WO2022184114A1 - 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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WO2022184114A1
WO2022184114A1 PCT/CN2022/078917 CN2022078917W WO2022184114A1 WO 2022184114 A1 WO2022184114 A1 WO 2022184114A1 CN 2022078917 W CN2022078917 W CN 2022078917W WO 2022184114 A1 WO2022184114 A1 WO 2022184114A1
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antibody
weeks
subject
need
once
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French (fr)
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许倩
邹建军
孙飘扬
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苏州盛迪亚生物医药有限公司
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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    • 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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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 of treating autoimmune diseases and inflammations, such as ankylosing spondylitis, with an anti-IL-17 antibody.
  • the cytokines of the interleukin-17 (IL-17) family are named interleukin-17A (IL-17A) to interleukin-17F, and these IL-17 cytokines can bind to the corresponding receptor members, thereby mediating different inflammatory response.
  • IL-17A The most representative member of this family is IL-17A.
  • IL-17A is secreted by lymphocytes that have migrated to infected or injured parts of the body.
  • IL-17A induces the expression of inflammatory factors and chemokines, thereby recruiting more immune cells to the site of inflammation to exacerbate the inflammatory response; on the other hand, IL-17A also induces the expression of some tissue repair-related factors, thereby Speed up the recovery of the body.
  • IL-17A plays a role in expanding the immune defense response and protecting the body in the process of host anti-infection and tissue repair
  • IL-17A is highly expressed in many autoimmune disease patients and tumor patients
  • excessive IL-17A 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 absence of IL-17A or the neutralization of IL-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 Approved by the FDA/EMA for the treatment of moderate to severe plaque psoriasis in adults.
  • Ankylosing spondylitis is a chronic inflammatory disease with a relatively insidious onset. Most of the patients present with progressive lower back or sacroiliac pain and/or morning stiffness. The disease mainly invades the sacroiliac joints, vertebral condyles, paraspinal soft tissues and peripheral joints. In severe cases, spinal deformity and rigidity may occur. AS can also be accompanied by extra-articular manifestations of multiple systems such as thorax, lung, heart, and iris. The global prevalence of AS ranges from 0.1 to 1.4%, and the prevalence of AS in my country is about 0.3%, with a male to female ratio of about 2 to 3:1. The age of onset of this disease is usually 13-31 years old, and the peak age is 20-30 years old. Most of the patients are young adults, which has a huge impact on the physical and mental health of patients and brings a huge burden to the society.
  • the present disclosure provides advantageous IL-17 antibodies (eg, anti-IL-17A antibodies) and clinical dosing regimens thereof for the treatment of autoimmune diseases and inflammations (eg, ankylosing spondylitis).
  • advantageous IL-17 antibodies eg, anti-IL-17A antibodies
  • clinical dosing regimens thereof for the treatment of autoimmune diseases and inflammations (eg, ankylosing spondylitis).
  • the disclosure provides a method of treating, preventing a disease or disorder comprising an induction regimen; or a) an induction regimen and b) a maintenance regimen. Both the a) induction regimen and b) maintenance regimen comprise administering an anti-IL-17 antibody to a subject in need thereof. In some embodiments, b) the maintenance regimen is followed by the a) induction regimen.
  • a method of treating, preventing a disease or disorder comprising: an induction regimen during which an anti-IL-17 antibody is administered to a subject in need thereof; wherein the induction regimen comprises: The anti-IL-17 antibody is administered to a subject in need thereof at a dosing frequency of once every 2 weeks or once every 3 weeks.
  • a method of treating, preventing a disease or disorder comprising: a) an induction regimen during which an anti-IL-17 antibody is administered to a subject in need thereof; wherein the induction regimen comprising administering an anti-IL-17 antibody to a subject in need thereof at a dosing frequency of once every 2 weeks or once every 3 weeks, and the method further comprises b) a maintenance regimen followed by administering to all subjects during the maintenance regimen The subject in need thereof is administered an anti-IL-17 antibody.
