosure comprises a heavy chain constant region of human IgG1, IgG2, IgG3 or IgG4 isotype, preferably comprising IgG1 or IgG4 isotype Of the heavy chain constant region.
  • the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain constant region of a light chain constant region of ⁇ or ⁇ .
  • the humanized antibody comprises the light chain variable region shown in SEQ ID NO: 10 or a variant thereof, and the variant preferably has 0- in the light chain variable region shown in SEQ ID NO: 10 10 amino acid changes, more preferably A43S amino acid changes; the humanized antibody comprises the heavy chain variable region shown in SEQ ID NO: 9 or a variant thereof, the variant is preferably shown in SEQ ID NO: 9
  • the heavy chain variable region has 0-10 amino acid changes, more preferably G44R amino acid changes.
  • 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, the amino acid change of A43S; the humanized antibody comprises the heavy chain shown in SEQ ID NO: 7 or a variant thereof, and the variant preferably has a 0-10 amino acid change in the variable region of the heavy chain, more preferably Amino acid changes of G44R.
  • 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 dose of the anti-PD-1 antibody or antigen-binding fragment thereof described in the present disclosure in a human subject is 0.1 to 10.0 mg/kg, and may be 0.1 mg/kg, 0.2 mg/kg , 0.3mg/kg, 0.4mg/kg, 0.5mg/kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg, 1.0mg/kg, 1.2mg/kg, 1.4mg/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 PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dosage of 1-600 mg, which may be 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, 2.0mg, 2.2mg, 2.4mg, 2.6mg, 2.8mg, 3.0mg, 3.2mg, 3.4mg, 3.6mg, 3.8mg, 4.0mg, 4.2mg, 4.4mg, 4.6mg, 4.8mg, 5.0mg, 5.2mg, 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, 9.6mg, 9.9
  • the frequency of administration of the anti-PD-1 antibody or antigen-binding fragment thereof in the present disclosure is selected from once a week, once every two weeks, once every three weeks, once every four weeks, or once a month;
  • the administration frequency of the salt is once a day, twice a day, three times a day, once a day, once a day or once a week.
  • the compound represented by the formula I or its pharmaceutically acceptable salt is continuously administered for three times Withdrawal for 1 week.
  • the anti-PD-1 antibody or antigen-binding fragment thereof in combination with the compound represented by Formula I or a pharmaceutically acceptable salt thereof has a cycle of every 4 weeks.
  • the compound of formula I described in the present disclosure or a pharmaceutically acceptable salt thereof has a synergistic effect in combination with an anti-PD-1 antibody or antigen-binding fragment thereof.
  • the dosage of the compound of Formula I or a pharmaceutically acceptable salt thereof described in the present disclosure in a human subject is selected from 5 mg, 10 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, 125mg, 150mg, 175mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, 1000mg or any value between any two values, preferably 100mg or 150mg.
  • the dosage of the anti-PD-1 antibody or antigen-binding fragment thereof in a human subject is selected from 1 to 600 mg, and the compound of formula I or a pharmaceutically acceptable salt thereof is administered in humans
  • the dosage of the test subject is selected from 20 to 500 mg.
  • the dose of the anti-PD-1 antibody or antigen-binding fragment thereof in a human subject is selected from 1 to 600 mg, once every 1 to 4 weeks, the compound of formula I or The dosage of pharmaceutically acceptable salts in human subjects is selected from 20 to 500 mg once a day.
  • the dose of the anti-PD-1 antibody or antigen-binding fragment thereof in a human subject is selected from 200 mg, once every 2 weeks, the compound of formula I or a pharmaceutically acceptable salt thereof
  • the administered dose in human subjects is selected from 150 mg once a day.
  • the dose of the anti-PD-1 antibody or antigen-binding fragment thereof in a human subject is selected from 200 mg, once every 2 weeks, intravenous injection, the compound of formula I or its
  • the dosage of the pharmaceutically acceptable salt in human subjects is selected from 150 mg, once a day, orally.
  • the dose of the anti-PD-1 antibody or antigen-binding fragment thereof in a human subject is selected from 200 mg, once every 2 weeks, intravenous injection, the compound of formula I or its
  • the dosage of the pharmaceutically acceptable salt in human subjects is selected from 150 mg, once a day, orally, and the drug is discontinued for three consecutive weeks.
  • the patient prior to the administration of the anti-PD-1 antibody or antigen-binding fragment thereof in combination with the compound of Formula I or a pharmaceutically acceptable salt thereof, the patient is first treated with the compound of Formula I or a pharmaceutically acceptable salt thereof
  • the induction protocol loading
  • the induction protocol refers to the initial stage of treatment with the compound of formula I or a pharmaceutically acceptable salt monotherapy.
  • the period of the induction regimen may be 1 week (or 7 days), 2 weeks (or 14 days), 3 weeks or longer, preferably 3 weeks (or 21 days); the compound of formula I or
  • the dosage of the pharmaceutically acceptable salt in human subjects is selected from 50 mg, 100 mg or 150 mg, and the frequency of administration is selected from once a day, once every two days or once every three days.
