WO2021018191A1 - Il-17拮抗剂治疗自身免疫疾病的方法 - Google Patents

Il-17拮抗剂治疗自身免疫疾病的方法 Download PDF

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WO2021018191A1
WO2021018191A1 PCT/CN2020/105510 CN2020105510W WO2021018191A1 WO 2021018191 A1 WO2021018191 A1 WO 2021018191A1 CN 2020105510 W CN2020105510 W CN 2020105510W WO 2021018191 A1 WO2021018191 A1 WO 2021018191A1
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patient
weeks
antibody
conjugate
once
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PCT/CN2020/105510
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English (en)
French (fr)
Inventor
孙飘扬
张连山
陈建文
许倩
高群杰
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN202080051903.6A priority Critical patent/CN114127108A/zh
Priority to EP20845895.0A priority patent/EP4006053A4/en
Priority to US17/631,289 priority patent/US20220267432A1/en
Publication of WO2021018191A1 publication Critical patent/WO2021018191A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • the present disclosure relates to a method for treating inflammation or autoimmune system diseases.
  • the cytokines of the interleukin-17 family are named as interleukin-17A to interleukin-17F. These interleukin-17 cytokines can bind to corresponding receptor members to mediate different inflammatory responses.
  • interleukin-17A The lymphocytes that migrate to the infected or injured part of the body secrete interleukin-17A.
  • interleukin-17A induces the expression of inflammatory factors and chemokines, thereby recruiting more immune cells to reach the inflammatory site to aggravate the inflammatory response; on the other hand, interleukin-17A also induces the expression of some tissue repair-related factors to accelerate Recovery of the body.
  • interleukin-17A plays a role in expanding the immune defense response and protecting the body during the host's anti-infection and tissue repair process, in many autoimmune disease patients and tumor patients, interleukin-17A is highly expressed and excessively high interleukin- The level of 17A has a worsening effect on pathological development, because it can induce the expression of many inflammatory factors. Many animal experiments have also proved that the absence of interleukin-17A or the neutralization of interleukin-17A by antibodies can effectively inhibit the pathological degree of a variety of autoimmune diseases.
  • IL-17 signaling is used as a target to treat autoimmune diseases, including rheumatoid arthritis (RA), psoriasis, axial spondyloarthritis, Crohn’s disease, multiple sclerosis (MS), Psoriasis diseases, asthma and lupus erythematosus all have certain curative effects (see, for example, Aggarwal et al., J. Leukoc. Biol., 71(1):1-8 (2002); Lubberts et al.).
  • RA rheumatoid arthritis
  • MS multiple sclerosis
  • Anti-IL-17 drugs that have been developed and marketed, especially humanized monoclonal antibodies against IL-17 are: Ixekizumab (Eli Lilly), Secukinumab (Novartis) and Brodalumab (SILIQ TM ). Secukinumab It has been approved by the US Food and Drug Administration (FDA), European Medicines Agency (EMA), Japan and Brazil for use in adult plaque psoriasis, ankylosing spondylitis and psoriatic arthritis. Ixekizumab Approved by FDA/EMA for the treatment of moderate to severe adult plaque psoriasis.
  • FDA US Food and Drug Administration
  • EMA European Medicines Agency
  • Ixekizumab Approved by FDA/EMA for the treatment of moderate to severe adult plaque psoriasis.
  • IL-17 receptor monoclonal antibody developed and approved by AstraZeneca/Valeant for patients with moderate to severe plaque psoriasis, and then the current IL-17 drug treatment regimen generally contains induction therapy Scheme (loading).
  • the disclosure provides a method for the treatment of inflammation or autoimmune system diseases.
  • the method includes administering an effective amount of IL-17A conjugate to a patient at a frequency of less than once a week.
  • the IL-17A conjugate comprises one or more CDR region sequences selected from the following or amino acid sequences having at least 95% sequence identity therewith:
  • sequence of the HCDR region of the antibody heavy chain variable region as shown in SEQ ID NO: 7, 8 and 9 amino acid sequences; and the sequence of the LCDR region of the antibody light chain variable region: as shown in SEQ ID NO: 10, 11, and 12 amino acid sequences .
  • the CDR sequences in the IL-17A antibody light and heavy chains are shown in the following table:
  • the IL-17A antibody or antigen-binding fragment thereof is selected from a murine antibody, a chimeric antibody, a recombinant antibody of a humanized antibody, or an antigen-binding fragment thereof.
  • the light chain and heavy chain FR region sequences on the light chain and heavy chain variable regions of the humanized antibody are respectively derived from human germline light chain and heavy chain or their mutant sequences.
  • the IL-17A antibody contains the heavy chain variable region shown in SEQ ID NO: 3 or a variant thereof, and the variant is preferably the heavy chain variable region shown in SEQ ID NO: 3
  • the region sequence has 0-10 amino acid changes, more preferably A93T and T71A amino acid back mutations;
  • the IL-17A antibody antibody contains the light chain variable region shown in SEQ ID NO: 4 or a variant thereof,
  • the variant preferably has a sequence of 0-10 amino acid changes in the light chain variable region shown in SEQ ID NO: 4, more preferably F71Y, K49Y, Y36F and L47W amino acid back mutations.
  • heavy chain variable region or light chain variable region of the aforementioned IL-17A antibody sequence is as follows:
  • Immunoglobulins can be derived from any commonly known isotype, including but not limited to IgA, secreted IgA, IgG, and IgM.
  • the IgG subclass is also well known to those skilled in the art, including but not limited to IgG1, IgG2, IgG3 and IgG4.
  • "Isotype" refers to the Ab class or subclass (for example, IgM or IgG1) encoded by the heavy chain constant region gene.
  • the IL-17A antibody described in the present disclosure comprises a heavy chain constant region of human IgG1, IgG2, IgG3 or IgG4 isotype, preferably a heavy chain constant region of IgG1 isotype.
  • the anti-IL-17A antibody or antigen-binding fragment thereof comprises a light chain constant region of kappa or lambda.
  • the light chain sequence of the humanized antibody is the sequence shown in SEQ ID NO: 13
  • the heavy chain sequence is the sequence shown in SEQ ID NO: 14
  • the IL-17A antibody of the present disclosure has the characteristics of high affinity, rapid onset of action, and low toxicity. Therefore, low-dose IL-17A can be used at low frequency to treat inflammation or autoimmune system diseases.
  • the dose of the IL-17A conjugate of the present disclosure is 40-300 mg, and in the embodiment may be 40 mg, 60 mg, 65 mg, 70 mg, 75 mg , 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,
  • the method for treating inflammation or autoimmune system diseases includes an induction program, which is that the IL-17A antibody can be treated at a low dose or at a high dose, when the patient responds or partially responds. , And then maintenance treatment.
  • Novartis's Secukinumab treatment regimen for moderate to severe plaque psoriasis is: subcutaneous injection of 150 mg 5 times a week (0, 1, 2, 3, and 4 weeks), followed by subcutaneous injection of 150 mg of Secukinumab every 4 weeks for maintenance treatment.
  • Eli Lilly’s Ixekizumab regimen for the treatment of moderate to severe plaque psoriasis is: the first dose of 160 mg, followed by subcutaneous injection of 80 mg every 2 weeks for 5 times, and then 80 mg every 4 weeks for maintenance treatment.
  • the overall dosing regimen is complicated, and the intangible treatment burden has been added to the patients, and the patients have low treatment compliance.
  • the treatment scheme described in the present disclosure does not include an induction scheme, the treatment scheme is simple, and the probability of missed administration is low. At the same time, the treatment scheme without an induction scheme effectively reduces the treatment burden of the patient and improves the treatment compliance of the patient.
  • Some embodiments provide methods for treating inflammation or autoimmune system diseases, and do not include loading.
  • the loading regimen refers to the administration of IL-17A antibody at high dosing frequency (relative to the dosing frequency of maintenance therapy) at the initial stage of treatment to treat inflammation or autoimmune system diseases.
  • the high dosing frequency can be administered once a week from the zeroth week, or once every two weeks from the zeroth week, or once every three weeks from the zeroth week, or from the zeroth week Administer once every 4 weeks at the beginning, or once every 6 weeks from the zeroth week, or once every 8 weeks from the zeroth week, or a longer period of administration frequency.
  • the number of administrations in the induction scheme described in the present disclosure is at least one or more times, including but not limited to one time, two times, three times, four times, five times or more.
  • the frequency of administration in the induction protocol is once a week starting from week zero, and the number of administrations is 3 times.
  • the frequency of administration in the induction regimen is once a week starting from week zero, and the number of administrations is 4 times.