  • the anti-IL-17 antibody is administered to a subject in need thereof in a therapeutically effective amount. In other embodiments, the anti-IL-17 antibody is administered to a subject in need thereof in a prophylactically effective amount.
  • a) during the induction regimen 40-300 mg of anti-IL-17 antibody is administered to the subject in need at a dosing frequency of once every 2 weeks starting from week 0,
  • the number of times of the medicine is 1 to 5 times, for example, 3 times.
  • the subject in need is administered an anti-IL-IL-120 mg or 240 mg at a dosing frequency of once every 2 weeks starting from week zero.
  • the administration frequency is 1 to 5 times, for example, 2, 3, and 4 times.
  • a method of treating, preventing a disease or disorder comprising: a) administering to a subject in need thereof, during an induction regimen, 120 mg at a dosing frequency of once every 2 weeks starting at week zero or 240 mg of anti-IL-17 antibody, administered at a frequency of 1 to 5 times, such as 2, 3, 4 times; and, in the following b) once every 4 weeks, once every 8 weeks, every 12 weeks during the maintenance regimen
  • Subjects in need are administered 120 mg or 240 mg of anti-IL-17 antibody at a weekly or every 16-week dosing frequency.
  • a method of treating, preventing a disease or disorder comprising: a) administering to a subject in need thereof, during an induction regimen, 120 mg at a dosing frequency of once every 2 weeks starting at week zero or 240 mg of anti-IL-17 antibody in 3 doses; and, in subsequent b) during the maintenance regimen, administer 120 mg or 240 mg of anti-IL-17 antibody to subjects in need at a dosing frequency of once every 4 weeks IL-17 antibody.
  • the present disclosure provides a method of treating or preventing a disease or disorder, comprising:
  • an induction regimen during which an anti-IL-17 antibody is administered to a subject in need thereof; and, followed by b) a maintenance regimen, during which an anti-IL-17 antibody is administered to a subject in need thereof
  • An IL-17 antibody wherein the maintenance regimen comprises administering an anti-IL-17 antibody to a subject in need thereof at a dosing dose of 120 mg or 240 mg.
  • the method includes:
  • a maintenance regimen during which an anti-IL-17 antibody is administered to a subject in need thereof wherein the maintenance regimen comprises administration of an anti-IL-17 antibody every 4 weeks, every 8 weeks, every 12 weeks, or every 16 weeks
  • the anti-IL-17 antibody is administered to a subject in need thereof at a dosing dose of 120 mg or 240 mg at a one-time dosing frequency.
  • the dosage of maintenance regimen and induction regimen may be selected or adjusted according to the type of disease, severity, body weight of the subject in need, and tolerance to the drug of the subject in need.
  • the administered dose of anti-IL-17 antibody in the maintenance regimen is 40-300 mg, eg, selected from 40 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 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 240 mg, 245 mg, 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, such as
  • the administered dose of anti-IL-17 antibody in the induction regimen may be 40-300 mg, eg, selected from 40 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg , 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 , 240 mg, 245 mg, 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
  • the induction regimen and the maintenance regimen are administered at the same dose. In some alternatives, 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 weekly dosing starting at week zero for 3 dosings.
  • the induction regimen includes weekly dosing starting at week zero for 4 dosings.
  • the induction regimen includes weekly dosing starting at week zero for 5 dosings.
  • the induction regimen includes 3 dosing 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 dosings 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 dosings every 4 weeks starting at week zero.
  • the induction regimen in some embodiments comprises, as from week zero (eg, at week 0/1/2/3 or week 0/1/2/3/4/5), increasing The subject uses a dose of 40-300 mg (eg, 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg) of the aforementioned anti-IL-17 antibodies.
  • the induction regimen comprises administering to the subject in need 40-300 mg every 2 weeks (eg, dosing at Week 0/2 or Week 0/2/4), such as starting at Week 0 (eg, 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg) of the aforementioned anti-IL-17 antibodies.