  • the administration route in the present disclosure may be oral administration, parenteral administration, and transdermal administration.
  • the parenteral administration includes but is not limited to intravenous injection, subcutaneous injection, and intramuscular injection.
  • the PD-1 antibody or antigen-binding fragment thereof is administered by injection, such as subcutaneous or intravenous injection, and the PD-1 antibody or antigen-binding fragment needs to be formulated into an injectable form before injection .
  • a particularly preferred injectable form of the PD-1 antibody or antigen-binding fragment thereof is an injection solution or a lyophilized powder injection, for example, the injectable form of the PD-1 antibody, which contains the PD-1 antibody, buffer, stabilizer, optionally The ground also contains surfactants.
  • 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 pharmaceutically acceptable salts of the drugs described in this disclosure may be hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, acetate, oxalate, malonate, valerate Salt, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, methanesulfonate, isethionate, maleate .
  • the pharmaceutically acceptable salt of the compound of Formula I is selected from isethionates.
  • the isethionate of the compound of formula I is administered in combination with the PD-1 antibody or antigen-binding fragment thereof, thereby enhancing anti-lymphoma activity and improving lymphoma disease Treatment effect.
  • the lymphoma in the present disclosure is non-Hodgkin's lymphoma, preferably relapsed and/or refractory.
  • the recurrence refers to a patient who develops new lesions at the primary site or other sites after sufficient treatment to achieve complete or partial remission.
  • the refractory condition is any one of the following situations: the currently commonly used combination chemotherapy regimen in clinical use, the efficacy evaluation after 2 cycles is disease progression (PD), or the efficacy evaluation after 4 cycles Partial remission (PR) was not reached, or after 6 cycles, the efficacy evaluation was not completed (CR).
  • PD disease progression
  • PR Partial remission
  • the lymphoma patient described in this disclosure has received lymphoma treatment, and the tumor treatment is selected from one or more of chemotherapy, immunotherapy, surgery, or vaccines, preferably self-chemotherapy.
  • the patients with lymphoma described in the present disclosure receive at least 1 line therapy (excluding radiotherapy) after relapse.
  • the lymphoma patient has previously received combined chemotherapy with CHOP, R-CHOP, IMVP-I6, EPOCH, DHAP, or similar regimens.
  • CHOP regimen cyclophosphamide, 750 mg/m 2 , intravenous injection, first day; adriamycin, 50 mg/m 2 , intravenous injection, first day; vincristine, 1.4 mg/m 2 , intravenous injection, first Days; prednisone, 100 mg/m 2 , orally every day for the first to fifth days; the administration period is 21 days.
  • R-CHOP regimen Rituxan, 375 mg/m 2 , intravenous injection, first day * 6 cycles; cyclophosphamide, 750 mg/m 2 , intravenous injection, first day; doxorubicin, 50 mg/m 2 , intravenous injection, The first day; vincristine, 1.4 mg/m 2 , intravenously, the first day; prednisone, 100 mg/m 2 , daily oral, the first to fifth days; the administration period is 21 days.
  • E-CHOP regimen etoposide, 50 mg/m 2 , intravenous injection, day one to four days; vincristine, 1.4 mg/m 2 , intravenous injection, day one to four days; doxorubicin, 50 mg/ m 2 , intravenous injection, day one to four days; prednisone, 60 mg/m 2 , taken orally daily, day one to six days; cyclophosphamide, 750 mg/m 2 , intravenous injection, day six; administration 21 days cycle.
  • DHAP regimen cisplatin, 1000 mg/m 2 , intravenously, on the first day; cytarabine, 2 mg/m 2 , intravenously, twice a day; dexamethasone, 40 mg/d, oral or intravenous, first One day to four days; dosing cycle 21 days.
  • IMVP-I6 regimen ifosfamide, 1000 mg/m 2 , intravenous injection, day one to five days; mesna, 60% of the total amount of ifosfamide, intravenous injection 4h, 8h, day one to five Day, intravenous injection; methotrexate, 30 mg/m 2 , on days 3 and 10, etoposide, 100 mg/m 2 , intravenous injection, first day to three days; dosing cycle 21 days to 28 days .
  • the lymphoma patient has previously received L-asparaginase-based treatment.
  • the lymphoma patient has previously received a regimen containing rituximab or its analogs (single or combined chemotherapy drugs).
  • the combination optionally further includes other components, including but not limited to other drugs for treating lymphoma.
  • the present disclosure also provides a method for treating lymphoma, comprising: administering an effective dose of an anti-PD-1 antibody or antigen-binding fragment thereof and a compound represented by Formula I or a pharmaceutically acceptable salt thereof to a lymphoma patient.
  • the method of lymphoma according to the present disclosure includes administering 1 to 600 mg of an anti-PD-1 antibody or antigen-binding fragment thereof and 20 to 500 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient.
  • the method of lymphoma described in the present disclosure includes administering 200 mg of an anti-PD-1 antibody or antigen-binding fragment thereof to a patient once every 2 weeks and 150 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, one Once a day.
