WO2022144023A1 - 抗il-17抗体治疗自身免疫性疾病和炎症的方法 - Google Patents

抗il-17抗体治疗自身免疫性疾病和炎症的方法 Download PDF

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WO2022144023A1
WO2022144023A1 PCT/CN2022/070077 CN2022070077W WO2022144023A1 WO 2022144023 A1 WO2022144023 A1 WO 2022144023A1 CN 2022070077 W CN2022070077 W CN 2022070077W WO 2022144023 A1 WO2022144023 A1 WO 2022144023A1
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antibody
antigen
patient
weeks
binding fragment
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PCT/CN2022/070077
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English (en)
French (fr)
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许倩
邹建军
孙飘扬
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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
苏州盛迪亚生物医药有限公司
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Publication of WO2022144023A1 publication Critical patent/WO2022144023A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • 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

Definitions

  • the present disclosure relates to a method for treating autoimmune diseases and inflammations, such as rheumatoid arthritis and psoriasis, with an anti-IL-17 antibody or an antigen-binding fragment thereof.
  • the cytokines of the interleukin-17 family are named interleukin-17A to interleukin-17F, and these interleukin-17 cytokines can bind to the corresponding receptor members to mediate different inflammatory responses.
  • interleukin-17A The most representative member of this family is interleukin-17A.
  • Interleukin-17A is secreted by lymphocytes that have migrated to infected or damaged parts of the body.
  • interleukin-17A induces the expression of inflammatory factors and chemokines, thereby recruiting more immune cells to the site of inflammation to intensify the inflammatory response; on the other hand, interleukin-17A also induces the expression of some tissue repair-related factors, thereby accelerating the recovery of the body.
  • interleukin-17A plays a role in expanding the immune defense response and protecting the body in the process of host anti-infection and tissue repair, in many autoimmune disease patients and tumor patients, interleukin-17A is highly expressed, and excessive interleukin- 17A levels play an exacerbating role in pathological development because it can induce the expression of many inflammatory factors. Many animal experiments have also proved that the deletion of interleukin-17A or the neutralization of interleukin-17A by antibodies can effectively inhibit the pathological degree of various autoimmune diseases.
  • RA rheumatoid arthritis
  • MS multiple sclerosis
  • psoriatic disease asthma and lupus erythematosus
  • 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 Approved by the U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA), Japan and Brazil for plaque psoriasis, ankylosing spondylitis and psoriatic arthritis in adults. Ixekizumab FDA/EMA approved for the treatment of moderate to severe adult plaque psoriasis. Brodalumab (SILIQ TM ), a monoclonal antibody to the IL-17 receptor, was developed and approved by AstraZeneca/Valeant for patients with moderate to severe plaque psoriasis.
  • the disclosure provides a method of treating a disease or disorder comprising:
  • an anti-IL-17 antibody or antigen-binding fragment thereof administered to the patient during an induction regimen; wherein the induction regimen comprises administering to the patient a dosing dose of 60-300 mg at a dosing frequency of once every 2 weeks or once every 3 weeks administering an anti-IL-17 antibody or antigen-binding fragment thereof;
  • the method comprises: a) administering to the patient 60-300 mg of an anti-IL-17 antibody or antigen-binding fragment thereof at a dosing frequency of once every 2 weeks starting at week zero during the induction regimen, administering
  • the number of times is 1 to 5 times, for example, 3 times.
  • the method comprises administering to the patient 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg of an anti-IL-17 antibody or antigen thereof at a dosing frequency of once every 2 weeks starting at week zero during the induction regimen
  • the number of administrations is 1 to 5 times, for example, 3 times.
  • the method comprises: a) administering to the patient 240 mg of an anti-IL-17 antibody or antigen-binding fragment thereof at a dosing frequency of once every 2 weeks starting at week zero during the induction regimen for a number of doses 1 to 5 times, eg, 3 times; b) 240 mg of anti-IL-17 antibody or its antigen-binding fragment.
  • the method comprises: a) administering to the patient 240 mg of an anti-IL-17 antibody or antigen-binding fragment thereof at a dosing frequency of once every 2 weeks starting at week zero during the induction regimen for a number of doses 3 times; b) 240 mg of anti-IL-17 antibody or antigen-binding fragment thereof is administered to the patient at a dosing frequency of once every 4 weeks during the maintenance regimen.
  • the present disclosure provides a method of treating a disease or disorder comprising:
  • the maintenance regimen comprises administering the anti-IL-17 antibody or antigen-binding fragment thereof to the patient at a dosing dose of 240 mg.
  • the method includes:
  • the maintenance regimen comprises dosing at once every 4 weeks, once every 8 weeks, once every 12 weeks, or once every 16 weeks Frequency
  • the anti-IL-17 antibody or antigen-binding fragment thereof is administered to patients at a dosing dose of 240 mg.
  • the anti-IL-17 antibody or antigen-binding fragment thereof comprises one or more CDR region sequences selected from the group consisting of or an amino acid sequence having at least 95% sequence identity thereto:
  • Antibody heavy chain HCDR sequences as shown in SEQ ID NOs: 7, 8 and 9 amino acid sequences
  • antibody light chain LCDR sequences as shown in SEQ ID NOs: 10, 11 and 12 amino acid sequences.
  • the CDR sequences in the light and heavy chains of the anti-IL-17 antibody are shown in the following table:
  • the anti-IL-17 antibody or antigen-binding fragment thereof is selected from the group consisting of murine antibodies, chimeric antibodies, recombinant antibodies of humanized antibodies, or antigen-binding fragments thereof.
  • the light chain and heavy chain FR region sequences on the light chain and heavy chain variable regions of the humanized antibody are derived from human germline light chain and heavy chain or mutant sequences thereof, respectively.
  • the framework regions of the humanized antibody light and heavy chains are derived from human germline light and heavy chains, respectively, or mutants thereof;
  • the anti-IL-17 antibody contains a heavy chain framework region having an amino acid sequence as set forth in SEQ ID NO:3 or a variant thereof, preferably relative to the heavy chain as set forth in SEQ ID NO:3
  • the chain framework region sequence has 0-10 amino acid changes, especially amino acid back mutations A93T and T71A;
  • the anti-IL-17 antibody contains a light chain framework region or a variant thereof whose amino acid sequence is shown in SEQ ID NO: 4, Said variant preferably has a sequence with 0-10 amino acid changes relative to the light chain framework region shown in SEQ ID NO:4, in particular with amino acid back mutations F71Y, K49Y, Y36F and L47W.
  • the heavy chain variable region or light chain variable region of the aforementioned anti-IL-17 antibody or antigen-binding fragment thereof sequence is as follows:
  • Immunoglobulins can be derived from any commonly known isotype, including but not limited to IgA, secretory IgA, IgG, and IgM.
  • IgG subclasses are also well known to those of skill in the art and include, but are not limited to, IgGl, IgG2, IgG3, and IgG4.
  • Isotype refers to the class or subclass of Ab encoded by the heavy chain constant region gene (eg, IgM or IgGl).
  • the anti-IL-17 antibodies described in the present disclosure comprise a heavy chain constant region of a human IgGl, IgG2, IgG3 or IgG4 isotype, eg, a heavy chain constant region comprising an IgGl isotype.
  • the anti-IL-17 antibody or antigen-binding fragment thereof comprises a kappa or lambda light chain constant region.