  • the frequency of administration in the induction protocol is once a week starting from week zero, and the number of administrations is 5 times.
  • the frequency of administration in the induction protocol is once every two weeks starting from week zero, and the number of administrations is 3 times.
  • the frequency of administration in the induction regimen is once every 2 weeks starting from week zero, and the number of administrations is 4 times.
  • the frequency of administration in the induction regimen is once every 2 weeks starting from week zero, and the number of administrations is 5 times.
  • the frequency of administration in the induction program is once every 3 weeks starting from week zero, and the number of administrations is 3 times.
  • the frequency of administration in the induction protocol is once every 3 weeks starting from week zero, and the number of administrations is 4 times.
  • the frequency of administration in the induction regimen is once every 3 weeks starting from week zero, and the number of administrations is 5 times.
  • the frequency of administration in the induction protocol is once every 4 weeks starting from week zero, and the number of administrations is 3 times.
  • the frequency of administration in the induction program is once every 4 weeks starting from week zero, and the number of administrations is 4 times.
  • the frequency of administration in the induction protocol is once every 4 weeks starting from week zero, and the number of administrations is 5 times.
  • the unit "month” and "week” of the dosing cycle of the present disclosure can be appropriately converted in some cases, usually 4 weeks is about 1 month.
  • the method of treating inflammation or autoimmune system disease does not include an induction program, and the induction program includes, for example, every week (such as 0/1/2/3 weeks or 0/1 /2/3/4/5 weeks administration) to the patient using the aforementioned IL-17A conjugate at a dose of 40-300 mg (such as 80 mg, 120 mg, 160 mg, 200 mg or 240 mg).
  • the method of treating inflammation or autoimmune system disease does not include an induction regimen
  • the induction regimen includes, for example, every 2 weeks (such as 0/2 week or 0/2/4 week administration) starting from week zero
  • the aforementioned IL-17A conjugate is administered to the patient at a dose of 40-300 mg (such as 80 mg, 120 mg, 160 mg, 200 mg or 240 mg).
  • the method of treating inflammation or autoimmune system disease does not include an induction regimen
  • the induction regimen includes, for example, every 3 weeks (such as 0/3 week or 0/3/6 week administration) starting from week zero
  • the aforementioned IL-17A conjugate is administered to the patient at a dose of 40-300 mg (such as 80 mg, 120 mg, 160 mg, 200 mg or 240 mg).
  • the method of treating inflammation or autoimmune system disease does not include an induction regimen
  • the induction regimen includes, for example, every 4 weeks (such as 0/4 week or 0/4/8 week administration) starting from week zero
  • the aforementioned IL-17A conjugate is administered to the patient at a dose of 40-300 mg (such as 80 mg, 120 mg, 160 mg, 200 mg or 240 mg).
  • the method of treating inflammation or autoimmune system disease includes administering to the patient a dose of 40-300 mg (eg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg) of the IL-17A conjugate, and administering
  • the frequency of medication is once every three weeks.
  • the method for treating inflammation or autoimmune system disease includes administering to the patient a dose of 40-300 mg (eg, 80 mg, 120 mg, 160 mg, 200 mg or 240 mg) of the IL-17A conjugate, administered once every four weeks .
  • the method for treating inflammation or autoimmune system diseases includes administering to the patient a dose of 40-300 mg (such as 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg) of the IL-17A conjugate at a frequency of five weeks. once.
  • the method for treating inflammation or autoimmune system disease includes administering to the patient a dose of 40-300 mg (such as 80 mg, 120 mg, 160 mg, 200 mg or 240 mg) of the IL-17A conjugate at a frequency of six weeks. once.
  • the method for treating inflammation or autoimmune system disease includes administering to the patient a dose of 40-300 mg (such as 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg) of the IL-17A conjugate at a frequency of seven weeks. once.
  • the method for treating inflammation or autoimmune system disease includes administering to the patient a dose of 40-300 mg (such as 80 mg, 120 mg, 160 mg, 200 mg or 240 mg) of the IL-17A conjugate at a frequency of eight weeks. once.
  • the method for treating inflammation or autoimmune system diseases includes administering to the patient a dose of 40-300 mg (such as 80 mg, 120 mg, 160 mg, 200 mg or 240 mg) of the IL-17A conjugate at a frequency of ten weeks. once.
  • the method for treating inflammation or autoimmune system disease comprises administering to the patient a dose of 40-300 mg (such as 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg) of the IL-17A conjugate at a frequency of 12 Once a week.
  • Embodiments of the present disclosure provide a method for treating inflammation or autoimmune system diseases, including: before administering a 40-300 mg dose of IL-17A conjugate to the patient, the aforementioned patient is not treated with an induction regimen (loading).
  • the frequency of medicine can be given once a week starting from week zero, or once every 2 weeks starting from week zero, or once every 3 weeks starting from week zero, or every 4 weeks starting from week zero Dosing once, or once every 6 weeks from the zeroth week, or once every 8 weeks from the zeroth week, or the frequency of administration for a longer period; the number of administrations is at least once, including but not Limited to 1 time, 2 times, 3 times, 4 times, 5 times or more.
  • the method for treating inflammation or autoimmune system diseases described in the present disclosure includes: before administering the IL-17A conjugate at a dose of 40-300 mg to the patient, the aforementioned patient is not treated with a loading regimen.
  • a loading regimen such as including the use of 40-300mg (such as 20mg, 60mg, 80mg) to the patient every week (such as 0/1/2/3 weeks or 0/1/2/3/4/5 weeks administration) starting from week zero , 120mg, 160mg, 200mg or 240mg) of the aforementioned IL-17A conjugate.
  • the method for treating inflammation or autoimmune system diseases includes: before administering a 40-300 mg dose of IL-17A conjugate to the patient, the aforementioned patient is not treated with an induction regimen (loading), and the induction regimen includes Use 40-300 mg (e.g. 20 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg or 240 mg) of the aforementioned IL to the patient every 2 weeks (e.g. 0/2 week or 0/2/4 week administration) starting from week zero -17A conjugate.
  • an induction regimen includes Use 40-300 mg (e.g. 20 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg or 240 mg) of the aforementioned IL to the patient every 2 weeks (e.g. 0/2 week or 0/2/4 week administration) starting from week zero -17A conjugate.
  • the method for treating inflammation or autoimmune system diseases includes: before administering a 40-300 mg dose of IL-17A conjugate to the patient, the aforementioned patient is not treated with an induction regimen (loading), and the induction regimen includes Use 40-300 mg (e.g., 20 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg or 240 mg) of the aforementioned IL to the patient every 3 weeks (e.g. 0/3 week or 0/3/6 week administration) starting from week zero -17A conjugate.
  • an induction regimen includes Use 40-300 mg (e.g., 20 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg or 240 mg) of the aforementioned IL to the patient every 3 weeks (e.g. 0/3 week or 0/3/6 week administration) starting from week zero -17A conjugate.
  • the method for treating inflammation or autoimmune system diseases includes: before administering a 40-300 mg dose of IL-17A conjugate to the patient, the aforementioned patient is not treated with an induction regimen (loading), and the induction regimen includes Use 40-300 mg (e.g., 20 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg or 240 mg) of the aforementioned IL to the patient every 4 weeks (e.g. 0/4 week or 0/4/8 week administration) starting from week zero -17A conjugate.
  • the patient in the method for treating inflammation or autoimmune system diseases described in the present disclosure has moderate to severe active ankylosing spondylitis.
  • the patient has been previously treated with at least one nonsteroidal anti-inflammatory drug (NSAID) (such as aspirin, ibuprofen, acetaminophen, indomethacin, naproxen, naproxen, diclofenac, Nimesulide, rofecoxib, or celecoxib) treatment with insufficient response.
  • NSAID nonsteroidal anti-inflammatory drug
  • the treatment method described in the present disclosure includes: after administering a 40-300 mg dose of IL-17A conjugate to a patient suffering from moderate to severe active ankylosing spondylitis, the patient further administers NSAID , Methotrexate, sulfasalazine or prednisolone.
  • the patient in the method for treating inflammation or autoimmune system diseases described in the present disclosure, has active psoriatic arthritis, preferably the patient has coexisting psoriasis.
  • the patient has failed TNFi or methotrexate (DMARD) failure.
  • DMARD methotrexate
  • the treatment method described in the present disclosure includes: after administering a dose of 40-300 mg of IL-17A conjugate to a patient with active psoriatic arthritis, the patient further administers methotrexate .
  • the patient has plaque psoriasis, preferably the patient has moderate to severe plaque psoriasis.
  • the treatment methods described in the present disclosure include: before administering a dose of 40-300 mg of IL-17A conjugate to a patient suffering from plaque psoriasis, the patient has not previously used systemic psoriasis. Therapeutic treatment.