  • the method of lymphoma according to the present disclosure includes: before administering an anti-PD-1 antibody or antigen-binding fragment thereof in combination with a compound of Formula I or a pharmaceutically acceptable salt thereof, the patient is given Formula I
  • the indicated compound or its pharmaceutically acceptable salt induces a loading regimen, which refers to the monotherapy of the compound of formula I or its pharmaceutically acceptable salt administered at the initial stage of treatment.
  • the induction regimen period may be 1 week (or 7 days), 2 weeks (or 14 days), 3 weeks or longer, preferably 3 weeks (or 21 days); the compound of formula I Or a pharmaceutically acceptable salt thereof is administered in a human subject at a dosage selected from 50 mg, 100 mg, or 150 mg, and the frequency of administration is selected from once a day, once every two days, or once every three days.
  • the present disclosure also provides a method for reducing adverse reactions caused by an anti-PD-1 antibody or antigen-binding fragment thereof, a compound represented by Formula I, or a pharmaceutically acceptable salt thereof, including the simultaneous administration of an effective dose of anti-PD to patients with lymphoma -1 antibody or antigen-binding fragment thereof and a compound represented by formula I or a pharmaceutically acceptable salt thereof.
  • the present disclosure also provides a method for reducing the dose of a PD-1 antibody or antigen-binding fragment thereof, a compound represented by Formula I, or a pharmaceutically acceptable salt thereof, including simultaneous administration of an effective dose of anti-PD-1 to a lymphoma patient Antibodies or antigen-binding fragments thereof and compounds of formula I or pharmaceutically acceptable salts thereof.
  • Another aspect of the present disclosure also provides a pharmaceutical combination comprising a pharmaceutical composition containing the PD-1 antibody or antigen-binding fragment thereof and a pharmaceutical composition containing the compound represented by Formula I or a pharmaceutically acceptable salt thereof.
  • the PD-1 antibody or antigen-binding fragment thereof comprises a light chain as shown in SEQ ID NO: 8, and a heavy chain as shown in SEQ ID NO: 7.
  • the "humanized antibody” in the present disclosure also known as CDR-grafted antibody, refers to grafting the mouse CDR sequence into the framework of human antibody variable region, that is, different types Antibodies produced in the framework sequence of human germline antibodies. It can overcome the strong antibody variable antibody reaction induced by the chimeric antibody due to carrying a large amount of mouse protein components.
  • Such framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences.
  • the germline DNA sequences of human heavy and light chain variable region genes can be found in the "VBase" human germline sequence database (available on the Internet at www.mrccpe.com.ac.uk/vbase), as well as in Kabat, EA, etc. People, 1991 Sequences of Proteins of Immunological Interest, found in the 5th edition.
  • the CDR sequence of the PD-1 humanized antibody is selected from SEQ ID NO: 1, 2, 3, 4, 5, 6.
  • the "antigen-binding fragment” in the present disclosure refers to a Fab fragment having an antigen-binding activity, a Fab' fragment, an F(ab') 2 fragment, and an Fv fragment sFv fragment that binds to human PD-1; One or more CDR regions of the antibody selected from SEQ ID NO: 1 to SEQ ID NO: 6.
  • the Fv fragment contains the antibody heavy chain variable region and light chain variable region, but has no constant region, and has the smallest antibody fragment with all antigen binding sites.
  • Fv antibodies also contain a polypeptide linker between the VH and VL domains, and are capable of forming the structure required for antigen binding.
  • Different linkers can also be used to connect the variable regions of two antibodies into a single polypeptide chain, called single chain antibody (single chain antibody) or single chain Fv (sFv).
  • binding with PD-1 in this disclosure refers to being able to interact with human PD-1.
  • antigen binding site in the present disclosure refers to a discrete three-dimensional site on the antigen recognized by the antibody or antigen binding fragment in the present disclosure.
  • immunotherapy in this disclosure refers to the use of the immune system to treat diseases. In this disclosure, it mainly refers to the stimulation and enhancement of the body’s anti-tumor by increasing the immunogenicity of tumor cells and sensitivity to effector cell killing Immune response, and infusion of immune cells and effector molecules into the host body to cooperate with the body's immune system to kill tumors and inhibit tumor growth.
  • “Combination or combination” in this disclosure refers to a mode of administration, which means that at least one dose of the compound of formula I or a pharmaceutically acceptable salt thereof and at least one dose of PD-1 antibody or Antigen-binding 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, more preferably within 12 hours.
  • the compound represented by formula I or a pharmaceutically acceptable salt thereof and the PD-1 antibody or antigen-binding fragment can be administered simultaneously or sequentially. This period includes treatments in which the compound of formula I or a pharmaceutically acceptable salt thereof and the PD-1 antibody or antigen-binding fragment are administered by the same route of administration or different routes of administration.
  • the combined administration method of the present invention is selected from simultaneous administration, independently formulated and co-administered, or independently formulated and sequentially administered.
  • the "effective amount or effective dose” described in the present disclosure includes an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical condition.
  • An effective amount or effective dose also means an amount sufficient to allow or facilitate diagnosis.