  • the light chain sequence of the humanized antibody is the sequence set forth in SEQ ID NO: 13
  • the heavy chain sequence is the sequence set forth in SEQ ID NO: 14
  • the anti-IL-17 antibody of the present disclosure has the characteristics of high affinity, fast onset of action, and low toxicity and side effects, so the anti-IL-17 antibody can be used at low frequency to treat diseases or conditions.
  • the present disclosure provides a method of treating a disease or disorder comprising:
  • anti-IL-17 antibody or antigen-binding fragment thereof comprises one or more CDR region sequences selected from the group consisting of or amino acid sequences having at least 95% sequence identity thereto:
  • Antibody heavy chain HCDR sequences as shown in SEQ ID NOs: 7, 8 and 9 amino acid sequences
  • antibody light chain LCDR sequences as shown in SEQ ID NOs: 10, 11 and 12 amino acid sequences.
  • the light chain sequence of the anti-IL-17 antibody is set forth in SEQ ID NO:13 and the heavy chain sequence is set forth in SEQ ID NO:14.
  • the anti-IL-17 antibody or antigen-binding fragment thereof is administered at a dose of 60 to 300 mg, in embodiments 60 mg, 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, 275m
  • the administration dose of the induction regimen in the method of treatment may be 60-300 mg, such as 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg , 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 , 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, such as 80 mg, 120 mg, 160 mg, 200 mg or 240 mg.
  • the induction regimen and the maintenance regimen are administered at the same dose.
  • the induction and maintenance regimens are administered at different doses.
  • Loading as described in the present disclosure refers to the administration of an anti-IL-17 antibody at a high dosing frequency (relative to maintenance treatment dosing frequency) at the initial stage of treatment to treat a disease or condition.
  • the high frequency of dosing can be weekly dosing from week 0, or every 2 weeks from week 0, or every 3 weeks from week 0, or longer periods of time. Dosing frequency.
  • the number of administrations in the induction regimen described in the present disclosure is at least 1 time, including but not limited to 1 time, 2 times, 3 times, 4 times, 5 times or more.
  • the induction regimen includes dosing 3 times per week starting at week zero.
  • the induction regimen includes dosing 4 times a week starting at week zero.
  • the induction regimen includes weekly dosing starting at week zero for 5 dosings.
  • the induction regimen includes dosing 3 times every 2 weeks starting at week zero.
  • the induction regimen includes 4 dosing every 2 weeks starting at week zero.
  • the induction regimen includes 5 dosings every 2 weeks starting at week zero.
  • the induction regimen includes 3 dosing every 3 weeks starting at week zero.
  • the induction regimen includes 4 dosing every 3 weeks starting at week zero.
  • the induction regimen includes 5 dosings every 3 weeks starting at week zero.
  • the induction regimen includes 3 dosing every 4 weeks (or monthly dosing) starting at week zero.
  • the induction regimen includes 4 dosing every 4 weeks starting at week zero.
  • the induction regimen includes 5 dosing every 4 weeks starting at week zero.
  • some embodiments provide a method of treating a disease or disorder in which the induction regimen comprises, for example, weekly starting at week 0 (such as at week 0/1/2/3 or week 0/1/2/3/ 4/5 weeks) using a dose of 60-300 mg (eg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg) of the aforementioned anti-IL-17 antibody or antigen-binding fragment thereof to the patient.
  • the induction regimen comprises, for example, weekly starting at week 0 (such as at week 0/1/2/3 or week 0/1/2/3/ 4/5 weeks) using a dose of 60-300 mg (eg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg) of the aforementioned anti-IL-17 antibody or antigen-binding fragment thereof to the patient.
  • methods of treating a disease or disorder of the present disclosure are provided wherein the induction regimen comprises administering to the patient every 2 weeks (eg, dosing at Week 0/2 or Week 0/2/4), such as starting at Week 0
  • the aforementioned anti-IL-17 antibody or antigen-binding fragment thereof is used in a dose of 60-300 mg (eg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg).
  • methods of treating a disease or disorder comprising administering to the patient 600 mg every 3 weeks (eg, dosing at Weeks 0/3 or 0/3/6) starting at Week 0.
  • methods of treating a disease or disorder comprising administering to the patient 600 mg every 4 weeks (eg, dosing at weeks 0/4 or 0/4/8) starting at week zero.
  • the frequency of dosing during maintenance therapy in the methods of treating a disease or disorder of the present disclosure is selected from the group consisting of once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, once every 12 weeks, once every Dosing once every 14 weeks or every 16 weeks or less frequently.
  • Some embodiments provide a maintenance period regimen in a method of treating a disease or disorder comprising administering to a patient an anti-IL-17 antibody or antigen-binding fragment thereof at a dose of 60-300 mg (eg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg), at a frequency of dosing Every 4 weeks.
  • Some embodiments provide a maintenance period regimen in a method of treating a disease or disorder comprising administering to a patient an anti-IL-17 antibody or antigen-binding fragment thereof at a dose of 60-300 mg (eg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg), at a frequency of dosing Once a month.
  • Some embodiments provide a maintenance period regimen in a method of treating a disease or disorder comprising administering to a patient an anti-IL-17 antibody or antigen-binding fragment thereof at a dose of 60-300 mg (eg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg), at a frequency of dosing Every 6 weeks.
  • Some embodiments provide a maintenance period regimen in a method of treating a disease or disorder comprising administering to a patient an anti-IL-17 antibody or antigen-binding fragment thereof at a dose of 60-300 mg (eg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg), at a frequency of dosing Every 8 weeks.
  • Some embodiments provide a maintenance period regimen in a method of treating a disease or disorder comprising administering to a patient an anti-IL-17 antibody or antigen-binding fragment thereof at a dose of 60-300 mg (eg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg), at a frequency of dosing Every 2 months.
  • Some embodiments provide a maintenance period regimen in a method of treating a disease or disorder comprising administering to a patient an anti-IL-17 antibody or antigen-binding fragment thereof at a dose of 60-300 mg (eg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg), at a frequency of dosing Every 12 weeks.
  • Some embodiments provide a maintenance period regimen in a method of treating a disease or disorder comprising administering to a patient an anti-IL-17 antibody or antigen-binding fragment thereof at a dose of 60-300 mg (eg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg), at a frequency of dosing Every 3 months.
  • Some embodiments provide a maintenance period regimen in a method of treating a disease or disorder comprising administering to a patient an anti-IL-17 antibody or antigen-binding fragment thereof at a dose of 60-300 mg (eg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg), at a frequency of dosing Once every 4 months.
  • Some embodiments provide in a method of treating a disease or disorder comprising: a) administering 160 mg or 240 mg of an anti-IL-17 antibody or antigen-binding fragment thereof to the patient once weekly starting from week zero during an induction regimen, administering 3 or 5 times; b) 160 mg or 240 mg of the IL-17 antibody or antigen-binding fragment thereof is administered to the patient every 8 weeks or every 12 weeks during the maintenance regimen.
  • Some embodiments provide in a method of treating a disease or disorder comprising: a) administering 160 mg or 240 mg of an anti-IL-17 antibody or antigen-binding fragment thereof to the patient once weekly starting from week zero during an induction regimen, administering 3 or 5 times; b) 160 mg or 240 mg of the IL-17 antibody or antigen-binding fragment thereof is administered to the patient every two months or every three months during the maintenance regimen.
  • Some embodiments provide a method of treating a disease or disorder comprising: a) administering to the patient 160 mg or 240 mg of an anti-IL-17 antibody or antigen-binding fragment thereof during an induction regimen starting at week zero every 2 weeks, to the patient; 3 or 5 doses; b) 160 mg or 240 mg of the IL-17 antibody or antigen-binding fragment thereof is administered to the patient every 8 weeks or every 12 weeks during the maintenance regimen.