  • the treatment method described in the present disclosure includes: before administering a dose of 40-300 mg of IL-17A conjugate to a patient suffering from plaque psoriasis, the patient has previously been treated with systemic psoriasis. Therapeutic treatment.
  • the systemic treatment described in the present disclosure is selected from methotrexate, cyclosporine, fumarate, acitretin, Alefacept, adalimumab, efalizumab, etanercept, infliximab , Golimumab and Ustekinumab, preferably methotrexate.
  • the present disclosure provides the use of IL-17A antibodies in the preparation of drugs for the treatment of inflammation or autoimmune system diseases, wherein the drugs are formulated for storage in a container to allow the administration of an effective amount of IL-17A to patients with inflammation or autoimmune system diseases .
  • the present disclosure also provides a method for the treatment of inflammation or autoimmune system diseases, which comprises administering an effective amount of IL-17A conjugate to a patient at a frequency of 5-8 weeks once (such as once every five weeks, once every six weeks, Once every seven weeks or once every eight weeks).
  • the treatment method with a frequency of 5-8 weeks in the present disclosure may or may not include an induction regimen (loading).
  • the treatment method with a frequency of administration of 5-8 weeks in the present disclosure includes an induction regimen (loading), and the induction regimen includes, for example, every 1 week (such as 0/1/2) starting from week zero. /3 weeks or 0/1/2/3/4/5 weeks administration), every 2 weeks (such as 0/2 weeks or 0/2/4 weeks administration), every 3 weeks or every 4 weeks as described
  • the patient uses the aforementioned IL-17A conjugate at a dose of 40-300 mg (such as 80 mg, 120 mg, 160 mg, 200 mg or 240 mg).
  • the duration of the induction program may be 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, and 15 weeks.
  • the treatment of inflammation or autoimmune system disease is selected from inflammation or autoimmune disease; the disease is preferably psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, inflammatory arthritis.
  • the treatment period of the treatment method described in the present disclosure is 20 weeks.
  • the route of administration described in the present disclosure may be oral, parenteral, or transdermal administration.
  • the parenteral administration includes but is not limited to intravenous injection, subcutaneous injection, intramuscular injection, and preferably subcutaneous injection.
  • the IL-17A antibody is administered by injection, such as subcutaneous or intravenous injection, and the IL-17A antibody needs to be formulated into an injectable form before injection.
  • the injectable form of IL-17A antibody is an injection or a lyophilized powder injection, which contains IL-17A antibody, a buffer, a stabilizer, and optionally a surfactant.
  • the buffer is a histidine-hydrochloride system; the stabilizer can be selected from sugars or amino acids, preferably disaccharides, such as sucrose, lactose, trehalose, and 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 IL-17A antibody comprises IL-17A antibody, histidine hydrochloride buffer, sucrose and polysorbate 80.
  • conjugate refers to a soluble receptor or a fragment or analog thereof, or an antibody or a fragment or analog thereof capable of binding to a target.
  • IL-17A conjugate described in the present disclosure refers to an antibody or a fragment or analog thereof that can specifically recognize IL-17A and bind to IL-17A.
  • IL-17A generally refers to natural or recombinant human IL-17A, and non-human homologs of human IL-17A. Unless otherwise indicated, the molar concentration of IL-17A is calculated using the molecular weight of the homodimer of IL-17A (for example, 30 KDa for human IL-17A).
  • immunoglobulin which is a tetrapeptide chain structure formed by two identical heavy chains and two identical light chains connected by interchain disulfide bonds.
  • the amino acid composition and sequence of the constant region of immunoglobulin heavy chains are different, so their antigenicity is also different.
  • immunoglobulins can be divided into five categories, or isotypes of immunoglobulins, namely IgM, IgD, IgG, IgA and IgE.
  • the same type of Ig can be divided into different subclasses according to the difference in the amino acid composition of the hinge region and the number and position of heavy chain disulfide bonds.
  • IgG can be divided into IgG1, IgG2, IgG3, and IgG4.
  • the light chain is divided into ⁇ or ⁇ chain by the difference of the constant region.
  • variable region The sequence of about 110 amino acids near the N-terminus of the antibody heavy and light chains varies greatly and is the variable region (V region); the remaining amino acid sequences near the C-terminus are relatively stable and are the constant region (C region).
  • the variable region includes 3 hypervariable regions (HVR) and 4 framework regions (FR) with relatively conservative sequences. Three hypervariable regions determine the specificity of the antibody, also known as complementarity determining regions (CDR).
  • CDR complementarity determining regions
  • Each light chain variable region (VL) and heavy chain variable region (VH) consists of 3 CDR regions and 4 FR regions.
  • the sequence from the amino terminal to the carboxy terminal is: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the 3 CDR regions of the light chain refer to LCDR1, LCDR2, and LCDR3; the 3 CDR regions of the heavy chain refer to HCDR1, HCDR2 and HCDR3.
  • the "antigen-binding fragment” in the present disclosure refers to Fab fragments, Fab' fragments, F(ab')2 fragments, or single Fv fragments that have antigen-binding activity.
  • Fv antibody is the smallest antibody fragment that 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 all the antigen binding sites.
  • Fv antibodies also include a polypeptide linker between the VH and VL domains, and can form the structure required for antigen binding.
  • the "humanized antibody” in this disclosure also called CDR-grafted antibody, refers to the transplantation of mouse CDR sequences into the human antibody variable region framework, that is, different types Of human germline antibody framework sequences. It can overcome the strong variable antibody response induced by the chimeric antibody due to the 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 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), and in Kabat, EA, etc. People, 1991 Sequences of Proteins of Immunological Interest, found in the 5th edition.
  • the "murine antibody” in the present disclosure is a monoclonal antibody to human TIM-3 prepared according to the knowledge and skills in the art. During preparation, the test subject is injected with TIM-3 antigen, and then hybridomas expressing antibodies with the desired sequence or functional properties are isolated.
  • the murine TIM-3 antibody or antigen-binding fragment thereof may further comprise the light chain constant region of murine kappa, lambda chain or a variant thereof, or further comprise murine IgG1 , IgG2, IgG3 or its variant heavy chain constant region.
  • the "chimeric antibody” mentioned in this disclosure is an antibody formed by fusing the variable region of a murine antibody with the constant region of a human antibody, which can reduce the immune response induced by the murine antibody.
  • To establish a chimeric antibody it is necessary to first establish a hybridoma secreting murine-derived specific monoclonal antibodies, and then clone the variable region genes from the mouse hybridoma cells, and then clone the constant region genes of the human antibody as needed. It is connected with the human constant region gene to form a chimeric gene and inserted into an expression vector, and finally the chimeric antibody molecule is expressed in a eukaryotic system or a prokaryotic system.
  • the heavy chain or light chain variable region sequence of the IL-17A antibody sequence described in the present disclosure is analyzed by Molecular Operating Environment (MOE, Molecular Operating Environment) database software and translated into an amino acid sequence.
  • MOE Molecular Operating Environment
  • the heavy chain or light chain variable region sequence of the IL-17A antibody sequence can also be analyzed by database software such as IMGT/DomainGapAlign and translated into amino acid sequence (see J. Methods Mol Biol, 2012, 882, 605 -633).
  • database software such as MOE or IMGT to provide antibody sequences or structures, it is necessary to note that different databases have different encoding methods or interpretations for the same antibody sequence.
  • 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 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 general health, the method of administration and dosage, and the severity of side effects.
  • the effective amount or effective dose may be the maximum dose or dosing schedule that avoids significant side effects or toxic effects.
  • Treatment means administering an internal or external therapeutic agent, such as a composition comprising any combination of the present disclosure, to a patient who has one or more disease symptoms, and the therapeutic agent is known to have Therapeutic effect.
  • the therapeutic agent is administered in the patient or population to be treated in an amount effective to alleviate one or more disease symptoms, whether by inducing the regression of such symptoms or inhibiting the development of such symptoms to any clinically measured extent.
  • the amount of the therapeutic agent effective to alleviate the symptoms of any particular disease can vary depending on various factors, such as the patient's disease state, age and weight, and the ability of the drug to produce the desired therapeutic effect in the patient.
  • antigen-binding fragment of an antibody refers to an antibody fragment that retains the ability to specifically bind to an antigen, such as IL-17. It has been shown that the antigen-binding function of antibodies can be performed by fragments of full-length antibodies.