  • the induction regimen comprises administering to the subject in need 40-300 mg every 3 weeks (eg, dosing at Week 0/3 or Week 0/3/6), such as starting at Week 0 (eg, 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg) of the aforementioned anti-IL-17 antibodies.
  • the induction regimen comprises administering to the subject in need 40-300 mg every 4 weeks (eg, dosing at Week 0/4 or Week 0/4/8), such as starting at Week 0 (eg, 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg) of the aforementioned anti-IL-17 antibodies.
  • the frequency of administration during maintenance treatment is selected from the group consisting of once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, and once every 12 weeks Dosing once, every 14 weeks, or every 16 weeks or less frequently.
  • the maintenance regimen comprises administering to a subject in need thereof a dose of 40-300 mg (eg, 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg) of an anti-IL-17 antibody at a frequency of every 4 weeks .
  • the maintenance regimen comprises administering to a subject in need thereof a dose of 40-300 mg (eg, 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg) of an anti-IL-17 antibody, with a monthly dosing frequency.
  • a dose of 40-300 mg eg, 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg
  • the maintenance regimen comprises administering to a subject in need thereof a dose of 40-300 mg (eg, 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg) of an anti-IL-17 antibody at a frequency of every 6 weeks .
  • the maintenance regimen comprises administering to a subject in need thereof a dose of 40-300 mg (eg, 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg) of an anti-IL-17 antibody, once every 8 weeks .
  • a dose of 40-300 mg eg, 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg
  • the maintenance regimen comprises administering to a subject in need thereof a dose of 40-300 mg (eg, 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg) of an anti-IL-17 antibody, once every 2 months .
  • a dose of 40-300 mg eg, 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg
  • the maintenance regimen comprises administering to a subject in need thereof a dose of 40-300 mg (eg, 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg) of an anti-IL-17 antibody, once every 12 weeks .
  • a dose of 40-300 mg eg, 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg
  • the maintenance regimen comprises administering to a subject in need thereof a dose of 40-300 mg (eg, 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg) of an anti-IL-17 antibody, once every 3 months .
  • a dose of 40-300 mg eg, 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg
  • the maintenance regimen comprises administering to a subject in need thereof a dose of 40-300 mg (eg, 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg) of an anti-IL-17 antibody, at a frequency of every 4 months .
  • a dose of 40-300 mg eg, 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg
  • the methods of treating, preventing a disease or disorder of the present disclosure comprise: a) administering to a subject in need thereof 160 mg or 240 mg of anti-IL-17 once weekly starting from week zero during an induction regimen Antibody, administered 3 or 5 times; and, following b) administration of 160 mg or 240 mg of IL-17 antibody to subjects in need every 4 weeks or every 8 weeks during the maintenance regimen.
  • a method of treating, preventing a disease or disorder of the present disclosure comprises: a) administering to a subject in need thereof 120 mg or 240 mg of anti-IL- 17 antibody, administered 3 or 5 times; and, following b) administer 120 mg or 240 mg of IL-17 antibody to subjects in need every 4 weeks or every 8 weeks during the maintenance regimen.
  • a method of treating, preventing a disease or disorder of the present disclosure comprises: a) administering to a subject in need thereof 120 mg or 240 mg of the Anti-IL-17 antibody, administered at a frequency of 1 to 5, eg, 3; and, b) 120 mg or 240 mg administered to subjects in need thereof at a dosing frequency of once every 4 weeks during the maintenance regimen of anti-IL-17 antibodies.
  • a method of treating, preventing a disease or disorder of the present disclosure comprises: a) administering to a subject in need thereof 120 mg of anti-IL at a dosing frequency of once every 2 weeks starting at week zero during an induction regimen -17 antibody, administered 3 times; and, following b) administer 120 mg of anti-IL-17 antibody to subjects in need at a dosing frequency of once every 4 weeks during the maintenance regimen for at least 6 doses (eg 6, 7, 8, 9, 10, 11, 12 times).