  • Some embodiments provide a method of treating a disease or disorder comprising: a) administering to the patient 160 mg or 240 mg of an anti-IL-17 antibody or antigen-binding fragment thereof during an induction regimen starting at week zero every 4 weeks, to the patient; 3 or 5 doses; b) 160 mg or 240 mg of the IL-17 antibody or antigen-binding fragment thereof is administered to the patient every two or three months during the maintenance regimen.
  • Some embodiments provide a method of treating a disease or disorder comprising: a) administering to the patient 160 mg or 240 mg of an anti-IL-17 antibody or antigen-binding fragment thereof during an induction regimen starting at week zero every 4 weeks, to the patient; 1-5 doses; b) 160 mg or 240 mg of anti-IL-17 antibody or antigen-binding fragment thereof is administered to the patient once every two months, every three months or every four months during the maintenance regimen.
  • Some embodiments provide a method of treating a disease or disorder comprising: a) administering to the patient 160 mg or 240 mg of an anti-IL-17 antibody or antigen-binding fragment thereof during an induction regimen starting at week zero every 4 weeks, to the patient; 1-5 doses; b) 160 mg or 240 mg of anti-IL-17 antibody or antigen-binding fragment thereof is administered to the patient once every 8 weeks, every 12 weeks, or every 16 weeks during the maintenance regimen.
  • Another embodiment provides a method of treating a disease or disorder comprising a) administering to the patient 160 mg or 240 mg of an anti-IL-17 antibody or antigen-binding fragment thereof during an induction regimen starting at week zero every 4 weeks, to the patient; The number of doses is 3; b) 240 mg of anti-IL-17 antibody or antigen-binding fragment thereof is administered to the patient once every 12 weeks during the maintenance regimen.
  • Another embodiment provides a method of treating a disease or disorder, comprising: a) administering to the patient 240 mg of an anti-IL-17 antibody or antigen-binding fragment thereof at a dosing frequency of once every 2 weeks starting from week zero during an induction regimen , the number of administrations is 1 to 5 times, eg, 3 times; b) 240 mg of anti-IL-17 antibody or antigen-binding fragment thereof is administered to the patient at a dosing frequency of once every 4 weeks during the maintenance regimen.
  • a treatment cycle includes the total length of an induction regimen and a maintenance regimen.
  • each treatment cycle is at least 6 weeks, at least 10 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks , at least 48 weeks, at least 52 weeks, at least 56 weeks, at least 1 year, at least 2 years or more.
  • each treatment cycle is 6 to 52 weeks, eg, 16 to 48 weeks, eg, 20 to 48 weeks.
  • time units "month” and “week”, “month” and “year” in the disclosure can be appropriately converted in some cases, usually 4 weeks is about 1 month, and 12 months is about 1 year.
  • the patient has moderately to severely active ankylosing spondylitis.
  • the patient is previously treated with at least one nonsteroidal anti-inflammatory drug (NSAID) (eg, aspirin, ibuprofen, acetaminophen, indomethacin, naproxen, naprodone, diclofenac, nimesulide, rofecoxib, or celecoxib) with insufficient response.
  • NSAID nonsteroidal anti-inflammatory drug
  • the methods of treatment described in the present disclosure comprise: following administration of a 60-300 mg dose of an anti-IL-17 antibody or antigen-binding fragment thereof to a patient with moderately to severely active ankylosing spondylitis, the Patients were further administered NSAIDs, methotrexate, sulfasalazine, or prednisolone.
  • the patient is TNFi failure or methotrexate (DMARD) failure.
  • DMARD methotrexate
  • the methods of treatment described in the present disclosure comprise: after administering to a patient with active psoriatic arthritis a dose of 60-300 mg of an anti-IL-17 antibody or antigen-binding fragment thereof, the patient is further Administer methotrexate.
  • the methods of the present disclosure for treating a disease or disorder mediated by an anti-IL-17 antibody or antigen-binding fragment thereof, wherein the patient has plaque psoriasis, eg, the patient has moderate to severe disease Plaque psoriasis.
  • the patient has moderate to severe chronic plaque psoriasis.
  • the methods of treatment described in the present disclosure comprise: prior to administering a 60-300 mg dose of an anti-IL-17 antibody or antigen-binding fragment thereof to a patient with plaque psoriasis, the patient has not previously been treated with Systemic therapeutic agent treatment of psoriasis.
  • the methods of treatment described in the present disclosure comprise: prior to administering a 60-300 mg dose of an anti-IL-17 antibody or antigen-binding fragment thereof to a patient with plaque psoriasis, the patient has previously been treated with Systemic therapeutic agent treatment of psoriasis.
  • the systemic therapy described in this disclosure is selected from methotrexate, cyclosporine, fumarate, acitretin, Alefacept, adalimumab, efalizumab, etanercept, infliximab , Golimumab, and Ustekinumab, such as methotrexate.
  • the present disclosure provides the use of an anti-IL-17 antibody in the manufacture of a medicament for the treatment of a disease or disorder, wherein the medicament is formulated for storage in a container to allow treatment of a patient with a disease or disorder mediated by the anti-IL-17 antibody or antigen-binding fragment thereof An effective amount of bound IL-17 is administered.
  • the present disclosure also provides a method of treating a disease or disorder, the method comprising administering to a patient an effective amount of an anti-IL-17 antibody or antigen-binding fragment thereof at a frequency of every 4-16 weeks, including but not limited to 4, Once every 6, 8, 10, 12, 14 or 16 weeks.
  • the treatment methods of the present disclosure with a dosing frequency of once every 4-12 weeks may or may not include an induction regimen.
  • the induction protocol is as described above.
  • the routes of administration described in the present disclosure may be oral, parenteral, transdermal, including but not limited to intravenous injection, subcutaneous injection, intramuscular injection, such as subcutaneous injection.
  • an injectable form of an anti-IL-17 antibody or antigen-binding fragment thereof is an injection or lyophilized powder comprising an anti-IL-17 antibody or antigen-binding fragment thereof, a buffer, a stabilizer, and optionally a surface active agent.
  • the buffer is a histidine-hydrochloride system; the stabilizer can be selected from sugars or amino acids, eg disaccharides, eg sucrose, lactose, trehalose, maltose.
  • the surfactant is selected from polyoxyethylene hydrogenated castor oil, glycerol fatty acid ester, polyoxyethylene sorbitan fatty acid ester, for example, the polyoxyethylene sorbitan fatty acid ester is polysorbate 20, 40, 60 or 80 , such as polysorbate 20.
  • an injectable form of an IL-17 antibody or antigen-binding fragment thereof comprises an anti-IL-17 antibody or antigen-binding fragment thereof, histidine hydrochloride buffer, sucrose, and polysorbate 80.
  • the present disclosure also provides the use of an anti-IL-17 antibody or an antigen-binding fragment thereof in the manufacture of a medicament for the treatment of autoimmune diseases and inflammations, such as rheumatoid arthritis and psoriasis.
  • IL-17A generally refers to native or recombinant human IL-17A, as well as non-human homologs of human IL-17A. Unless otherwise indicated, the molar concentration of IL-17A was calculated using the molecular weight of the homodimer of IL-17A (eg, 30 KDa for human IL-17A).
  • immunoglobulin which is a tetrapeptide chain structure composed of two identical heavy chains and two identical light chains connected by interchain disulfide bonds.