  • binding fragments included in the "antigen-binding portion" of the term antibody include Fab fragments, monovalent fragments composed of VL, VH, CL and CH1 domains; F(ab')2 fragments, including two Fab fragments in the hinge region A bivalent fragment connected by a disulfide bridge; Fd fragment composed of VH and CH1 domains; Fv fragment composed of VL and VH domains of one arm of an antibody; dAb fragment (Ward et al., 1989 Nature 341:544-546), which consists of VH domain composition; and isolated complementarity determining region (CDR).
  • Fab fragments monovalent fragments composed of VL, VH, CL and CH1 domains
  • F(ab')2 fragments including two Fab fragments in the hinge region A bivalent fragment connected by a disulfide bridge
  • Fd fragment composed of VH and CH1 domains
  • Fv fragment composed of VL and VH domains of one arm of an antibody
  • dAb fragment Ward e
  • human IL-17A (huIL-17A)
  • natural human IL-17A refer to the mature form of human IL-17A protein accession numbers NP-002181 and AAT22064 (ie residues 24-155) , And its natural variants and polymorphisms.
  • rhIL-17A refers to recombinant human IL-17A.
  • this nomenclature is used to indicate various forms of IL-17A, which may not match the usage in the literature.
  • His-huIL-17A refers to recombinant human IL-17A with a His tag attached to the N-terminus.
  • FLAG-huIL-17A refers to recombinant human IL-17A with a Flag tag attached to the N-terminus. In some experiments, FLAG-huIL-17A was biotinylated.
  • the R&D Systerms human IL-17A mentioned in this article refers to the recombinant human IL-17A purchased from R&D Systerms.
  • “Optional” or “optionally” means that the event or environment described later can but does not necessarily occur, and the description includes the occasion where the event or environment occurs or does not occur.
  • “optionally comprising 1-3 antibody heavy chain variable regions” means that the antibody heavy chain variable regions of a specific sequence may but need not be present, and there may be one, two or three when present.
  • the steps of transforming host cells with recombinant DNA described in the present disclosure can be performed by conventional techniques well known to those skilled in the art.
  • the obtained transformant can be cultured by conventional methods, and the transformant expresses the polypeptide encoded by the gene of the present disclosure.
  • the medium used in the culture can be selected from various conventional mediums. The culture is carried out under conditions suitable for the growth of the host cell.
  • the engineered antibodies or antigen-binding fragments in the present disclosure can be prepared and purified by conventional methods.
  • the cDNA sequences encoding the heavy and light chains can be cloned and recombined into a GS expression vector.
  • the recombinant immunoglobulin expression vector can be stably transfected into CHO cells.
  • mammalian expression systems can lead to glycosylation of antibodies, especially in the highly conserved N-terminal site of the Fc region.
  • Stable clones are obtained by expressing antibodies that specifically bind to human TIM-3. Positive clones are expanded in the serum-free medium of the bioreactor to produce antibodies.
  • the antibody-secreted culture medium can be purified by conventional techniques.
  • a or G Sepharose FF column with adjusted buffer for purification. Wash away non-specifically bound components. Then the bound antibody was eluted by the PH gradient method, and the antibody fragment was detected by SDS-PAGE and collected. The antibody can be filtered and concentrated by conventional methods. Soluble mixtures and polymers can also be removed by conventional methods, such as molecular sieves and ion exchange. The resulting product needs to be frozen immediately, such as -70°C, or lyophilized.
  • Affinity refers to the degree of interaction between an antibody and an antigen at a single antigenic site. Within each antigenic site, the variable region of the antibody “arm” interacts with the antigen at many sites via weak non-covalent forces. The more interactions, the stronger the affinity.
  • the "homology" in the present disclosure refers to the sequence similarity between two polynucleotide sequences or between two polypeptides.
  • positions in two comparison sequences are occupied by the same base or amino acid monomer subunit, for example, if each position of two DNA molecules is occupied by adenine, then the molecules are homologous at that position .
  • the percentage of homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences divided by the number of positions compared ⁇ 100.
  • the two sequences are 60% homologous; if there are 95 matches in 100 positions in the two sequences Or homology, then the two sequences are 95% homologous.
  • the comparison is made when two sequences are aligned to obtain the maximum percent homology.
  • Partial responders From the baseline PASI score, patients who achieved 50% improvement (also called PASI50) but less than 75% improvement (also called PASI75) were defined as partial responders.
  • Non-responders Since the baseline PASI score, patients whose PASI decreases ⁇ 50% are defined as non-responders.
  • ⁇ Rebound (rebound) Baseline PASI value worsens (or psoriasis skin lesions worsen within 8 weeks after stopping therapy, for example, PASI>125% of baseline PASI value.
  • erythema, thickening (plaque uplift, hardening), and scaling (desquamation) of the head, trunk, upper limbs and lower limbs are assessed respectively, as defined in Table 1.
  • the average severity of each symptom in each of the four body areas is given a score of 0 to 4.
  • the area covered by the lesion on each body area was evaluated as a percentage of the total area of the specific body area. Because the head and neck, upper limbs, trunk, and lower limbs correspond to approximately 10%, 20%, 30%, and 40% of the body surface area, respectively, the PASI score is calculated using the following formula:
  • PASI 0.1(EH+IH+DH)AH+0.2(EU+IU+DU)AU+0.3(ET+IT+DT)AT+0.4(EL+IL+DL)AL
  • the PASI score can range from a low value of 0 (corresponding to no psoriasis symptoms) to a theoretical maximum of 72.0.
  • the PASI score is accurate to one tenth, such as 9.0, 10.1, 14.2, 17.3, etc.
  • Other information about the PASI score can be obtained from Henseler T, Schmitt-Rau K (2008) Int. J. Dermatol.; 47: 1019-1023, or refer to related content in CN10315403 or US9717791, and incorporate it into this disclosure for Show instructions.
  • the heavy and light chain sequences are as shown in SEQ ID NO: 13 and SEQ ID NO: 14, 200 mg/mL, and 80 mg/mL for use.
  • the subject is a candidate for systemic therapy (systemic therapy)/or phototherapy/or chemo-phototherapy.
  • ⁇ BSA is affected by 10% or more of plaque psoriasis.
  • the patients who meet the enrollment criteria are randomly divided into groups according to the order of screening number and 1:1:1:1:1:1:1
  • Scheme 1 IL-17A antibody, a fixed dose of 40mg, subcutaneous injection, once every 4 weeks;
  • Scheme 2 IL-17A antibody, a fixed dose of 80mg, subcutaneous injection, once every 4 weeks;
  • Scheme 3 IL-17A antibody, a fixed dose of 160mg, subcutaneous injection, once every 4 weeks;
  • Scheme 4 IL-17A antibody, a fixed dose of 240 mg, subcutaneous injection, once every 4 weeks;
  • Scheme 5 IL-17A antibody, a fixed dose of 240mg, subcutaneous injection, once every 8 weeks;
  • Comfort group not receiving any active treatment.
  • TEAEs adverse events after treatment included upper respiratory tract infections (treatment group, 13.3% vs placebo, 16.2%) and hyperuricemia (treatment group, 7.3% vs placebo, 5.4%).
  • TEAEs are mostly mild or moderate.
  • the IL-17A antibody of the present disclosure shows better curative effect in patients with moderate to severe plaque psoriasis.
  • the 240 mg dose of PASI75 had a higher number of responders than other doses.
  • the IL-17A antibody of the present disclosure was well tolerated in this test.