  • a method of treating, preventing a disease or disorder of the present disclosure comprises: a) administering to a subject in need thereof 240 mg of anti-IL at a dosing frequency of once every 2 weeks starting at week zero during an induction regimen -17 antibody, administered 3 times; and, following b) administer 240 mg of anti-IL-17 antibody to subjects in need at a dosing frequency of once every 4 weeks for at least 6 doses during the maintenance regimen (eg 6, 7, 8, 9, 10, 11, 12 times).
  • 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, 16 to 32 weeks.
  • the disease or disorder in the aforementioned methods of the present disclosure is an autoimmune disease or inflammation.
  • the disease or disorder in the aforementioned methods of the present disclosure is spondyloarthritis, such as axial spondyloarthritis or peripheral spondyloarthritis, as well as ankylosing spondylitis, psoriatic arthritis, enteropathic arthritis , such as moderate to severe ankylosing spondylitis.
  • examples of axial spondyloarthritis in the aforementioned methods of the present disclosure include, but are not limited to, ankylosing spondylitis, non-radiation axial spondyloarthritis (nr-axSpA).
  • the disease or disorder in the aforementioned methods of the present disclosure is active ankylosing spondylitis, eg, moderately to severely active ankylosing spondylitis.
  • the disease or disorder in the aforementioned methods of the present disclosure is Graves' eye disease, plaque psoriasis.
  • the subject in need thereof in the methods of the present disclosure has been diagnosed with, or is expected to have, the aforementioned disease or disorder.
  • the subject in need is one who has had an inadequate response to prior treatment with at least one non-steroidal anti-inflammatory drug (NSAID), or the subject in need is contraindicated or not to NSAIDs. tolerance.
  • NSAIDs include, but are not limited to, aspirin, ibuprofen, acetaminophen, indomethacin, naproxen, naprodone, diclofenac, nimesulide, rofecoxib, and celecoxib cloth.
  • the subject in need is further administered an NSAID, acetaminophen, a weak opioid after administration of an anti-IL-17 antibody in the aforementioned method of treatment of the present disclosure to the subject in need , disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, sulfasalazine, or glucocorticoids such as prednisolone.
  • DMARDs disease-modifying antirheumatic drugs
  • the subject in need thereof has not been previously treated with one or more therapeutic agents selected from the group consisting of TNF-alpha inhibition prior to anti-IL-17 antibody treatment with the aforementioned methods of treatment of the present disclosure IL-6 inhibitors, IL-1 inhibitors, anti-CD20 antibodies, cytotoxic T lymphocyte-associated antigen 4 antibodies, IL-23 inhibitors, and other IL-17 inhibitors.
  • one or more therapeutic agents selected from the group consisting of TNF-alpha inhibition prior to anti-IL-17 antibody treatment with the aforementioned methods of treatment of the present disclosure IL-6 inhibitors, IL-1 inhibitors, anti-CD20 antibodies, cytotoxic T lymphocyte-associated antigen 4 antibodies, IL-23 inhibitors, and other IL-17 inhibitors.
  • the subject in need has been previously treated with one or more therapeutic agents selected from the group consisting of TNF- ⁇ inhibition prior to anti-IL-17 antibody treatment with the aforementioned methods of treatment of the present disclosure IL-6 inhibitors, IL-1 inhibitors, anti-CD20 antibodies, cytotoxic T lymphocyte-associated antigen 4 antibodies, IL-23 inhibitors, and other IL-17 inhibitors.
  • one or more therapeutic agents selected from the group consisting of TNF- ⁇ inhibition prior to anti-IL-17 antibody treatment with the aforementioned methods of treatment of the present disclosure IL-6 inhibitors, IL-1 inhibitors, anti-CD20 antibodies, cytotoxic T lymphocyte-associated antigen 4 antibodies, IL-23 inhibitors, and other IL-17 inhibitors.