  • the effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of the method of administration, and the severity of side effects.
  • the effective amount or effective dose may be the maximum dose or dosage regimen to avoid significant side effects or toxic effects.
  • treatment failure in the present disclosure means that the subject is accompanied by measurable tumor lesions at baseline, and is classified as disease progression (PD) or intolerable according to the RECIST 1.1 efficacy evaluation standard.
  • 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.
  • the tumor response assessment standard (RECIST 1.1 standard) was used to evaluate the 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 the RECIST 1.1 standard.
  • 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 isethionate of the compound represented by formula I in the present disclosure can be prepared according to the method described in WO2016124067, and other equipment or reagents used can be obtained commercially.
  • Relapse is defined as a patient who develops a new lesion at the primary site or elsewhere after sufficient treatment to achieve complete or partial remission. After relapse of B-cell lymphoma, at least receive ⁇ 1 line of treatment (excluding radiotherapy).
  • Refractory is defined as any of the following conditions: the currently commonly used combination chemotherapy in clinical use, the efficacy evaluation after 2 cycles is disease progression (PD), or the efficacy evaluation after 4 cycles does not reach partial response (PR), or After 6 cycles, the efficacy evaluation did not reach complete remission (CR)
  • T-NHL Previously received combined chemotherapy such as CHOP, EPOCH or similar regimens.
  • NKTL Previous treatment based on L-asparaginase.
  • B-NHL For CD20-positive B-NHL, it is necessary to receive treatment with rituximab or its analogs (single or combined chemotherapy drugs).
  • Drug A (PD-1, prepared according to the method in patent application WO2017054646A): dose 200 mg, intravenous injection, 30 min per infusion (not less than 20 min, not more than 60 min), once every 2 weeks, every 4 weeks 1 cycle;
  • Drug B (a isethionate tablet of the compound represented by formula I, prepared according to the method disclosed in WO2017133542): 125 mg/tablet or 150 mg, taken orally, once a day, once a time, continuously for 3 weeks Withdrawal for 1 week, 4 weeks as a cycle.

Abstract

一种CDK4/6抑制剂联合免疫治疗在制备治疗淋巴的药物中的用途，具体为I所示化合物或其可药用盐联合抗PD-1抗体或其抗原结合片段在制备治疗淋巴瘤的药物中的用途。该方法耐受性良好、毒性可控、抗肿瘤效果增强。

Description

CDK4/6抑制剂联合免疫治疗在制备治疗淋巴瘤的药物中的用途 技术领域
本公开中属于药学领域，涉及一种CDK4/6抑制剂联合免疫治疗在制备治疗淋巴瘤的药物中的用途。
背景技术