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Abstract

本公开涉及IL-17拮抗剂治疗自身免疫疾病的方法。本公开中涉及一种IL-17A结合物在制备治疗自身免疫系统疾病，如类风湿关节炎、强直性脊柱炎、银屑病的药物中的用途，具体而言，提供一种治疗炎症或自身免疫系统疾病的方法，包括向患者施用有效量的IL-17结合物，给药频率低于一周一次。

Description

IL-17拮抗剂治疗自身免疫疾病的方法
本申请要求申请日为2019年7月30日的中国专利申请201910695261.2和申请日为2020年6月10日的中国专利申请202010523393.X的优先权。本申请引用上述中国专利申请的全文。
技术领域
本公开中涉及一种治疗炎症或自身免疫系统疾病的方法。
背景技术
白介素-17家族的细胞因子被分别命名为白介素-17A到白介素-17F，这些白介素-17细胞因子可以结合到相对应的受体成员上，从而介导不同的炎症反应。
该家族中最具代表性的成员是白介素-17A。迁移到机体受感染或损伤处的淋巴细胞会分泌白介素-17A。白介素-17A一方面会诱导炎症因子以及趋化因子的表达，从而招募更多的免疫细胞到达炎症部位加剧炎症反应；另一方面，白介素-17A还会诱导一些组织修复相关因子的表达，从而加速机体的恢复。虽然白介素-17A在宿主抗感染和组织修复过程中起到扩大免疫防御反应和保护机体的作用，但是在很多自身免疫病病人和肿瘤病人当中，白介素-17A是高表达的，过高的白介素-17A水平对于病理发展起到恶化作用，因为它可以诱导很多炎症因子的表达。很多动物实验也证明，白介素-17A的缺失或者白介素-17A被抗体中和，可以有效抑制多种自身免疫病病理程度。有证据证明以IL-17信号为靶点治疗自身免疫病，包括类风湿关节炎(RA)、银屑病、中轴型脊柱关节炎、克罗恩氏病、多发性硬化症(MS)、银屑病疾病、哮喘和红斑狼疮，均有一定的疗效(参见例如Aggarwal等人,J.Leukoc.Biol.,71(1):1-8(2002)；Lubberts等人)。
目前已有专利报道的抗IL-17A抗体专利，如CN101001645A，CN101326195A，CN101646690A。CN201480003663.7也公开了一种有效降低或抵消IL-17活性的改良的抗体。
已开发上市的抗IL-17药物，尤其是针对IL-17的人源化单克隆抗体有：Ixekizumab(Eli Lilly)、Secukinumab(诺华)和Brodalumab(SILIQ TM)。Secukinumab
Figure PCTCN2020105510-appb-000001
已获美国食品和药物管理局(FDA)、欧洲药品管理局(EMA)、日本和巴西批准，用于成人斑块状银屑病，强直性脊柱炎和银屑病关节炎。Ixekizumab
Figure PCTCN2020105510-appb-000002
获FDA/EMA批准用于治疗中度至重度成人斑块状银屑病。Brodalumab(SILIQ TM)，IL-17受体单克隆抗体，由AstraZeneca/Valeant开发并批准用于患者中度至重度斑块状银屑病，然后现有IL-17药物治疗方案中普遍含有诱导治疗方案(loading)。
为此，开发新的治疗自身免疫疾病的方法引起药学研究者的足够兴趣。
发明内容
本公开(The disclosure)提供了一种治疗炎症或自身免疫系统疾病的方法，该方法包括向患者施用有效量的IL-17A结合物，给药频率低于一周一次。
在一些实施方案中，所述IL-17A结合物包含1个或多个选自以下的CDR区序列或与其具有至少95％序列同一性的氨基酸序列：
抗体重链可变区HCDR区序列：如SEQ ID NO:7、8和9氨基酸序列所示；和抗体轻链可变区LCDR区序列：如SEQ ID NO:10、11和12氨基酸序列所示。
在一些实施方案中IL-17A抗体轻重链中CDR序列如下表所示：
Figure PCTCN2020105510-appb-000003
Figure PCTCN2020105510-appb-000004
优选地，在一些实施方案中IL-17A抗体或其抗原结合片段选自鼠源抗体、嵌合抗体、人源化抗体的重组抗体或其抗原结合片段。
进一步地，所述人源化抗体轻链和重链可变区上的轻链和重链FR区序列分别来源于人种系轻链和重链或其突变序列。
在可选实施方案中，所述IL-17A抗体含有SEQ ID NO:3所示的重链可变区或其变体，所述变体优选在SEQ ID NO:3所示的重链可变区序列上具有0-10个氨基酸变化，更优选为A93T和T71A的氨基酸回复突变；所述IL-17A抗体抗体含有SEQ ID NO:4所示的轻链可变区或其变体，所述变体优选在SEQ ID NO:4所示的轻链可变区上具有0-10个氨基酸变化的序列，更优选为F71Y、K49Y、Y36F和L47W的氨基酸回复突变。
重链可变区(VH1-18)
Figure PCTCN2020105510-appb-000005
轻链可变区(A10)
Figure PCTCN2020105510-appb-000006
进一步地，前述IL-17A抗体序列的重链可变区或轻链可变区如下所示：
重链可变区
Figure PCTCN2020105510-appb-000007
轻链可变区
Figure PCTCN2020105510-appb-000008
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IL-17A抗体包含人源IgG1、IgG2、IgG3或IgG4同种型的重链恒定区，优选包含IgG1同种型的重链恒定区。
在另一些可选实施方案中，所述抗IL-17A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。
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:13所示的序列，重链序列为如SEQ ID NO:14所示的序列，
轻链
Figure PCTCN2020105510-appb-000009
重链
Figure PCTCN2020105510-appb-000010
另外，本公开IL-17A抗体具有高亲和力、起效快和毒副性低等特点，因此可以低频率使用低剂量的IL-17A治疗炎症或自身免疫系统疾病。
根据疾病的类型、严重性、患者的体重和患者对药物耐受性，本公开IL-17A结合物的给药剂量为40～300mg，在实施方案中可为40mg、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，优选80mg、120mg、160mg、200mg或240mg。
治疗炎症或自身免疫系统疾病的方法中包括诱导方案，所述诱导方案为IL-17A抗体可以低的给药剂量进行治疗，或以高的给药剂量进行治疗，待患者出现应答或部分应答时，再进行维持治疗。如诺华公司Secukinumab治疗中重度斑块状银屑病的给药方案为：每周皮下注射150mg共5次(0、1、 2、3和4周)，之后每4周皮下注射150mgSecukinumab维持治疗。礼来公司Ixekizumab治疗中重度斑块状银屑病的给药方案为：第1次给药160mg，接着每2周皮下注射80mg共5次，之后每4周给药80mg维持治疗。整体给药方案复杂，无形曾加患者的治疗负担，患者治疗顺应性低。本公开所述治疗方案不包括诱导方案，治疗方案简单，遗漏给药的概率低，同时无诱导方案的治疗方案有效减轻患者的治疗负担，提高患者治疗顺应性。
一些实施方案提供治疗炎症或自身免疫系统疾病的方法，不包含诱导方案(loading)。所述诱导方案(loading)是指治疗初始阶段以高的给药频率(相对维持治疗给药频率而言)给予IL-17A抗体治疗炎症或自身免疫系统疾病。所述高给药频率可以是从第零周开始每周给药一次，或从第零周开始每2周给药一次，或从第零周开始每3周给药一次，或从第零周开始每4周给药一次，或从第零周开始每6周给药一次，或从第零周开始每8周给药一次，或更长期间的给药频率。
进一步地，本公开中所述诱导方案中给药次数至少1次以上，包括但不限于1次、2次、3次、4次、5次或更多。
在一些实施方案中，所述诱导方案中给药频率为从第零周开始每周给药一次，给药次数3次。
一些实施方案中所述诱导方案中给药频率为从第零周开始每周给药一次，给药次数4次。
一些实施方案中所述诱导方案中给药频率为从第零周开始每周给药一次，给药次数5次。
一些实施方案中所述诱导方案中给药频率为从第零周开始每2周给药一次，给药次数3次。
一些实施方案中所述诱导方案中给药频率为从第零周开始每2周给药一次，给药次数4次。
一些实施方案中所述诱导方案中给药频率为从第零周开始每2周给药一 次，给药次数5次。
一些实施方案中所述诱导方案中给药频率为从第零周开始每3周给药一次，给药次数3次。