  • the amino acid composition and sequence of the immunoglobulin heavy chain constant region are different, so their antigenicity is also different.
  • immunoglobulins can be divided into five classes, or isotypes called 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 disulfide bonds in the heavy chain.
  • IgG can be divided into IgG1, IgG2, IgG3, and IgG4.
  • Light chains are classified into kappa or lambda chains by differences in 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, which 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 three hypervariable regions (HVR) and four relatively conserved framework regions (FR). Three hypervariable regions determine the specificity of antibodies, also known as complementarity determining regions (CDRs).
  • Each light chain variable region (VL) and heavy chain variable region (VH) consists of 3 CDR regions and 4 FR regions. The order from the amino terminus to the carboxyl terminus is: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the three CDR regions of the light chain are referred to as LCDR1, LCDR2, and LCDR3; the three CDR regions of the heavy chain are referred to as HCDR1, HCDR2, and HCDR3.
  • the "antigen-binding fragment” referred to in the present disclosure refers to a Fab fragment, a Fab' fragment, an F(ab')2 fragment, or a single Fv fragment having antigen-binding activity.
  • Fv antibodies are the smallest antibody fragments that contain antibody heavy chain variable regions, light chain variable regions, but no constant regions, and have all antigen-binding sites. Typically, Fv antibodies also contain a polypeptide linker between the VH and VL domains and are capable of forming the structure required for antigen binding.
  • the "humanized antibody” in this disclosure also known as CDR-grafted antibody, refers to the transplantation of mouse CDR sequences into human antibody variable region frameworks, that is, different types of antibodies.
  • Antibodies generated from human germline antibody framework sequences The strong antibody variable antibody response induced by chimeric antibodies can be overcome because they carry a large number 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), and in Kabat, E.A. et al. People, 1991 Sequences of Proteins of Immunological Interest, 5th ed.
  • the "murine antibodies” referred to in the present disclosure are monoclonal antibodies directed against human IL-17 prepared according to the knowledge and skills in the art. In preparation, test subjects are injected with IL-17 antigen, and hybridomas expressing antibodies with the desired sequence or functional properties are isolated.
  • the murine anti-IL-17 antibody or antigen-binding fragment thereof may further comprise a light chain constant region of a murine ⁇ , ⁇ chain or a variant thereof, or further comprise murine IgG1, IgG2, Heavy chain constant region of IgG3 or a variant thereof.
  • the "chimeric antibody” described in the present disclosure is an antibody obtained 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 build a chimeric antibody first establish a hybridoma that secretes a mouse-specific monoclonal antibody, then clone the variable region gene from the mouse hybridoma cell, and then clone the constant region gene of the human antibody as needed, and then clone the mouse variable region gene from the mouse hybridoma cell. After connecting with human constant region gene into chimeric gene, it is inserted into expression vector, and finally chimeric antibody molecule is expressed in eukaryotic system or prokaryotic system.
  • the heavy chain or light chain variable region sequences of the anti-IL-17 antibody or its antigen-binding fragment sequences described in the present disclosure were analyzed using Molecular Operating Environment (MOE, Molecular Operating Environment) database software, and translated into amino acid sequences.
  • MOE Molecular Operating Environment
  • the heavy chain or light chain variable region sequence of the anti-IL-17 antibody or its antigen-binding fragment sequence can also be analyzed using database software such as IMGT/DomainGapAlign and translated into amino acid sequences (see J.Methods Mol Biol, 2012, 882, 605-633).
  • database software such as MOE or IMGT to provide antibody sequences or structures, it should be noted that different databases encode or parse the same antibody sequence differently.
  • an "effective amount or effective dose” as used in the present disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition 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 being treated, the general health of the patient, the method, route and dosage of administration, and the severity of side effects.
  • An effective amount or effective dose can be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.
  • Treatment means administering an internal or external therapeutic agent, such as a composition comprising any of the antibodies or antigen-binding fragments thereof of the present disclosure, to a patient having one or more disease symptoms for which the therapeutic agent is known Treat these symptoms.
  • the therapeutic agent is administered in an amount effective to alleviate one or more symptoms of a disease in a patient or population to be treated, either by inducing regression of such symptoms or inhibiting the progression of such symptoms to any clinically measured degree.
  • the amount of a therapeutic agent effective to relieve symptoms of any particular disease can vary depending on factors such as the patient's disease state, age and weight, and the ability of the drug to produce the desired effect in the patient.
  • antigen-binding fragment of an antibody refers to a fragment of an antibody that retains the ability to specifically bind to an antigen (eg, IL-17). It has been shown that the antigen-binding function of antibodies can be performed by fragments of full-length antibodies.
  • binding fragments encompassed within the term "antigen-binding portion" of an antibody include Fab fragments, monovalent fragments consisting of the VL, VH, CL and CH1 domains; F(ab')2 fragments, comprising two Fab fragments in the hinge region Bivalent fragments linked by disulfide bridges; Fd fragments composed of VH and CH1 domains; Fv fragments composed of the VL and VH domains of an antibody one-arm; dAb fragments (Ward et al., 1989 Nature 341:544-546), which are VH domain composition; and isolated complementarity determining regions (CDRs).
  • Fab fragments monovalent fragments consisting of the VL, VH, CL and CH1 domains
  • F(ab')2 fragments comprising two Fab fragments in the hinge region Bivalent fragments linked by disulfide bridges
  • Fd fragments composed of VH and CH1 domains Fv fragments composed of the VL and VH domains of an antibody one-arm
  • the steps of transforming host cells with recombinant DNA described in this disclosure can be performed using conventional techniques well known to those skilled in the art.
  • the obtained transformants can be cultured by conventional methods, and the transformants express the polypeptides encoded by the genes of the present disclosure.
  • the medium used in the culture can be selected from various conventional media depending on the host cells used. Cultivation is carried out under conditions suitable for growth of the host cells.
  • the engineered antibodies or antigen-binding fragments of the present disclosure can be prepared and purified using conventional methods.
  • cDNA sequences encoding heavy and light chains can be cloned and recombined into a GS expression vector.
  • the recombinant immunoglobulin expression vector can stably transfect CHO cells.
  • mammalian-like expression systems lead to glycosylation of the antibody, especially at the highly conserved N-terminal site of the Fc region.
  • Stable clones were obtained by expressing antibodies that specifically bind human IL-17. Positive clones were expanded in serum-free medium in bioreactors for antibody production.
  • the antibody-secreted culture medium can be purified by conventional techniques.
  • a or G Sepharose FF column with adjusted buffer. Non-specifically bound components are washed away. The bound antibody was eluted by a pH gradient method, and the antibody fragments were detected by SDS-PAGE and collected. Antibodies can be filtered and concentrated by conventional methods. Soluble mixtures and polymers can also be removed by conventional methods, such as molecular sieves, ion exchange. The obtained product should be frozen immediately, eg -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 numerous sites via weak non-covalent forces. The more interactions, the stronger the affinity.
  • Homology refers to the sequence similarity between two polynucleotide sequences or between two polypeptides. Two DNA molecules are homologous when a position in the two compared sequences is occupied by the same base or amino acid monomer subunit, for example if each position is occupied by an adenine, then the molecules are homologous at that position . The percent homology between the two sequences is a function of the number of matches or homologous positions shared by the two sequences divided by the number of positions compared x 100.
  • sequences are optimally aligned, two sequences are 60% homologous if 6 matches or homology at 10 positions in the two sequences; if 95 matches at 100 positions in the two sequences or homologous, then the two sequences are 95% homologous. In general, comparisons are made when the two sequences are aligned for the greatest percent homology.