目前免疫治疗已成为难治性或者复发性肿瘤的一种新的治疗方法，其中以抗PD-l/PD-Ll单抗为代表的肿瘤免疫疗法代表了肿瘤治疗的研究方向。程序性细胞死亡蛋白-1(PD-1)的免疫检查点抑制受体主要在活化的T细胞中表达。PD-1信号级联负性调节T细胞受体激活的同时也减弱T细胞的增殖和功能，最终结果为T细胞耗竭。在肿瘤浸润的淋巴细胞中，PD-1表达明显上调。而当在肿瘤微环境中出现起刺激作用的细胞因子如IFN-α和IFN-γ时，肿瘤细胞及肿瘤相关的免疫细胞中PD-1配体(PD-L1)的表达也明显上升。这些数据为使用PD-1的拮抗剂作为癌症免疫治疗剂提供了基础。
最近在多个肿瘤类型中证明了阻断PD-1和PD-L1的相互作用这一治疗方法的有效性。PD-1的单克隆抗体，如nivolumab和pembrolizumab，具有与PD-1结合的能力，从而破坏PD-1蛋白质及其配体(PD-L1和PD-L2)之间的相互作用，并阻止T细胞微环境中的抑制信号。这些单克隆抗体现已被批准用于治疗多种癌症，包括膀胱、肺、头颈部鳞状细胞癌，并且在美国、欧洲及其它地区被批准用于治疗黑色素瘤。同时，使用抗PD-1单克隆抗体(mAb)实现PD-1阻断已证明对于复发/难治性经典霍奇金淋巴瘤是有效的，对非霍奇金淋巴瘤也显示一定的疗效，对于EBV阳性的NK/T淋巴瘤和纵隔B细胞淋巴瘤的获益率分别为44％和25％。在1期研究中用抗PD-1抗体治疗复发性T细胞淋巴瘤，也观察到临床缓解。既往研究显示，EBV感染可能增强肿瘤细胞中PD-L1的表达，一些EBV相关非霍奇金淋巴瘤如成熟T细胞和NK细胞淋巴瘤表达高水平的PD-L1，表明与EBV相关的成熟T细胞和NK细胞淋巴瘤可能更易受PD-1阻断。但很多非霍奇金淋巴瘤患者单用抗PD-l/PD-Ll单抗并未获得良好的疗效，因此仍需继续寻找使抗PD-l/PD-Ll单抗增效的联合药物。
张等人(Nature vol 553,pages 91–95)研究发现，PD-L1蛋白丰度受到细胞周 期蛋白D-CDK4激酶以及Cullin 3-SPOP E3连接酶的调节，调节过程属于经典的蛋白酶体介导降解途径。体内研究发现，CDK4/6抑制剂通过阻碍细胞周期蛋白D-CDK4介导speckle型POZ(SPOP)蛋白磷酸化，促进FZR1降解SPOP，增加PD-L1的表达。这篇文章奠定了PD-L1抗体联合CDK4/6抑制剂增强抗肿瘤的免疫治疗的理论基础。
已知CDK4/6抑制剂有abemaciclib、ribociclib或palbociclib，W02014183520提供了一种有效的CDK4/6抑制剂，其结构如式I所示，WO2016124067公开了CDK4/6抑制剂式I化合物的羟乙基磺酸盐，
Figure PCTCN2019124831-appb-000001
上述研究让科学家们对与新的CDK4/6抑制剂联用疗在治疗淋巴瘤，尤其是非霍奇金淋巴瘤的药物的用途产生了兴趣。
发明内容
本公开中提供一种式I所示化合物或其可药用盐联合抗PD-1抗体或其抗原结合片段在制备治疗金淋巴瘤的药物中的用途，
Figure PCTCN2019124831-appb-000002
在一些实施方案中，本公开中所述抗PD-1抗体或其抗原结合片段选自AMP-224、GLS-010、IBI-308、REGN-2810、PDR-001、BGB-A317、Pidilizumab、PF-06801591、Genolimzumab、CA-170、MEDI-0680、JS-001、TSR-042、Camrelizumab、 Pembrolizumab、LZM-009、AK-103和Nivolumab。
在另一些实施方案中，所述抗PD-1抗体或其抗原结合片段的轻链可变区包含分别如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示的LCDR1、LCDR2和LCDR3；重链可变区包含分别如SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3所示的HCDR1、HCDR2和HCDR3。
在一些实施方案中，所述PD-1抗体或其抗原结合片段的各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
在另一些实施方案中，所述抗PD-1抗体或其抗原结合片段选自人源化抗体或其片段。
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，本公开中所述抗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的轻链恒定区的轻链恒定区。
进一步地，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 PCTCN2019124831-appb-000003
轻链可变区
Figure PCTCN2019124831-appb-000004
在另一些可选实施方案中，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 PCTCN2019124831-appb-000005
轻链
Figure PCTCN2019124831-appb-000006
Figure PCTCN2019124831-appb-000007
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或10.0mg/kg。
在另一可选实施方案中，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1～600mg，可以为1.0mg、1.2mg、1.4mg、1.6mg、1.8mg、2.0mg、2.2mg、2.4mg、2.6mg、2.8mg、3.0mg、3.2mg、3.4mg、3.6mg、3.8mg、4.0mg、4.2mg、4.4mg、4.6mg、4.8mg、5.0mg、5.2mg、5.4mg、5.6mg、5.8mg、6.0mg、6.2mg、6.4mg、6.6mg、6.8mg、7.0mg、7.2mg、7.4mg、7.6mg、7.8mg、8.0mg、8.2mg、8.4mg、8.6mg、8.8mg、9.0mg、9.2mg、9.4mg、9.6mg、9.8mg、10.0mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、145mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、195mg、200mg、205mg、210mg、215mg、220mg、225mg、230mg、235mg、240mg、245mg、250mg、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。