一些实施方案中所述诱导方案中给药频率为从第零周开始每3周给药一次，给药次数4次。
一些实施方案中所述诱导方案中给药频率为从第零周开始每3周给药一次，给药次数5次。
在一些实施方案中，所述诱导方案中给药频率为从第零周开始每4周给药一次，给药次数3次。
一些实施方案中所述诱导方案中给药频率为从第零周开始每4周给药一次，给药次数4次。
一些实施方案中所述诱导方案中给药频率为从第零周开始每4周给药一次，给药次数5次。
本公开给药周期的单位“月”与“周”在某些情况下可以适当换算，通常4周约为1月。
进一步地，在一些实施方案中，治疗炎症或自身免疫系统疾病的方法不包含诱导方案，所述诱导方案包括如从第零周开始每周(如0/1/2/3周或0/1/2/3/4/5周给药)向所述患者使用40～300mg(如80mg、120mg、160mg、200mg或240mg)剂量的前述IL-17A结合物。
在一些实施方案中，治疗炎症或自身免疫系统疾病的方法不包含诱导方案，所述诱导方案包括如从第零周开始每2周(如0/2周或0/2/4周给药)向所述患者使用40～300mg(如80mg、120mg、160mg、200mg或240mg)剂量的前述IL-17A结合物。
在一些实施方案中，治疗炎症或自身免疫系统疾病的方法不包含诱导方案，所述诱导方案包括如从第零周开始每3周(如0/3周或0/3/6周给药)向所述患者使用40～300mg(如80mg、120mg、160mg、200mg或240mg)剂 量的前述IL-17A结合物。
在一些实施方案中，治疗炎症或自身免疫系统疾病的方法不包含诱导方案，所述诱导方案包括如从第零周开始每4周(如0/4周或0/4/8周给药)向所述患者使用40～300mg(如80mg、120mg、160mg、200mg或240mg)剂量的前述IL-17A结合物。
另一方面，在一些实施方案中，所述治疗炎症或自身免疫系统疾病的方法，包括向患者施用40～300mg(如80mg、120mg、160mg、200mg或240mg)剂量的IL-17A结合物，给药频率三周一次。
在一些实施方案中，所述治疗炎症或自身免疫系统疾病的方法，包括向患者施用40～300mg(如80mg、120mg、160mg、200mg或240mg)剂量的IL-17A结合物，给药频率四周一次。
在一些实施方案中，所述治疗炎症或自身免疫系统疾病的方法，包括向患者施用40～300mg(如80mg、120mg、160mg、200mg或240mg)剂量的IL-17A结合物，给药频率五周一次。
在一些实施方案中，所述治疗炎症或自身免疫系统疾病的方法，包括向患者施用40～300mg(如80mg、120mg、160mg、200mg或240mg)剂量的IL-17A结合物，给药频率六周一次。
在一些实施方案中，所述治疗炎症或自身免疫系统疾病的方法，包括向患者施用40～300mg(如80mg、120mg、160mg、200mg或240mg)剂量的IL-17A结合物，给药频率七周一次。
在一些实施方案中，所述治疗炎症或自身免疫系统疾病的方法，包括向患者施用40～300mg(如80mg、120mg、160mg、200mg或240mg)剂量的IL-17A结合物，给药频率八周一次。
在一些实施方案中，所述治疗炎症或自身免疫系统疾病的方法，包括向患者施用40～300mg(如80mg、120mg、160mg、200mg或240mg)剂量的IL-17A结合物，给药频率十周一次。
在一些实施方案中，所述治疗炎症或自身免疫系统疾病的方法，包括向患者施用40～300mg(如80mg、120mg、160mg、200mg或240mg)剂量的IL-17A结合物，给药频率十二周一次。
本公开实施方案提供治疗炎症或自身免疫系统疾病的方法，包括：在向患者施用40～300mg剂量的IL-17A结合物前，不对前述患者进行诱导方案(loading)治疗，所述诱导方案中给药频率可以为从第零周开始每周给药一次，或从第零周开始每2周给药一次，或从第零周开始每3周给药一次，或从第零周开始每4周给药一次，或从第零周开始每6周给药一次，或从第零周开始每8周给药一次，或更长期间的给药频率；给药次数至少1次以上，包括但不限于1次、2次、3次、4次、5次或更多。
进一步地，本公开所述治疗炎症或自身免疫系统疾病的方法，包括：在向患者施用40～300mg剂量的IL-17A结合物前，不对前述患者进行诱导方案(loading)治疗，所述诱导方案如包括从第零周开始每周(如0/1/2/3周或0/1/2/3/4/5周给药)向所述患者使用40～300mg(如20mg、60mg、80mg、120mg、160mg、200mg或240mg)的前述IL-17A结合物。
本公开所述治疗炎症或自身免疫系统疾病的方法，包括：在向患者施用40～300mg剂量的IL-17A结合物前，不对前述患者进行诱导方案(loading)治疗，所述诱导方案如包括从第零周开始每2周(如0/2周或0/2/4周给药)向所述患者使用40～300mg(如20mg、60mg、80mg、120mg、160mg、200mg或240mg)的前述IL-17A结合物。
本公开所述治疗炎症或自身免疫系统疾病的方法，包括：在向患者施用40～300mg剂量的IL-17A结合物前，不对前述患者进行诱导方案(loading)治疗，所述诱导方案如包括从第零周开始每3周(如0/3周或0/3/6周给药)向所述患者使用40～300mg(如20mg、60mg、80mg、120mg、160mg、200mg或240mg)的前述IL-17A结合物。
本公开所述治疗炎症或自身免疫系统疾病的方法，包括：在向患者施用 40～300mg剂量的IL-17A结合物前，不对前述患者进行诱导方案(loading)治疗，所述诱导方案如包括从第零周开始每4周(如0/4周或0/4/8周给药)向所述患者使用40～300mg(如20mg、60mg、80mg、120mg、160mg、200mg或240mg)的前述IL-17A结合物。
本公开所述治疗炎症或自身免疫系统疾病的方法中所述患者患有中度至严重活动强直性脊柱炎。
在一些实施方案中，所述患者为先前经至少一种非类固醇抗炎药(NSAID)(如阿司匹林、布洛芬、乙酰氨基酚、吲哚美辛、萘普生、萘普酮、双氯芬酸、尼美舒利、罗非昔布或塞来昔布)治疗而应答不足的。
在另一些实施方案中，本公开所述治疗方法包括：在向患有中度至严重活动性强直性脊柱炎的患者施用40～300mg剂量的IL-17A结合物后，所述患者进一步施用NSAID、甲氨碟呤、柳氮磺吡啶或泼尼松龙。
在另一些实施方案中，本公开所述治疗炎症或自身免疫系统疾病的方法中所述患者患有活跃性银屑病关节炎，优选所述患者患有共存银屑病。
在某一些实施方案中，所述患者是TNFi失败或甲氨碟呤(DMARD)失败。
在某一些实施方案中，本公开所述治疗方法包括：在向患有活跃性银屑病关节炎的患者施用40～300mg剂量的IL-17A结合物后，所述患者进一步施用甲氨碟呤。
另一方面，本公开所述治疗炎症或自身免疫系统疾病的方法中所述患者患有斑块状银屑病，优选所述患者患有中度至重度斑块状银屑病。
在一些实施方案中，本公开所述治疗方法包括：在向患有斑块状银屑病的患者施用40～300mg剂量的IL-17A结合物前，所述患者先前未用银屑病的全身治疗剂治疗。
在一些实施方案中，本公开所述治疗方法包括：在向患有斑块状银屑病的患者施用40～300mg剂量的IL-17A结合物前，所述患者先前已经用银屑 病的全身治疗剂治疗。
本公开中所述全身治疗选自甲氨蝶呤，环孢菌素，富马酸酯，阿曲汀，Alefacept，阿达木单抗，依法珠单抗，依那西普，英夫利昔单抗，戈利木单抗和Ustekinumab，优选甲氨蝶呤。
本公开提供了IL-17A抗体在制备治疗治疗炎症或自身免疫系统疾病的药物中用途，其中所述药物经配制以容器存放，以容许向炎症或自身免疫系统疾病患者施用有效量的IL-17A。
本公开还提供了一种治疗炎症或自身免疫系统疾病的方法，该方法包括向患者施用有效量的IL-17A结合物，给药频率5-8周一次(如五周一次、六周一次、七周一次或八周一次)。
进一步地，在可选实施方案中，本公开中给药频率5-8周一次的治疗方法中可包括或不包括诱导方案(loading)。
在一些实施方案中，本公开中给药频率5-8周一次的治疗方法中包括含诱导方案(loading)，所述诱导方案包括如从第零周开始每1周(如0/1/2/3周或0/1/2/3/4/5周给药)，每2周(如0/2周或0/2/4周给药)，每3周或每4周向所述患者使用40～300mg(如80mg、120mg、160mg、200mg或240mg)剂量的前述IL-17A结合物。
更进一步地，在可选实施方案中，所述诱导方案持续周期可以为6周、7周、8周、9周、10周、11周、12周、13周、14周、15周。
本公开中治疗炎症或自身免疫系统疾病选自炎症或自身免疫疾病；所述疾病优选银屑病、银屑病关节炎、强直性脊柱炎、多发性硬化症、炎性关节炎。
本公开所述治疗方法的治疗周期20周。