  • examples of TNF-alpha inhibitors include, but are not limited to, adalimumab, infliximab, certolizumab, golimumab, or etanercept; Examples include, but are not limited to, Tocilizumab or Sarilumab; IL-1 inhibitors such as anakinra; anti-CD20 antibodies such as rituximab; cytotoxic T lymphocyte-associated antigen 4 antibodies such as abatacept; examples of IL-23 inhibitors include, but are not limited to, tilazumab or Guselkunab; or examples of other IL-17 inhibitors include, but are not limited to, Secukinumab, ixekizumab ( Ixekizumab) or Brodalumab.
  • the present disclosure also provides a method of treating or preventing the aforementioned disease or disorder (eg, ankylosing spondylitis), the method comprising administering to a subject in need thereof an effective amount of the aforementioned anti-IL-17 antibody of the present disclosure, administering Frequency every 4-16 weeks, including but not limited to 4, 6, 8, 10, 12, 14, or 16 weeks.
  • the aforementioned disease or disorder eg, ankylosing spondylitis
  • 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 aforementioned anti-IL-17 antibodies are anti-IL-17A and/or anti-IL-17F antibodies.
  • the anti-IL-17A antibody 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 sequence shown as SEQ ID NO: 5, 6 and 7 amino acid sequence respectively; antibody light chain LCDR sequence: shown as SEQ ID NO: 8, 9 and 10 amino acid sequence respectively.
  • the CDR sequences in the heavy chain variable region (VH) and light chain variable region (VL) of the anti-IL-17A antibody are shown in the following table:
  • the anti-IL-17A antibody is selected from the group consisting of murine antibodies, chimeric antibodies, recombinant antibodies of humanized antibodies.
  • the light and heavy chain FR region sequences on the light and heavy chain variable regions of the humanized anti-IL-17A antibody, respectively, are derived from human germline light and heavy chains or mutant sequences thereof.
  • the anti-IL-17A antibody contains a heavy chain framework region having an amino acid sequence set forth in SEQ ID NO: 1 or a variant thereof, preferably relative to the heavy chain set forth in SEQ ID NO: 1
  • the framework region sequence has 0-10 amino acid changes, especially with amino acid back mutations A93T and/or 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: 2
  • the variant preferably has a sequence with 0-10 amino acid changes relative to the light chain framework region shown in SEQ ID NO: 2, in particular with amino acid back mutations F71Y, K49Y, Y36F and/or L47W.
  • the anti-IL-17A antibody contains a heavy chain variable region having an amino acid sequence set forth in SEQ ID NO:3 and a light chain variable region having an amino acid sequence set forth in SEQ ID NO:4.
  • the anti-IL-17A antibody comprises HCDR1, HCDR2, HCDR3 having the amino acid sequences set forth in SEQ ID NOs: 5, 6, and 7, respectively, and the amino acids set forth in SEQ ID NOs: 8, 9, and 10, respectively Sequence LCDR1, LCDR2, LCDR3.
  • the light chain sequence of the anti-IL-17 antibody is set forth in SEQ ID NO: 11 and the heavy chain sequence is set forth in SEQ ID NO: 12.
  • VH1-18 Human germline heavy chain variable region
  • Humanized antibody design also takes into account factors such as mutation of Q1E to eliminate N-terminal pyroglutamic acid formation, and mutations including those that maintain identity within the selected VH family to maintain the canonical structure of the CDRs and VH /VL interface to avoid N-glycosylation patterns (N- ⁇ P ⁇ -S/T) in humanized structures, etc.
  • 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-17A antibody comprises a kappa or lambda light chain constant region.
  • the light chain of the humanized anti-IL-17A antibody comprises or is the amino acid sequence set forth in SEQ ID NO: 11
  • the heavy chain comprises or is the amino acid sequence set forth in SEQ ID NO: 12
  • the route of administration of the anti-IL-17 antibody in the present disclosure can be oral administration, parenteral administration, and the parenteral administration includes but is not limited to intravenous injection, subcutaneous injection, and intramuscular injection.