本公开中所述抗PD-1抗体或其抗原结合片段的给药频次选自一周一次、二周一次、三周一次、四周一次或一月一次；所述式I所示化合物或其可药用盐给药频次为一日一次、一日二次、一日三次、二日一次、三日一次或一周一次，进一步地，所述式I所示化合物或其可药用盐连续给药三周停药1周。
在另一些实施方案中，所述抗PD-1抗体或其抗原结合片段联合所述式I所示化合物或其可药用盐每4周为1个周期。
本公开中所述式I所示化合物或其可药用盐与抗PD-1抗体或其抗原结合片段联合具有协同药效作用。
在可选实施方案中，本公开中所述式I所示化合物或其可药用盐在人类受试者中的施用剂量选自5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、125mg、150mg、175mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg、850mg、900mg、950mg、1000mg或任意两数值间任意值，优选100mg或150mg。
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选自1～600mg，所述式I所示化合物或其可药用盐在人类受试者中的施用剂量选自20～500mg。
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选自1～600mg、每1～4周一次，所述式I所示化合物或其可药用盐在人类受试者中的施用剂量选自20～500mg、一日一次。
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选自200mg、每2周一次，所述式I所示化合物或其可药用盐在人类受试者中的施用剂量选自150mg、一日一次。
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选自200mg、每2周一次、静脉注射，所述式I所示化合物或其可药用盐在人类受试者中的施用剂量选自150mg、一日一次、口服。
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选自200mg、每2周一次、静脉注射，所述式I所示化合物或其可药用盐在人类受试者中的施用剂量选自150mg、一日一次、口服、连续给药三周停药一次。
在另一些实施方案中，在抗PD-1抗体或其抗原结合片段联合式I所示化合物或其可药用盐给药之前，先给予患者以式I所示化合物或其可药用盐治疗的诱导方案(loading)，所述诱导方案是指治疗初始阶段给予式I所示化合物或其可药用盐单药治疗。
在一些实施方案中，所述诱导方案周期可以是1周(或7天)、2周(或14天)、3周或更长，优选3周(或21天)；式I所示化合物或其可药用盐在人类受试者中的施用剂量选自50mg、100mg或150mg，给药频次选自一日一次、二日一次或三日一次。
本公开中所述给药途径可以为经口给药、胃肠外给药、经皮给药，所述胃肠外给药包括但不限于静脉注射、皮下注射、肌肉注射。
在可选实施方案中，所述PD-1抗体或其抗原结合片段以注射的方式给药，例如皮下或静脉注射，注射前需将PD-1抗体或其抗原结合片段配制成可注射的形式。特别优选的PD-1抗体或其抗原结合片段的可注射形式是注射液或冻干粉针，例如PD-1抗体的可注射形式，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。
本公开中所述药物的可药用盐可以是盐酸盐、磷酸盐、磷酸氢盐、硫酸盐、硫酸氢盐、亚硫酸盐、乙酸盐、草酸盐、丙二酸盐、戊酸盐、谷氨酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、对甲苯磺酸盐、甲磺酸盐、羟乙基磺酸盐、马来酸盐。苹果酸盐、酒石酸盐、苯甲酸盐、双羟萘酸盐、水杨酸盐、香草酸盐、扁桃酸盐、琥珀酸盐、葡萄糖酸盐、乳糖酸盐或月桂基磺酸盐等。
在一些实施方案中，所述式I所示化合物的可药用盐选自羟乙基磺酸盐。
在一些实施方案中，所述式I所示化合物的羟乙基磺酸盐与所述PD-1抗体或其抗原结合片段联合给药，从而增强了抗淋巴瘤活性，以及改善了淋巴瘤疾病的治疗效果。
进一步地，本公开中所述淋巴瘤为非霍奇金淋巴瘤，优选复发性和/或难治性的。所述复发是指经充分治疗达完全或部分缓解后，在原发部位或其它部位出现 新病灶的患者。
在另一些实施方案中，所述难治性为以下任一种情况:当前临床上通常选择的联合化疗方案使用，2个周期后疗效评价为疾病进展(PD)，或4个周期后疗效评价未达部分缓解(PR)，或6个周期后疗效评价未达完全缓解(CR)。
在可选实施方案中，本公开中所述淋巴瘤患者曾接受过淋巴瘤治疗，所述肿瘤治疗选自化疗、免疫治疗、外科手术或疫苗中的一种或多种，优选自化疗。
在一些可选实施方案中，本公开中所述淋巴瘤患者为复发后至少接受≥1线方案的治疗(不包括放疗)。
在一些实施方案中，所述淋巴瘤患者既往接受CHOP、R-CHOP、IMVP-I6、EPOCH、DHAP或类似方案的联合化疗。
CHOP方案：环磷酰胺，750mg/m 2，静脉注射，第一天；阿霉素，50mg/m 2，静脉注射，第一天；长春新碱，1.4mg/m 2，静脉注射，第一天；***，100mg/m 2，每日口服，第一至五天；给药周期21天。
R-CHOP方案：美罗华，375mg/m 2，静脉注射，第一天*6周期；环磷酰胺，750mg/m 2，静脉注射，第一天；阿霉素，50mg/m 2，静脉注射，第一天；长春新碱，1.4mg/m 2，静脉注射，第一天；***，100mg/m 2，每日口服，第一至五天；给药周期21天。