  • Partial Response A patient who achieves a 50% improvement (also referred to as PASI50) but less than 75% improvement (also referred to as PASI75) from the baseline PASI score is defined as a Partial Responder.
  • Non-responders Patients with a ⁇ 50% reduction in PASI from baseline PASI score were defined as non-responders.
  • Relapse (Relapsers) Patients are considered “relapsers” if they have lost 50% of the PASI benefit achieved during the previous time period in the study.
  • Rebound Deterioration of baseline PASI value (or worsening of psoriatic lesions within 8 weeks of stopping therapy, eg, PASI > 125% of baseline PASI value.
  • the head and neck (H), upper extremities (U), trunk (T), and lower extremities (L) were assessed for erythema (E), thickening (plaque elevation, sclerosis) (I), and scaling (desquamation), respectively. crumbs) (D).
  • the mean severity of symptoms in each of the four body regions was assigned a score of 0 to 4.
  • the area covered by lesions on each body volume was estimated as a percentage of the total area of that particular body volume. Because the head and neck, upper extremities, trunk, and lower extremities correspond to approximately 10%, 20%, 30%, and 40% of body surface area, respectively, the PASI score was calculated using the following formula (the meaning of each parameter in the formula is as defined in Table 1):
  • 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 scores can range from a low value of 0 (corresponding to no symptoms of psoriasis) to a theoretical maximum of 72.0. PASI scores are accurate to one tenth, such as 9.0, 10.1, 14.2, 17.3, etc. Additional information on PASI scores can be obtained from Henseler T, Schmitt-Rau K (2008) Int. J. Dermatol.; 47: 1019-1023, or see related content in CN10315403 or US9717791, which are incorporated into the present disclosure for show instructions.
  • the sPGA is a static global assessment used by physicians to assess the current status/severity of a subject's psoriasis, usually by the sPGA score and the following words to estimate the severity: "clear”, “near clear”, “mild” , Moderate, Severe, or Very Severe.
  • sPGA(0,1) indicates that the current status/severity of psoriasis is clear or nearly clear.
  • sPGA response was defined as an sPGA score of 0 or 1 and an improvement of at least 2 points on the sPGA scale from baseline.
  • Anti-IL-17A antibody the sequences of heavy and light chains are shown in SEQ ID NO: 13 and SEQ ID NO: 14 in the present disclosure, 200 mg/branch, and 80 mg/mL for use.
  • the subject is a candidate for systemic therapy (systemic therapy)/or phototherapy/or chemophototherapy; or a subject poorly controlled by local therapy or phototherapy or previous systemic therapy (systemic therapy);
  • the PASI score of the subjects at the 12th week could be reduced by more than 90% compared with the baseline (Fig. 1 and Figure 2); when the steady-state trough concentration of the drug is greater than 12ug/mL, the PASI score of the subjects can be basically maintained at more than 90% after 12 weeks compared with the baseline.
  • TEAEs treatment-emergent adverse events
  • upper respiratory tract infection treatment group, 13.3% vs placebo, 16.2%
  • hyperuricemia treatment group, 7.3% vs placebo, 5.4%
  • TEAEs were mostly mild or moderate.
  • Serious TEAEs occurred in 1 (0.7%) treatment group subject and 2 (5.4%) placebo subjects, both considered unrelated to the drug.
  • One (0.7%) subject in the treatment group and one (2.7%) subject on placebo discontinued treatment due to TEAEs. No deaths were reported.
  • the anti-IL-17A antibodies of the present disclosure show better efficacy in patients with moderate to severe plaque psoriasis.
  • the number of PASI75 responders at the 240 mg dose was higher than at the other doses.
  • the anti-IL-17A antibodies of the present disclosure were well tolerated in this assay.

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Abstract

一种抗IL-17抗体治疗自身免疫性疾病和炎症的方法。具体而言，提供一种治疗自身免疫性疾病和炎症的方法，其包括：a)在诱导方案期间向患者施用抗IL-17抗体或其抗原结合片段；其中所述诱导方案包括以每2周一次或每3周一次的给药频率以60～300mg的给药剂量向患者施用抗IL-17抗体或其抗原结合片段；b)此后在维持方案期间向患者施用抗IL-17抗体或其抗原结合片段；且诱导方案和维持方案的给药剂量相同。

Description

抗IL-17抗体治疗自身免疫性疾病和炎症的方法 技术领域
本公开中涉及一种抗IL-17抗体或其抗原结合片段治疗自身免疫性疾病和炎症，如类风湿性关节炎、银屑病的方法。