  • the anti-IL-17 antibody of the present disclosure is administered by injection, eg, subcutaneously or intravenously, and the anti-IL-17 antibody is formulated into a pharmaceutical composition in injectable form prior to injection.
  • the injectable form of the anti-IL-17 antibody is an injection or lyophilized powder, which contains the anti-IL-17 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, eg disaccharides, eg sucrose, lactose, trehalose, maltose.
  • the surfactant is selected from the group consisting of polyoxyethylene hydrogenated castor oil, glycerol fatty acid esters, polyoxyethylene sorbitan fatty acid esters such as polysorbate 20, 40, 60 or 80 , such as polysorbate 20.
  • the pH of the injectable form of the anti-IL-17 antibody may range from 5.0 to 7.0, eg, 5.4 to 6.2, 5.8 to 6.0.
  • the present disclosure provides a pharmaceutical composition comprising the aforementioned anti-IL-17 antibody, the pharmaceutical composition comprising the aforementioned anti-IL-17 antibody injectable form, optionally, further comprising a pharmaceutically acceptable salt or carrier .
  • the anti-IL-17 antibody-containing pharmaceutical composition of the present disclosure comprises the aforementioned anti-IL-17 antibody, histidine hydrochloride buffer, sucrose, and polysorbate 80.
  • the pharmaceutical composition of the anti-IL-17 antibody comprises about 80 mg/mL of the aforementioned anti-IL-17 antibody, about 10 mM histidine hydrochloride, about 76 mg/mL sucrose, and about 0.6 mg/mL polysorbate Alcohol ester 80, pH about 5.8.
  • the protocols for anti-IL-17A antibodies and pharmaceutical compositions thereof in CN201610739134.4 are incorporated herein in their entirety.
  • the present disclosure provides any of the aforementioned anti-IL-17 antibodies or a pharmaceutical composition containing the anti-IL-17 antibodies in the preparation and treatment of the aforementioned diseases or conditions (such as autoimmune diseases and inflammation, and also for example spondyloarthritis, axial spine Arthritis, Peripheral Spondyloarthritis, Ankylosing Spondylitis, Nonradiative Axial Spondyloarthritis (nr-axSpA), Psoriatic Arthritis, Enteropathic Arthritis, Moderate to Severe Ankylosing Spondylitis, Graves Eye disease, plaque psoriasis) use in medicine, comprising administering the anti-IL-17 antibody or a pharmaceutical composition thereof to a subject in need thereof with any of the aforementioned treatment methods or dosage regimens provided by the present disclosure.
  • diseases or conditions such as autoimmune diseases and inflammation, and also for example spondyloarthritis, axial spine Arthritis, Peripheral Spondylo
  • the present disclosure provides any of the aforementioned anti-IL-17 antibodies or pharmaceutical compositions containing the same, and their use in the treatment of the aforementioned diseases or disorders (eg, autoimmune diseases and Axial spondyloarthritis, peripheral spondyloarthritis, ankylosing spondylitis, nonradiative axial spondyloarthritis (nr-axSpA), psoriatic arthritis, enteropathic arthritis, moderate to severe ankylosing spondylitis inflammation, Graves' eye disease, plaque psoriasis), comprising administering the anti-IL-17 antibody or pharmaceutical composition thereof to a subject in need thereof in any of the aforementioned treatment methods or dosing regimens provided by the present disclosure.
  • the anti-IL-17 antibody or pharmaceutical composition thereof is administered at a frequency of once every 4-16 weeks, eg, once every 4, 6, 8, 10, 12, 14 or 16 weeks.
  • anti-IL-17A antibodies provided by the present disclosure have the characteristics of high affinity, fast onset of action, and low toxicity and side effects, so anti-IL-17 antibodies can be used at low frequency to treat diseases or disorders.
  • FIG. 1 Histogram of ASAS20 Response Rate at Week 16 of Treatment Period (FAS)
  • Figure 2 Line graph (FAS) of the changes of NRS, BASFI, BASDAI and ASDAS scores at each time point in the treatment period relative to the baseline, in which, Figure 2A, Figure 2B, Figure 2C, Figure 2D are NRS, BASFI, BASDAI, ASDAS, respectively score.