E-CHOP方案：依托泊苷，50mg/m 2，静脉注射，第一天至四天；长春新碱，1.4mg/m 2，静脉注射，第一天至四天；阿霉素，50mg/m 2，静脉注射，第一天至四天；***，60mg/m 2，每日口服，第一至六天；环磷酰胺，750mg/m 2，静脉注射，第六天；给药周期21天。
DHAP方案：顺铂，1000mg/m 2，静脉注射，第一天；阿糖胞苷，2mg/m 2，静脉注射，一日二次；***，40mg/d，口服或静脉注射，第一天至四天；给药周期21天。
IMVP-I6方案：异环磷酰胺，1000mg/m 2，静脉注射，第一天至五天；美司钠，异环磷酰胺总量的60％，4h、8h静脉注射，第一天至五天，静脉注射；甲氨蝶呤，30mg/m 2，第三天和第10天，依托泊苷，100mg/m 2，静脉注射，第一天至三天；给药周期21天至28天。
在一些实施方案中，所述淋巴瘤患者既往接受以L-天冬酰胺酶为基础的治疗。
在另一些实施方案中，所述淋巴瘤患者既往接受含利妥昔单抗或其类似物的 方案治疗(单用或联合化疗药物)。
本公开中所述的方案，所述的联合任选的还包含其他组分，所述其他组分包括但不限于其他治疗淋巴瘤的药物等。
本公开中还提供了一种治疗淋巴瘤的方法，包括：向淋巴瘤患者施用有效剂量的抗PD-1抗体或其抗原结合片段和式I所示化合物或其可药用盐。
在一些实施方案中，本公开所述淋巴瘤的方法，包括向患者施用1～600mg抗PD-1抗体或其抗原结合片段和20～500mg式I所示化合物或其可药用盐。
在一些实施方案中，本公开所述淋巴瘤的方法，包括向患者施用200mg抗PD-1抗体或其抗原结合片段，每2周一次和150mg式I所示化合物或其可药用盐，一日一次。
在另一些实施方案中，本公开所述淋巴瘤的方法包括：在抗PD-1抗体或其抗原结合片段联合式I所示化合物或其可药用盐给药之前，先给予患者以式I所示化合物或其可药用盐诱导方案(loading)，所述诱导方案是指治疗初始阶段给予式I所示化合物或其可药用盐单药治疗。
在另一些实施方案中，所述诱导方案周期可以是1周(或7天)、2周(或14天)、3周或更长，优选3周(或21天)；式I所示化合物或其可药用盐在人类受试者中的施用剂量选自50mg、100mg或150mg，给药频次选自一日一次、二日一次或三日一次。
本公开还提供了一种降低抗PD-1抗体或其抗原结合片段、式I所示化合物或其可药用盐所导致的不良反应的方法，包括同步向淋巴瘤患者施用有效剂量的抗PD-1抗体或其抗原结合片段和式I所示化合物或其可药用盐。
本公开中还提供了一种减少PD-1抗体或其抗原结合片段、式I所示化合物或其可药用盐单独施用剂量的方法，包括同步向淋巴瘤患者施用有效剂量的抗PD-1抗体或其抗原结合片段和式I所示化合物或其可药用盐。
本公开另一方面还提供了一种药物组合，包含含有所述PD-1抗体或其抗原结合片段的药物组合物与含有式I所示化合物或其可药用盐的药物组合物。
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:8所示的轻链，和如SEQ ID NO:7所示的重链。
如无相反解释，本公开中中术语具有如下含义：
本公开中所述“人源化抗体(humanized antibody)”，也称为CDR移植抗体 (CDR-grafted antibody)，是指将小鼠的CDR序列移植到人的抗体可变区框架，即不同类型的人种系抗体构架序列中产生的抗体。可以克服嵌合抗体由于携带大量小鼠蛋白成分，从而诱导的强烈的抗体可变抗体反应。此类构架序列可以从包括种系抗体基因序列的公共DNA数据库或公开的参考文献获得。如人重链和轻链可变区基因的种系DNA序列可以在“VBase”人种系序列数据库(在因特网www.mrccpe.com.ac.uk/vbase可获得)，以及在Kabat，E.A.等人，1991Sequences of Proteins of Immunological Interest，第5版中找到。在本公开中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。
本公开中所述“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；包含本公开中所述抗体的选自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)。本公开中的术语“与PD-1结合”，指能与人PD-1相互作用。本公开中的术语“抗原结合位点”指抗原上不连续的，由本公开中抗体或抗原结合片段识别的三维空间位点。
本公开中所述“免疫疗法”指免疫疗法是利用免疫***来治疗疾病，在本公开中中主要指通过提高肿瘤细胞的免疫原性和对效应细胞杀伤的敏感性，激发和增强机体抗肿瘤免疫应答，并应用免疫细胞和效应分子输注宿主体内，协同机体免疫***杀伤肿瘤、抑制肿瘤生长。
本公开中“联合或联用”是一种给药方式，是指一定时间期限内给予至少一种剂量的式I所示化合物或其可药用盐和至少一种剂量的PD-1抗体或抗原结合片段，其中两种药物都显示药理学作用。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式I所示化合物或其可药用盐以及PD-1抗体或抗原结合片段。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式I所示化合物或其可药用盐以及PD-1抗体或抗原结合片段。本发明所述联合的给药方式选自同时给药、独立地配制并共给药或独立地配制并相继给药。
本公开中所述“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。有效量或有效剂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。有效量或有效剂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。
本公开中所述“治疗失败”是指受试者在基线时伴有可测量的肿瘤病灶，根据RECIST 1.1疗效评定标准为疾病进展(PD)或不能耐受的。
本公开中所述“不能耐受的”是指因药物引起的不良反应不能继续接受治疗。
总生存期(OS)指从随机期至任何原因导致死亡的期。末次随访时仍存活的受试者，其OS以末次随访时间计为数据删失。失访的受试者，其OS以失访前末次证实存活时间计为数据删失。数据删失的OS定义为从随机分组到删失的时间。