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、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 PCTCN2022070077-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性关节炎。Ixekizumab
Figure PCTCN2022070077-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。
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)提供了一种治疗疾病或病症的方法，其包括：
a)在诱导方案期间向患者施用抗IL-17抗体或其抗原结合片段；其中所述诱导方案包括以每2周一次或每3周一次的给药频率以60～300mg的给药剂量向患者施用抗IL-17抗体或其抗原结合片段；
b)此后在维持方案期间向患者施用抗IL-17抗体或其抗原结合片段；
且诱导方案和维持方案的给药剂量相同。
在一些实施方案中，该方法包括：a)在诱导方案期间从第零周开始以每2周一次的给药频率向患者施用60～300mg的抗IL-17抗体或其抗原结合片段，给药次数为1～5次，例如3次。
在一些实施方案中，该方法包括：在诱导方案期间从第零周开始以每2周一次的给药频率向患者施用为80mg、120mg、160mg、200mg或240mg的抗IL-17抗体或其抗原结合片段，给药次数为1～5次，例如3次。
在一些实施方案中，该方法包括：a)在诱导方案期间从第零周开始以每2周一次的给药频率向患者施用240mg的抗IL-17抗体或其抗原结合片段，给药次数为1～5次，例如3次；b)在维持方案期间以每4周一次、每8周一次、每12周一次或每16周一次的给药频率向患者施用240mg的抗IL-17抗体或其抗原结合片段。
在一些实施方案中，该方法包括：a)在诱导方案期间从第零周开始以每2周一次的给药频率向患者施用240mg的抗IL-17抗体或其抗原结合片段，给药次数为3次；b)在维持方案期间以每4周一次的给药频率向患者施用240mg的抗IL-17抗体或其抗原结合片段。
本公开提供了一种治疗疾病或病症的方法，其包括：
a)在诱导方案期间向患者施用抗IL-17抗体或其抗原结合片段；
b)此后在维持方案期间向患者施用抗IL-17抗体或其抗原结合片段，其中所述维持方案包括以240mg的给药剂量向患者施用抗IL-17抗体或其抗原结合片段。
在一些实施方案中，该方法包括：
a)在诱导方案期间向患者施用抗IL-17抗体或其抗原结合片段；
b)此后在维持方案期间向患者施用抗IL-17抗体或其抗原结合片段，其中所述维持方案包括以每4周一次、每8周一次、每12周一次或每16周一次的给药频率以240mg 的给药剂量向患者施用抗IL-17抗体或其抗原结合片段。
在本公开的实施方案中，所述抗IL-17抗体或其抗原结合片段包含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HCDR序列：如SEQ ID NO：7、8和9氨基酸序列所示；和抗体轻链LCDR序列：如SEQ ID NO：10、11和12氨基酸序列所示。
在一些实施方案中抗IL-17抗体轻重链中CDR序列如下表所示：
Figure PCTCN2022070077-appb-000003
在一些实施方案中抗IL-17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。
在一些实施方案中，所述人源化抗体轻链和重链的框架区分别来源于人种系轻链和重链或其突变体；
在一些实施方案中，所述抗IL-17抗体含有氨基酸序列如SEQ ID NO:3所示的重链框架区或其变体，所述变体优选相对于SEQ ID NO:3所示的重链框架区序列具有0-10个氨基酸变化，特别是具有氨基酸回复突变A93T和T71A；所述抗IL-17抗体含有氨基酸序列如SEQ ID NO:4所示的轻链框架区或其变体，所述变体优选相对于SEQ ID NO:4所示的轻链框架区具有0-10个氨基酸变化的序列，特别是具有氨基酸回复突变F71Y、K49Y、Y36F和L47W。
重链可变区(VH1-18)
Figure PCTCN2022070077-appb-000004
Figure PCTCN2022070077-appb-000005
轻链可变区(A10)
Figure PCTCN2022070077-appb-000006
在一些实施方案中，前述抗IL-17抗体或其抗原结合片段序列的重链可变区或轻链可变区如下所示：
重链可变区
Figure PCTCN2022070077-appb-000007
轻链可变区
Figure PCTCN2022070077-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，本公开中所述抗IL-17抗体包含人源IgG1、IgG2、IgG3或IgG4同种型的重链恒定区，例如包含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-17抗体或其抗原结合片段包含κ或λ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 PCTCN2022070077-appb-000009
重链
Figure PCTCN2022070077-appb-000010
Figure PCTCN2022070077-appb-000011
另外，本公开抗IL-17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抗IL-17抗体治疗疾病或病症。
本公开提供了一种治疗疾病或病症的方法，其包括：
a)在诱导方案期间向患者施用抗IL-17抗体或其抗原结合片段；
b)此后在维持方案期间向患者施用抗IL-17抗体或其抗原结合片段；
其中所述抗IL-17抗体或其抗原结合片段包含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HCDR序列：如SEQ ID NO：7、8和9氨基酸序列所示；和抗体轻链LCDR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，所述抗IL-17抗体的轻链序列如SEQ ID NO:13所示，重链序列如SEQ ID NO:14所示。
根据疾病的类型、严重性、患者的体重和患者对药物耐受性，维持期间方案的抗IL-17抗体或其抗原结合片段的给药剂量为60～300mg，在实施方案中可为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，例如80mg、120mg、160mg、200mg或240mg，例如240mg。
进一步地，一些实施方案提供治疗方法中所述诱导方案的给药剂量可为60～300mg，例如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，例如80mg、120mg、160mg、200mg或240mg。
在一些实施方案中，诱导方案和维持方案的给药剂量相同。
在一些替代方案中，诱导方案和维持方案的给药剂量不同。
本公开所述诱导方案(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)给予抗IL-17抗体治疗疾病或病症。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，所述诱导方案包括从第零周开始每周给药一次，给药3次。
一些实施方案中所述诱导方案包括从第零周开始每周给药一次，给药4次。
一些实施方案中所述诱导方案包括从第零周开始每周给药一次，给药5次。
在一些实施方案中，所述诱导方案包括从第零周开始每2周给药一次，给药3次。
一些实施方案中所述诱导方案包括从第零周开始每2周给药一次，给药4次。
一些实施方案中所述诱导方案包括从第零周开始每2周给药一次，给药5次。
在一些实施方案中，所述诱导方案包括从第零周开始每3周给药一次，给药3次。
一些实施方案中所述诱导方案包括从第零周开始每3周给药一次，给药4次。
一些实施方案中所述诱导方案包括从第零周开始每3周给药一次，给药5次。
在一些实施方案中，所述诱导方案包括从第零周开始每4周给药一次(或每月给药一次)，给药3次。
一些实施方案中所述诱导方案包括从第零周开始每4周给药一次，给药4次。
一些实施方案中所述诱导方案包括从第零周开始每4周给药一次，给药5次。
进一步地，一些实施方案提供的治疗疾病或病症的方法中所述诱导方案包括如从第零周开始每周(如在第0/1/2/3周或第0/1/2/3/4/5周)向所述患者使用60～300mg(如80mg、120mg、160mg、200mg或240mg)剂量的前述抗IL-17抗体或其抗原结合片段。
一些实施方案中提供本公开治疗疾病或病症的方法中所述诱导方案包括如从第零周开始每2周(如第0/2周或第0/2/4周给药)向所述患者使用60～300mg(如80mg、120mg、160mg、200mg或240mg)剂量的前述抗IL-17抗体或其抗原结合片段。
一些实施方案中提供治疗疾病或病症的方法中所述诱导方案包括如从第零周开始每3周(如第0/3周或第0/3/6周给药)向所述患者使用60～300mg(如80mg、120mg、160mg、200mg或240mg)剂量的前述抗IL-17抗体或其抗原结合片段。
一些实施方案中提供治疗疾病或病症的方法中所述诱导方案包括如从第零周开始每4周(如第0/4周或第0/4/8周给药)向所述患者使用60～300mg(如80mg、120mg、160mg、200mg或240mg)剂量的前述抗IL-17抗体或其抗原结合片段。