  • FAS Line graph
  • 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 this 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).
  • An "antibody” of the present disclosure encompasses an "antigen-binding fragment," eg, an "anti-IL-17 antibody” encompasses an "antigen-binding fragment of an anti-IL-17 antibody.”
  • 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.
  • the evaluation of the effectiveness of the anti-IL-17 antibodies of the present disclosure covers multiple aspects: including improvement of symptoms and signs of AS, disease activity, physiological function, spinal mobility, peripheral arthritis and tendonitis, quality of life, and reflecting inflammatory changes Evaluation of laboratory indicators (CRP and ESR).
  • the scoring system developed by the Assessment of SpondyloArthritis International Society includes:
  • VAS score (0-100mm) to evaluate the overall condition of the subjects
  • Morning stiffness average VAS score of the last two items in BASDAI related to morning stiffness
  • ASAS20 means a 20% improvement from baseline in at least 3 of the above 1-4 indicators and an improvement of at least 10 units (on the 0-100mm VAS scale), and the remaining one Index deterioration ⁇ 20% and ⁇ 10 units (on a scale of 0-100 mm VAS).
  • ASAS40 means a 40% improvement from baseline in at least 3 of the above 1-4 indicators, and an improvement of at least 20 units (on a scale of 0-100mm VAS), and the remaining one Metrics did not worsen from baseline.
  • ASAS5/6 means that at least 5 of the above 1-6 indicators have an improvement rate of ⁇ 20%.
  • Subjects will rate the severity of pain with a 100mm VAS of 0 for no pain and 100 for worst pain, and subjects will place a mark on the VAS to indicate the intensity of pain.
  • BASDAI The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) is a composite measure of disease activity by subjects, consisting of 6 questions related to the 5 main symptoms of AS.
  • BASFI Bath Ankylosing Spondylitis Functional Index
  • BASMI Bath Ankylosing Spondylitis Measure Index
  • MASES Maastricht Ankylosing Spondylitis Enthesitis Score
  • MASES Maastricht Ankylosing Spondylitis Enthesitis Score
  • MASES is an evaluation of the degree of inflammation at the starting point of AS, including 13 parts: left and right first costal cartilage joints (a), left and right seventh ribs Cartilage joint (b), left and right anterior superior iliac spine (c), left and right iliac crest (d), left and right posterior superior iliac spine (e), fifth lumbar vertebra spinous process (f), left and right Achilles tendon proximal joint joint ( g).
  • Each site was rated as 0 or 1, with 0 indicating no inflammation at the site and 1 indicating inflammation.
  • the total score is a maximum of 13 points. Ultrasound confirmation is required for the location of pressure pain.
  • the subjects held their heads with both hands, and measured the chest circumference during deep inhalation and exhalation in the fourth anterior intercostal space (general situation: male nipple; female breast lower edge). For each measurement, 2 measurements are required, and the one with the largest difference in bust circumference is used for reporting.
  • Chest mobility chest circumference when inhaling - chest circumference when exhaling.
  • the Ankylosing Spondylitis Quality of Life (ASQoL) questionnaire will assess the quality of life of AS subjects.
  • the questionnaire consisted of 18 yes/no questions. One point is awarded for each "yes” answer, with a total score between 0 and 18, with lower scores indicating better quality of life.
  • the 36-item Short Form Health Survey contains 36 items to evaluate the overall health status.
  • the survey measures the following eight categories of general health concepts: physical function, physical role, physical pain, general health, vitality, social functioning, emotional role, and mental health.
  • ASDAS-CRP AS Disease Activity Score
  • ASDAS-CRP 0.121 ⁇ low back pain+0.110 ⁇ subject overall evaluation+0.073 ⁇ peripheral joint pain/swelling+0.058 ⁇ duration of morning stiffness+0.579 ⁇ Ln(CRP+1); Ln(CRP+1):CRP (unit: mg/L)+1 natural logarithm.