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，优选皮下注射。
在本公开中一些实施方案中，所述IL-17A抗体以注射的方式给药，例 如皮下或静脉注射，注射前需将IL-17A抗体配制成可注射的形式。特别优选IL-17A抗体的可注射形式是注射液或冻干粉针，其包含IL-17A抗体、缓冲剂、稳定剂，任选地还含有表面活性剂。缓冲剂为组氨酸-盐酸盐体系；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IL-17A抗体的可注射形式包含IL-17A抗体、组氨酸盐酸盐缓冲剂、蔗糖和聚山梨醇酯80。
如无相反解释，本公开中术语具有如下含义：
本文所述的“结合物”是指能够与靶结合的可溶性受体或其片段或其类似物，或抗体或其片段或其类似物。本公开所述的“IL-17A结合物”，是指能特异性识别IL-17A并与IL-17A结合的抗体或其片段或其类似物。
术语“IL-17A”一般是指天然的或重组的人IL-17A，以及人IL-17A的非人同源物。除非另有指示，否则使用IL-17A的同源二聚体的分子量(例如对于人IL-17A为30KDa)计算IL-17A的摩尔浓度。
本公开所述的抗体指免疫球蛋白，是由两条相同的重链和两条相同的轻链通过链间二硫键连接而成的四肽链结构。免疫球蛋白重链恒定区的氨基酸组成和排列顺序不同，故其抗原性也不同。据此，可将免疫球蛋白分为五类，或称为免疫球蛋白的同种型，即IgM、IgD、IgG、IgA和IgE。同一类Ig根据其铰链区氨基酸组成和重链二硫键的数目和位置的差别，又可分为不同的亚类，如IgG可分为IgG1、IgG2、IgG3、IgG4。轻链通过恒定区的不同分为κ或λ链。
抗体重链和轻链靠近N端的约110个氨基酸的序列变化很大，为可变区(V区)；靠近C端的其余氨基酸序列相对稳定，为恒定区(C区)。可变区包括3个高变区(HVR)和4个序列相对保守的骨架区(FR)。3个高变区决定抗体的特异性，又称为互补性决定区(CDR)。每条轻链可变区(VL) 和重链可变区(VH)由3个CDR区4个FR区组成，从氨基端到羧基端依次排列的顺序为：FR1，CDR1，FR2，CDR2，FR3，CDR3，FR4。轻链的3个CDR区指LCDR1，LCDR2，和LCDR3；重链的3个CDR区指HCDR1，HCDR2和HCDR3。本公开中所述的“抗原结合片段”，指具有抗原结合活性的Fab片段，Fab’片段，F(ab’)2片段，或单一Fv片段。Fv抗体是含有抗体重链可变区、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。
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。
本公开中所述“鼠源抗体”在本公开中为根据本领域知识和技能制备的对人TIM-3的单克隆抗体。制备时用TIM-3抗原注射试验对象，然后分离表达具有所需序列或功能特性的抗体的杂交瘤。在本公开一个优选的实施方案中，所述的鼠源TIM-3抗体或其抗原结合片段，可进一步包含鼠源κ、λ链或其变体的轻链恒定区，或进一步包含鼠源IgG1、IgG2、IgG3或其变体的重链恒定区。
本公开中所述“嵌合抗体(chimeric antibody)”，是将鼠源性抗体的可变区与人抗体的恒定区融合而成的抗体，可以减轻鼠源性抗体诱发的免疫应答反应。建立嵌合抗体，要先建立分泌鼠源性特异性单抗的杂交瘤，然后从鼠 杂交瘤细胞中克隆可变区基因，再根据需要克隆人抗体的恒定区基因，将鼠可变区基因与人恒定区基因连接成嵌合基因后插入表达载体中，最后在真核系统或原核系统中表达嵌合抗体分子。
本公开中所述IL-17A抗体序列的重链或轻链可变区序列采用分子操作环境(MOE，Molecular Operating Environment)数据库软件进行分析，并翻译成氨基酸序列。另一方面，所述IL-17A抗体序列的重链或轻链可变区序列也可采用如IMGT/DomainGapAlign等数据库软件进行分析，并翻译成氨基酸序列(参见J.Methods Mol Biol,2012,882,605-633)。然而，在使用MOE或IMGT等数据库软件提供抗体序列或结构时，需要注意不同数据库对同一抗体序列的编码方式或解析不尽相同。
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。
“治疗”意指给予患者内用或外用治疗剂，诸如包含本公开的任一种结合物的组合物，所述患者具有一种或多种疾病症状，而已知所述治疗剂对这些症状具有治疗作用。通常，在受治疗患者或群体中以有效缓解一种或多种疾病症状的量给予治疗剂，无论是通过诱导这类症状退化还是抑制这类症状发展到任何临床右测量的程度。有效缓解任何具体疾病症状的治疗剂的量(也称作“治疗有效量”)可根据多种因素变化，例如患者的疾病状态、年龄和体重，以及药物在患者产生需要疗效的能力。
术语抗体的“抗原结合片段”是指保留特异性结合于抗原(例如IL-17)的能力的抗体片段。已显示抗体的抗原结合功能可由全长抗体的片段执行。涵盖于术语抗体的“抗原结合部分”内的结合片段的实例包括Fab片段，由VL、VH、CL及CH1域组成的单价片段；F(ab')2片段，包含两个Fab片段 在铰链区由二硫桥连接的二价片段；由VH及CH1域组成的Fd片段；由抗体单臂的VL及VH域组成的Fv片段；dAb片段(Ward等人，1989Nature341:544-546)，其由VH域组成；及分离的互补决定区(CDR)。
本文指出了人IL-17A蛋白的4种变体：
1)本文使用的术语“人IL-17A(huIL-17A)”和“天然人IL-17A”是指人IL-17A蛋白登录号NP-002181和AAT22064的成熟形式(即残基24-155)，及其天然变体和多态性。
2)本文使用的术语“rhIL-17A”是指重组人IL-17A为方便起见，采用该命名法指示多种形式的IL-17A，可能与文献中的用法不匹配。
3)本文使用的术语“His-huIL-17A”是指在N-末端附加His标签的重组人IL-17A。FLAG-huIL-17A是指在N-末端附加Flag标签的重组人IL-17A。在某些实验中，FLAG-huIL-17A被生物素化。
4)在本文中指出的R&D Systerms人IL-17A指从R&D Systerms购买的重组人IL-17A。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选包含1-3个抗体重链可变区”意味着特定序列的抗体重链可变区可以但不必须存在，存在时可以是1个，2个或3个。
本公开中所述的用重组DNA转化宿主细胞的步骤可用本领域技术人员熟知的常规技术进行。获得的转化子可以用常规方法培养，转化子表达本公开的基因所编码的多肽。根据所用的宿主细胞，培养中所用的培养基可选自各种常规培养基。在适于宿主细胞生长的条件下进行培养。
本公开中工程化的抗体或抗原结合片段可用常规方法制备和纯化。比如，编码重链和轻链的cDNA序列，可以克隆并重组至GS表达载体。重组的免疫球蛋白表达载体可以稳定地转染CHO细胞。作为一种更推荐的现有技术，哺乳动物类表达系统会导致抗体的糖基化，特别是在Fc区的高度保守N端 位点。通过表达与人TIM-3特异性结合的抗体得到稳定的克隆。阳性的克隆在生物反应器的无血清培养基中扩大培养以生产抗体。分泌了抗体的培养液可以用常规技术纯化。比如，用含调整过的缓冲液的A或G Sepharose FF柱进行纯化。洗去非特异性结合的组分。再用PH梯度法洗脱结合的抗体，用SDS-PAGE检测抗体片段，收集。抗体可用常规方法进行过滤浓缩。可溶的混合物和多聚体，也可以用常规方法去除，比如分子筛、离子交换。得到的产物需立即冷冻，如-70℃，或者冻干。
“亲和力”是指在单一抗原点上抗体与抗原之间的相互作用度。在各抗原点内，抗体“臂”的可变区经由微弱非共价力与抗原在众多位点相互作用，相互作用愈多，亲和力愈强。
本公开所述“同源性”是指两个多核苷酸序列之间或两个多肽之间的序列相似性。当两个比较序列中的位置均被相同碱基或氨基酸单体亚基占据时，例如如果两个DNA分子的每一个位置都被腺嘌呤占据时，那么所述分子在该位置是同源的。两个序列之间的同源性百分率是两个序列共有的匹配或同源位置数除以比较的位置数×100的函数。例如，在序列最佳比对时，如果两个序列中的10个位置有6个匹配或同源，那么两个序列为60％同源；如果两个序列中的100个位置有95个匹配或同源，那么两个序列为95％同源。一般而言，当比对两个序列而得到最大的同源性百分率时进行比较。
以下定义可参照使用：评估人类用药的欧洲药物管理局(European Medicines Agency for the Evaluation of Medicines for Human Use)人用医药产品委员会(Committee for medicinal products for humanuse；CHMP)，(2004)用于治疗银屑病(俗称牛皮癣)的药物产品的临床研究指南，CHMP/EWP/2454/02corr文件(London，英国)：治疗应答(应答者)：与基线相比，银屑病面积及严重度指数(PASI)评分实现75％改善(减小)(也称作PASI75)的患者定义为治疗应答者。