另一方面，本公开所述治疗疾病或病症的方法中维持治疗期间的给药频率选自每4周一次、每6周一次、每8周一次、每10周一次、每12周一次、每14周一次或每16周一次或更低给药频率。
一些实施方案提供治疗疾病或病症的方法中的维持期间方案包括向患者施用60～300mg(如80mg、120mg、160mg、200mg或240mg)剂量的抗IL-17抗体或其抗原结合片段，给药频率每4周一次。
一些实施方案提供治疗疾病或病症的方法中的维持期间方案包括向患者施用60～300mg(如80mg、120mg、160mg、200mg或240mg)剂量的抗IL-17抗体或其抗原结合片段，给药频率每月一次。
一些实施方案提供治疗疾病或病症的方法中的维持期间方案包括向患者施用60～300mg(如80mg、120mg、160mg、200mg或240mg)剂量的抗IL-17抗体或其抗原结合片段，给药频率每6周一次。
一些实施方案提供治疗疾病或病症的方法中的维持期间方案包括向患者施用60～300mg(如80mg、120mg、160mg、200mg或240mg)剂量的抗IL-17抗体或其抗原结合片段，给药频率每8周一次。
一些实施方案提供治疗疾病或病症的方法中的维持期间方案包括向患者施用60～300mg(如80mg、120mg、160mg、200mg或240mg)剂量的抗IL-17抗体或其抗原结合片段，给药频率每2月一次。
一些实施方案提供治疗疾病或病症的方法中的维持期间方案包括向患者施用60～300mg(如80mg、120mg、160mg、200mg或240mg)剂量的抗IL-17抗体或其抗原结合片段，给药频率每12周一次。
一些实施方案提供治疗疾病或病症的方法中的维持期间方案包括向患者施用60～300mg(如80mg、120mg、160mg、200mg或240mg)剂量的抗IL-17抗体或其抗原结合片段，给药频率每3月一次。
一些实施方案提供治疗疾病或病症的方法中的维持期间方案包括向患者施用60～300mg(如80mg、120mg、160mg、200mg或240mg)剂量的抗IL-17抗体或其抗原结合片段，给药频率每4月一次。
一些实施方案提供治疗疾病或病症的方法中，包括：a)在诱导方案期间从第零周开始每周给药一次向患者施用160mg或240mg的抗IL-17抗体或其抗原结合片段，给药3或5次；b)在维持方案期间以每8周或每12周一次向患者施用160mg或240mg的IL-17抗体或其抗原结合片段。
一些实施方案提供治疗疾病或病症的方法中，包括：a)在诱导方案期间从第零周开始每周给药一次向患者施用160mg或240mg的抗IL-17抗体或其抗原结合片段，给药3或5次；b)在维持方案期间以每两个月或每三个月一次向患者施用160mg或240mg的IL-17抗体或其抗原结合片段。
一些实施方案提供治疗疾病或病症的方法中，包括：a)在诱导方案期间从第零周开始每2周给药一次向患者施用160mg或240mg的抗IL-17抗体或其抗原结合片段，给药3或5次；b)在维持方案期间以以每8周或每12周一次向患者施用160mg或240mg的IL-17抗体或其抗原结合片段。
一些实施方案提供治疗疾病或病症的方法中，包括：a)在诱导方案期间从第零周开始每4周给药一次向患者施用160mg或240mg的抗IL-17抗体或其抗原结合片段，给药3或5次；b)在维持方案期间以每两个月或每三个月一次向患者施用160mg或240mg的IL-17抗体或其抗原结合片段。
一些实施方案提供治疗疾病或病症的方法中，包括：a)在诱导方案期间从第零周开始每4周给药一次向患者施用160mg或240mg的抗IL-17抗体或其抗原结合片段，给药1～5次；b)在维持方案期间以每两个月、每三个月或每四个月一次向患者施用160mg或240mg的抗IL-17抗体或其抗原结合片段。
一些实施方案提供治疗疾病或病症的方法中，包括：a)在诱导方案期间从第零周开始每4周给药一次向患者施用160mg或240mg的抗IL-17抗体或其抗原结合片段，给药1～5次；b)在维持方案期间以每8周、每12周或每16周一次向患者施用160mg或240mg的抗IL-17抗体或其抗原结合片段。
另一实施方案提供治疗疾病或病症的方法中，包括a)在诱导方案期间从第零周开始每4周给药一次向患者施用160mg或240mg的抗IL-17抗体或其抗原结合片段，给药次数为3次；b)在维持方案期间以每12周一次向患者施用240mg的抗IL-17抗体或其抗 原结合片段。
另一实施方案提供治疗疾病或病症的方法中，包括：a)在诱导方案期间从第零周开始以每2周一次的给药频率向患者施用240mg的抗IL-17抗体或其抗原结合片段，给药次数为1～5次，例如3次；b)在维持方案期间以每4周一次的给药频率向患者施用240mg的抗IL-17抗体或其抗原结合片段。
本公开的治疗方法进行一个或多个治疗周期，治疗周期是指按照特定的剂量方案从首次给药开始连续给药的一段时间。例如在本公开中，治疗周期包括诱导方案和维持方案的总时长。在一些实施方案中，每个治疗周期为至少6周、至少10周、至少16周、至少20周、至少24周、至少28周、至少32周、至少36周、至少40周、至少44周、至少48周、至少52周、至少56周、至少1年、至少2年或更久。在一些实施方案中，每个治疗周期为6周至52周，例如16至48周，例如20周至48周。
本公开时间单位“月”与“周”、“月”与“年”在某些情况下可以适当换算，通常4周约为1月，12个月约为1年。
本公开所述治疗抗IL-17抗体或其抗原结合片段介导的疾病或病症的方法中所述患者患有中度至严重活跃性强直性脊柱炎。
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跃性强直性脊柱炎的患者施用60～300mg剂量的抗IL-17抗体或其抗原结合片段后，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，本公开所述治疗抗IL-17抗体或其抗原结合片段介导的疾病或病症的方法中所述患者患有活跃性银屑病性关节炎，例如所述患者患有共存银屑病。
在一些实施方案中，所述患者是TNFi失败或甲氨碟呤(DMARD)失败。
在一些实施方案中，本公开所述治疗方法包括：在向患有活跃性银屑病性关节炎的患者施用60～300mg剂量的抗IL-17抗体或其抗原结合片段后，所述患者进一步施用甲氨碟呤。
另一方面，本公开所述治疗抗IL-17抗体或其抗原结合片段介导的疾病或病症的方法中所述患者患有斑块状银屑病，例如所述患者患有中度至重度斑块状银屑病。
本公开所述治疗抗IL-17抗体或其抗原结合片段介导的疾病或病症的方法中所述患 者患有中度至重度慢性斑块状银屑病。
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60～300mg剂量的抗IL-17抗体或其抗原结合片段前，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60～300mg剂量的抗IL-17抗体或其抗原结合片段前，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，例如甲氨蝶呤。
本公开提供了抗IL-17抗体在制备治疗疾病或病症的药物中用途，其中所述药物经配制以容器存放，以容许向抗IL-17抗体或其抗原结合片段介导的疾病或病症患者施用有效量的结合IL-17。
本公开还提供了一种治疗疾病或病症的方法，该方法包括向患者施用有效量的抗IL-17抗体或其抗原结合片段，给药频率每4-16周一次，包括但不限于4、6、8、10、12、14或16周一次。
进一步地，在可选实施方案中，本公开中给药频率4-12周一次的治疗方法中可包括或不包括诱导方案(loading)。例如所述诱导方案如前所述。
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，例如皮下注射。
在本公开中的实施方案中，所述抗IL-17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，注射前需将抗IL-17抗体或其抗原结合片段配制成可注射的形式。例如，抗IL-17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，其包含抗IL-17抗体或其抗原结合片段、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，例如二糖，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，例如所述聚氧乙烯山梨醇酐脂肪酸酯为聚山梨酯20、40、60或80，例如聚山梨酯20。例如IL-17抗体或其抗原结合片段的可注射形式包含抗IL-17抗体或其抗原结合片段、组氨酸盐酸盐缓冲剂、蔗糖和聚山梨醇酯80。
本公开还提供了抗IL-17抗体或其抗原结合片段在制备治疗自身免疫性疾病和炎 症，如类风湿性关节炎、银屑病的药物中的用途。
如无相反解释，本公开中术语具有如下含义：
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针对人 IL-17的单克隆抗体。制备时用IL-17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。在本公开一个的实施方案中，鼠源抗IL-17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。
本公开中所述抗IL-17抗体或其抗原结合片段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，所述抗IL-17抗体或其抗原结合片段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抗体或其抗原结合片段的组合物，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)。