客观缓解率(Objective response rate，ORR)指肿瘤缩小达到一定并且保持一定时间的病人的比例，包含了CR和PR的病例。采用肿瘤缓解评估标准(RECIST1.1标准)来评定肿瘤客观缓解。受试者在基线时必须伴有可测量的肿瘤病灶，疗效评定标准根据RECIST 1.1标准分为完全缓解(CR)、部分缓解(PR)、稳定(SD)、进展(PD)。
疾病控制率(Disease Control Rate，DCR)指经确认的完全缓解、部分缓解和疾病稳定(≥8周)病例数在可评价疗效患者中的百分比。
完全缓解(CR)：所有靶病灶消失，全部病理***(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。
本公开中式I所示化合物的羟乙基磺酸盐可按照WO2016124067所述方法制备，其他所用到设备或试剂均可通过商业途径获得。
具体实施方式
以下结合实施例用于进一步描述本公开，但这些实施例并非限制本公开的范围。
实施例1：
入组标准：
1)经组织病理确诊的复发性成熟T细胞和NK细胞或B细胞淋巴瘤。复发定义为经充分治疗达完全或部分缓解后，在原发部位或其它部位出现新病灶的患者。对B细胞淋巴瘤复发后至少接受≥1线方案的治疗(不包括放疗)。难治定义为以下任一种情况:当前临床上通常选择的联合化疗方案使用，2个周期后疗效评价为疾病进展(PD)，或4个周期后疗效评价未达部分缓解(PR)，或6个周期后疗效评价未达完全缓解(CR)
T-NHL:既往接受如CHOP、EPOCH或类似方案的联合化疗。
NKTL:既往接受以L-天冬酰胺酶为基础的治疗。
B-NHL:对于CD20阳性B-NHL既往需接受含利妥昔单抗或其类似物的方案治疗(单用或联合化疗药物)。
2)具有至少一个二维可测量病灶作为评估依据：对于结内病灶，定义为：长径≥1.5cm且短径≥1.0cm；对于结外病灶，长径应≥1.0cm。
给药方案：
药物A(PD-1，按照专利申请WO2017054646A中的方法制备)：剂量200mg，静脉注射，每次输注30min(不少于20min，不超过60min)，2周给药1次，每4周为1个周期；
药物B(式I所示化合物的羟乙基磺酸盐片剂，按照WO2017133542公开的方法制备)：125mg/片或150mg，口服，每日1次，每次1次，连续服药，服药3周停药1周，4周为1个周期。
结论：在药物A 200mg、药物B 150mg的组别的4例可评价受试者中，4例受试者表现均表现为疾病稳定(SD)，疾病控制率(Disease Control Rate，DCR)为100％。

Claims (13)

  1. 式I所示化合物或其可药用盐联合抗PD-1抗体或其抗原结合片段在制备治疗淋巴瘤的药物中的用途，优选所述式I所示化合物的可药用盐选自羟乙基磺酸盐，
    Figure PCTCN2019124831-appb-100001
  2. 权利要求1所述的用途，其中所述抗PD-1抗体或其抗原结合片段选自AMP-224、GLS-010、IBI-308、REGN-2810、PDR-001、BGB-A317、Pidilizumab、PF-06801591、Genolimzumab、CA-170、MEDI-0680、JS-001、TSR-042、Camrelizumab、Pembrolizumab、LZM-009、AK-103和Nivolumab。
  3. 权利要求1所述的用途，其中所述抗PD-1抗体或其抗原结合片段的轻链可变区包含分别如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示的LCDR1、LCDR2和LCDR3所述的PD-1抗体的重链可变区包含分别如SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3所示的HCDR1、HCDR2和HCDR3。
  4. 如权利要求3所述的用途，其中所述抗PD-1抗体或其抗原结合片段选自人源化抗体或其片段。
  5. 如权利要求3或4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IgG4同种型的重链恒定区。
  6. 权利要求4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。
  7. 权利要求4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。
  8. 权利要求1-7任一项所述的用途，其中所述淋巴瘤为非霍奇金淋巴瘤，优选复发性和/或难治性的。
  9. 权利要求1-8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在人类受试者中的施用剂量选自0.1～10.0mg/kg。
  10. 根据权利要求1-9任一项所述的用途，其中所述式I所示化合物或其可药用盐在人类受试者中的施用剂量选自1～1000mg，优选100mg或150mg。
  11. 权利要求1-10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在人类受试者中的施用剂量为1～600mg，优选200mg。
  12. 权利要求1-11任一项所述的用途，其中在抗PD-1抗体或其抗原结合片段联合式I所示化合物或其可药用盐给药之前，先给予式I所示化合物或其可药用盐治疗的诱导方案(loading)，所述诱导方案优选治疗初始阶段给予式I所示化合物或其可药用盐单药治疗，更优选从第零天开始每天或每2天或每3天向所述患者使用50mg、100mg或150mg剂量的所述式I所示化合物或其可药用盐
  13. 一种治疗淋巴瘤的方法，包括：向淋巴瘤患者施用有效剂量的抗PD-1抗体或其抗原结合片段和式I所示化合物或其可药用盐，
    Figure PCTCN2019124831-appb-100002
PCT/CN2019/124831 2018-12-13 2019-12-12 Cdk4/6抑制剂联合免疫治疗在制备治疗淋巴瘤的药物中的用途 WO2020119757A1 (zh)

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