■部分应答(部分应答者)：自基线PASI评分，实现50％改善(也称作 PASI50)但小于75％改善(也称作PASI75)的患者定义为部分应答者。
■无应答(无应答者)：自基线PASI评分，PASI减小<50％的患者定义为无应答者。
■复发(复发者)：若患者损失在研究中前面时间期间所实现的PASI获益的50％，则患者视作“复发”。
■回弹(回弹者)：基线PASI值恶化(或在停止疗法8周内银屑病皮损加重，例如PASI>基线PASI值的125％。
在PASI评分系统中，分别评估头、躯干、上肢及下肢的红斑、增厚(斑块隆起、硬化)及起鳞(脱屑)，如表1中所定义。对四个体区每一区中各症状的平均严重程度给定0至4的评分。各体区上经病变覆盖的面积以该特定体区的总面积的百分比评估。因为头颈、上肢、躯干及下肢分别对应于约10％、20％、30％及40％体表面积，所以使用下式计算PASI评分：
PASI＝0.1(EH+IH+DH)AH+0.2(EU+IU+DU)AU+0.3(ET+IT+DT)AT+0.4(EL+IL+DL)AL
PASI评分可介于低值0(对应于无银屑病症状)至理论最大值72.0的范围内。PASI评分精确至十分之一，例如9.0、10.1、14.2、17.3等。关于PASI评分的其他信息可自Henseler T,Schmitt-Rau K(2008)Int.J.Dermatol.；47:1019-1023中得到，或参见CN10315403或US9717791中相关内容，并将其引入本公开中以示说明。
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
1、受试抗体和化合物
IL-17A抗体，重、轻链的序列如本公开中SEQ ID NO:13和SEQ ID  NO:14，200mg/支，配80mg/mL备用。
2、入组标准
(1)检查确诊的具有至少6个月的慢性斑块型银屑病。
(2)受试者是全身治疗(系统治疗)/或光疗/或化学光疗的候选人。
(3)中度至重度斑块型银屑病，定义如下：
·PASI分数为12或更高，且
·PGA得分3分或更高，且
·BSA受10％或以上斑块型银屑病的影响。
3、试验分组
符合入组条件的患者按筛选号顺序，并按1:1:1:1:1:1比例随机分组
4、治疗方案
方案1：IL-17A抗体，固定剂量40mg，皮下注射，每4周1次；
方案2：IL-17A抗体，固定剂量80mg，皮下注射，每4周1次；
方案3：IL-17A抗体，固定剂量160mg，皮下注射，每4周1次；
方案4：IL-17A抗体，固定剂量240mg，皮下注射，每4周1次；
方案5：IL-17A抗体，固定剂量240mg，皮下注射，每8周1次；
安慰组：不接受任何积极治疗。
5、结果
187受试者被随机接受40毫克(37名受试者)、80毫克(38名受试者)、160毫克(38名受试者)或240毫克(37名受试者)剂量的IL-17A抗体或安慰剂(37名受试者)。与安慰剂相比，所有组患者的PASI评分较基线降低的百分比有了较大的改善。与安慰剂组(5.4％)相比，在第12周，所有组(40、80、160、240mg:56.8％、65.8％、81.6％、89.2％；p<0.001(用卡方检验计算))的PASI 75应答率显著高于安慰剂组。与安慰剂组(5.4％)相比，在第12周，所有组(40、80、160、240mg:29.7％，36.8％，55.3％，64.9％；p<0.001(用卡方检验计算))的PASI 90应答率显著高于安慰剂组。
另外，与安慰剂组(8.1％)相比，在第12周，所有组(40、80、160、240mg:45.9％，47.4％，60.5％，73％)PGA0/1均明显高于安慰剂组。
最常见的治疗后出现不良事件(TEAEs)包括上呼吸道感染(治疗组，13.3％Vs安慰剂，16.2％)和高尿酸血症(治疗组，7.3％Vs安慰剂，5.4％)。治疗组65例(43.3％)和安慰剂组11例(29.7％)有治疗相关TEAEs。TEAEs多为轻度或中度。1例(0.7％)治疗组受试者和2例(5.4％)安慰剂受试者出现严重TEAEs，均认为与药物无关。1例(0.7％)治疗组受试者，1例(2.7％)受试者服用安慰剂，因TEAEs而停止治疗。没有死亡报告。
与安慰剂组相比，本公开IL-17A抗体在中重度斑块型银屑病患者中显示出较好的疗效。在第12周，240毫克剂量的PASI75应答者数量高于其他剂量。本公开IL-17A抗体在本试验中耐受性良好。

Claims (22)

  1. 一种治疗炎症或自身免疫系统疾病方法，包括向患者施用有效量的IL-17结合物，给药频率低于一周一次。
  2. 如权利要求1所述的方法，其中所述IL-17A结合物的给药频率选自三周一次、四周一次、六周一次、八周一次、十周一次或十二周一次。
  3. 如权利要求1或2所述的方法，其中所述IL-17A结合物的给药剂量选自40～300mg，优选80mg、120mg、160mg、200mg或240mg。
  4. 如权利要求1-3任一项所述的方法，其中所述炎症或自身免疫系统疾病选自银屑病、银屑病关节炎、强直性脊柱炎、多发性硬化症、炎性关节炎，优选银屑病。
  5. 如权利要求1-4任一项所述的方法，其中所述IL-17A结合物包含1个或多个选自以下的CDR区序列或与其具有至少95％序列同一性的氨基酸序列：
    抗体重链可变区HCDR区序列：如SEQ ID NO:7、8和9氨基酸序列所示；和抗体轻链可变区LCDR区序列：如SEQ ID NO:10、11和12氨基酸序列所示。
  6. 如权利要求5所述的方法，其中所述IL-17A结合物选自鼠源抗体、嵌合抗体、人源化抗体的重组抗体或其抗原结合片段。
  7. 如权利要求6所述的方法，其中所述人源化抗体轻链和重链可变区上的轻链和重链FR区序列分别来源于人种系轻链和重链或其突变序列。
  8. 如权利要求6所述的方法，其中所述人源化抗体含有SEQ ID NO:3所示的重链可变区或其变体，所述变体优选在SEQ ID NO:3所示的重链可变区序列上具有0-10个氨基酸变化，更优选为A93T和T71A的氨基酸回复突变；所述的人源化抗体含有SEQ ID NO:4所示的轻链可变区或其变体，所述变体优选在SEQ ID NO:4所示的轻链可变区上具有0-10个氨基酸变化 的序列，更优选为F71Y、K49Y、Y36F和L47W的氨基酸回复突变。
  9. 如权利要求1-8任一项所述的方法，其中所述IL-17A结合物包含SEQ ID NO:13所示的轻链及其变体，SEQ ID NO:14所示的重链及其变体。
  10. 如权利要求5所述的方法，其中所述IL-17A结合物包含人源IgG1、IgG2、IgG3或IgG4同种型的重链恒定区，优选包含IgG1同种型的重链恒定区。
  11. 如权利要求5所述的方法，其中所述IL-17A结合物包含κ或λ的轻链恒定区。
  12. 如权利要求1-11任一项所述的方法，其中给药方式为口服、静脉或皮下给药。
  13. 如权利要求4所述的方法，其中所述患者患有中度至严重活动性强直性脊柱炎，优选所述患者为先前经至少一种NSAID治疗而应答不足的。
  14. 如权利要求13所述的方法，其中所述患者进一步施用NSAID、甲氨碟呤、柳氮磺吡啶或泼尼松龙。
  15. 如权利要求4所述的方法，其中所述患者患有活跃性银屑病关节炎，优选所述患者患有共存银屑病，更优选所述患者是TNFi治疗失败或甲氨碟呤(DMARD)失败的。
  16. 如权利要求15所述的方法，其中所述患者进一步施用甲氨碟呤。
  17. 如权利要求4所述的方法，其中所述患者患有斑块状银屑病，优选所述患者患有中度至重度斑块状银屑病。
  18. 如权利要求17所述的方法，其中，在用IL-17A结合物治疗之前，所述患者先前未用银屑病的全身治疗剂治疗。
  19. 如权利要求17所述的方法，其中，在用IL-17A抗体治疗之前，所述患者先前已经用银屑病的全身治疗剂治疗。
  20. 如权利要求18或19所述的方法，其中，所述全身治疗剂选自甲氨蝶呤、环孢菌素、富马酸酯、阿曲汀、Alefacept、阿达木单抗、依法珠单抗、 依那西普、英夫利昔单抗、戈利木单抗和Ustekinumab，优选甲氨蝶呤。
  21. 如权利要求1-20任一项所述的方法，其中不包含诱导方案。
  22. 如权利要求21所述的方法，其中所述诱导方案包括从第零周开始每周、每2周或每4周向所述患者使用40～300mg剂量的所述IL-17A结合物。
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