“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IL-17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，分别评估头颈(H)、上肢(U)、躯干(T)及下肢(L)的红斑(E)、增厚(斑块隆起、硬化)(I)及起鳞(脱屑)(D)。
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(公式中各参数的含义如表1中所定义)：
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
表1 公式中各参数的含义
Figure PCTCN2022070077-appb-000012
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。
sPGA是医师使用的静态全面评估，用于评估受试者银屑病的当前状态/严重程度，通常由sPGA分数和以下词语来估计严重程度：“清除”、“近乎清除”、“轻度”、“中度”、“重度”或“极重度”。sPGA(0,1)表示银屑病的当前状态/严重程度为清除或近乎清除。sPGA应答被定义为sPGA评分为0或1，且sPGA量表比基线时至少提高了2分。
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
抗IL-17A抗体，重、轻链的序列如本公开中SEQ ID NO:13和SEQ ID NO:14所示，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；或者局部治疗或光疗或先前的全身治疗(系统治疗)控制不良的受试者；
(3)中度至重度斑块型银屑病同时符合以下条件：
PASI评分≥12分；
PGA评分≥3分；和
BSA评分≥10％。
3、治疗方案
方案1：抗IL-17A抗体，固定剂量40mg，皮下注射，每4周1次；
方案2：抗IL-17A抗体，固定剂量80mg，皮下注射，每4周1次；
方案3：抗IL-17A抗体，固定剂量160mg，皮下注射，每4周1次；
方案4：抗IL-17A抗体，固定剂量240mg，皮下注射，每4周1次；
方案5：抗IL-17A抗体，固定剂量240mg，皮下注射，每8周1次；
方案6：抗IL-17A抗体，固定剂量240mg，皮下注射，每2周1次，给药3次，此后固定剂量240mg，皮下注射，每4周1次；
方案7：抗IL-17A抗体，固定剂量240mg，皮下注射，每4周1次，给药3次，此后固定剂量240mg，皮下注射，每12周1次；安慰剂组：不接受任何积极治疗。
4、结果
364例受试者参与临床试验，291例受试者暴露于抗IL-17A抗体(健康受试者72例和银屑病或者中轴型脊柱关节炎受试者219例)，73例受试者接受了安慰剂治疗。以80mg、160mg、240mg的剂量每2周一次连续3次皮下注射，在银屑病患者中PASI75和PASI90均逐渐升高，显示对银屑病患者有一定的疗效。分析药代动力学(PK)以及疗效数据发现：抗IL-17A抗体的血清暴露量与PASI评分较基线下降百分比存在较好的相关性，血清药物暴露量越高，PASI评分较基线下降百分比越大。当第12周的血清药物浓度大于8ug/mL，并且前12周内AUC 0-12W大于1300day*ug/mL时，受试者12周时的PASI评分较基线下降基本可达到90％以上(图1和图2)；当药物稳态谷浓度大于12ug/mL时，受试者12周后PASI评分较基线下降基本可维持在90％以上。
187受试者被随机接受40mg(37名受试者)、80mg(38名受试者)、160mg(38名受试者)或240mg(37名受试者)剂量的抗IL-17A抗体或安慰剂(37名受试者)，每4周给药一次给药12周。结果显示，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。具体地，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，本公开抗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，240mg剂量的PASI75应答者数量高于其他剂量。本公开抗IL-17A抗体在本试验中耐受性良好。

Claims (22)

  1. 一种治疗疾病或病症的方法，其包括：
    a)在诱导方案期间向患者施用抗IL-17抗体或其抗原结合片段；其中所述诱导方案包括以每2周一次或每3周一次的给药频率以60～300mg的给药剂量向患者施用抗IL-17抗体或其抗原结合片段；
    b)此后在维持方案期间向患者施用抗IL-17抗体或其抗原结合片段；
    且诱导方案和维持方案的给药剂量相同。
  2. 如权利要求1所述的方法，其中诱导方案中给药剂量为80mg、120mg、160mg、200mg或240mg，优选240mg。
  3. 如权利要求1或2所述的方法，其中，诱导方案中给药次数为1～6次，优选2～4次，更优选3次。
  4. 如权利要求1-3任一项所述的方法，包括：a)在诱导方案期间从第零周开始以每2周一次的给药频率向患者施用240mg的抗IL-17抗体或其抗原结合片段，给药次数为1～5次，优选3次；b)在维持方案期间向患者施用240mg的抗IL-17抗体或其抗原结合片段，优选在维持方案期间以每4周一次的给药频率向患者施用240mg的抗IL-17抗体或其抗原结合片段。
  5. 如权利要求1-4任一项所述的方法，所述方法进行一个或多个治疗周期，其中每个治疗周期为6周至52周，优选16至48周，更优选20周至48周。
  6. 一种治疗疾病或病症的方法，其包括：
    a)在诱导方案期间向患者施用抗IL-17抗体或其抗原结合片段；
    b)此后在维持方案期间向患者施用抗IL-17抗体或其抗原结合片段，其中所述维持方案包括以每4周一次、每8周一次、每12周一次或每16周一次，优选每4周一次的给药频率以240mg的给药剂量向患者施用抗IL-17抗体或其抗原结合片段。
  7. 如权利要求1-6任一项所述的方法，其中给药方式为口服、静脉或皮下给 药。
  8. 如权利要求1-7任一项所述的方法，其中所述疾病或病症选自炎症或自身免疫疾病；所述疾病或病症优选为银屑病、银屑病关节炎、强直性脊柱炎、多发性硬化症、和/或炎性关节炎，更优选银屑病。
  9. 如权利要求1-8任一项所述的方法，其中所述抗IL-17抗体或其抗原结合片段包含1个或多个选自以下的CDR或与其具有至少95％序列同一性的氨基酸序列：
    氨基酸序列分别如SEQ ID NO：7、8和9所示的抗体重链HCDR1、HCDR2和HCDR3；和氨基酸序列分别如SEQ ID NO：10、11和12所示的抗体轻链LCDR1、LCDR2和LCDR3。
  10. 如权利要求9所述的方法，其中所述抗IL-17抗体选自鼠源抗体、嵌合抗体、人源化抗体。
  11. 如权利要求10所述的方法，其中所述人源化抗体轻链和重链的框架区分别来源于人种系轻链和重链或其突变体；
    优选地，所述抗IL-17抗体含有氨基酸序列如SEQ ID NO:3所示的重链框架区或其变体，所述变体优选相对于SEQ ID NO:3所示的重链框架区序列具有0-10个氨基酸变化，特别是具有氨基酸回复突变A93T和T71A；所述抗IL-17抗体含有氨基酸序列如SEQ ID NO:4所示的轻链框架区或其变体，所述变体优选相对于SEQ ID NO:4所示的轻链框架区具有0-10个氨基酸变化的序列，特别是具有氨基酸回复突变F71Y、K49Y、Y36F和L47W。
  12. 如权利要求10所述的方法，其中所述人源化抗体含有SEQ ID NO:5所示的重链可变区；所述的人源化抗体含有SEQ ID NO:6所示的轻链可变区。
  13. 如权利要求1-13任一项所述的方法，其中所述抗IL-17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同种型的重链恒定区。
  14. 如权利要求1-13任一项所述的方法，其中所述抗IL-17抗体或其抗原结合片段包含κ或λ轻链恒定区。
  15. 如权利要求1-14任一项所述的方法，其中所述抗IL-17抗体或其抗原结合片段包含SEQ ID NO:13所示的轻链及其变体，和SEQ ID NO:14所示的重链及其变体。
  16. 如权利要求1-15任一项所述的方法，其中所述患者患有中度至严重活跃性强直性脊柱炎，优选所述患者为先前经至少一种NSAID治疗而应答不足的。
  17. 如权利要求16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，优选甲氨蝶呤。
  18. 如权利要求17所述的方法，其中所述患者患有活跃性银屑病性关节炎，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。
  19. 如权利要求1-18任一项所述的方法，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，更优选所述患者患有中度至重度慢性斑块状银屑病。
  20. 如权利要求1-19任一项所述的方法，其中，在用抗IL-17抗体或其抗原结合片段治疗之前，所述患者先前未用银屑病的全身治疗剂治疗。
  21. 如权利要求1-19任一项所述的方法，其中，在用抗IL-17抗体或其抗原结合片段治疗之前，所述患者先前已经用银屑病的全身治疗剂治疗。
  22. 如权利要求20或21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。
PCT/CN2022/070077 2021-01-04 2022-01-04 抗il-17抗体治疗自身免疫性疾病和炎症的方法 WO2022144023A1 (zh)

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