  • Anti-IL-17A antibody the sequences of heavy and light chains are as in SEQ ID NO: 11 and SEQ ID NO: 12 in the present disclosure; 80 mg/mL, 1 mL per bottle; or 120 mg prefilled needle.
  • Bath ankylosing spondylitis disease activity index (Bath Ankylosing Spondylitis-Disease Activity Index, BASDAI) ⁇ 4; use at least one non-steroidal anti-inflammatory drug (NSAID) before randomization and the efficacy is not good or intolerable, That is, 1 NSAID is used for ⁇ 4 weeks before randomization or ⁇ 2 NSAIDs are used before randomization, each NSAID is treated for ⁇ 2 weeks, and the efficacy is not good or intolerable;
  • NSAID non-steroidal anti-inflammatory drug
  • Subjects taking NSAIDs or oral corticosteroids should maintain a stable dose for 2 weeks before randomization and throughout the study period, and the daily oral corticosteroid dose should be less than or equal to 10 mg of prednisone or an equivalent dose of other analogs.
  • Inclusion criteria for ankylosing spondylitis (1) meet the diagnosis of active AS, and have radiographic evidence records that meet the modified New York classification criteria for ankylosing spondylitis revised in 1984;
  • Active AS was diagnosed during the screening period and before randomization (active AS was defined as: BASDAI ⁇ 4 points (0-10 scale), total back pain VAS score ⁇ 4 (0-10 scale) );
  • NSAIDs non-steroidal anti-inflammatory drugs
  • NSAIDs or other analgesics such as acetaminophen or weak opioids
  • randomization At least ⁇ 2 weeks before discontinuation;
  • MTX oral methotrexate
  • sulfasalazine ⁇ 3g/day
  • the dose needs to be ⁇ 10 mg/day of prednisolone (or equivalent dose of other glucocorticoids), and the stable dose needs to continue for ⁇ 4 weeks before randomization; No oral glucocorticoids, discontinued at least 4 weeks before randomization.
  • Placebo group did not receive any active treatment.
  • the proportion of subjects who achieved ASAS20 at week 16 was used as the primary efficacy indicator.
  • the ASAS20 response rate in each dose group increased numerically. Except for the 20 mg dose group, the response rate was 44.4%, and the response rates of the other dose groups were as high as 71%. above.
  • mean BASFI scores were reduced from baseline in each dose group compared with placebo.
  • the mean BASFI score (SD) changes in the 20-240 mg dose groups were -0.66 (3.21), -2.30 (0.98), -1.47 (0.72), -2.33 (1.77) and -1.80 (1.98), respectively, as shown in Figure 2B.
  • the mean BASDAI score (SD) changes in the 20-240 mg dose groups were -1.83 (2.13), -2.50 (1.03), -3.29 (1.69), -3.04 (1.68) and -2.21 (1.93), respectively, as shown in Figure 2C.
  • the mean BASMI score (SD) changes in the placebo group and the 20-240 mg dose group were -0.7 (1.9), -0.4 (1.0), -0.2 (1.0), 0 (0.9), -1.2 ( 1.1) and 0 (0.8).
  • a randomized, double-blind, multi-center, placebo-controlled adaptive seamless phase II/III clinical study was carried out with reference to Schemes 6 to 7 of Example 1.
  • dose groups received 1 subcutaneous administration of 120 mg or 240 mg of anti-IL-17A antibody once at weeks 0, 2 and 4 for a total of 3 doses; Weekly, the same dose was administered subcutaneously every 4 weeks, for a total of 6 doses; a follow-up period of 20 weeks after the end of the treatment period from the last efficacy evaluation.
  • Placebo group did not receive any active treatment.
  • an interim analysis was performed to select the optimal dose for the second phase, and the same dosing schedule as the first phase was carried out after the optimal dose was confirmed.
  • the entire study is expected to enroll 400 to 600 subjects.
  • the proportion of subjects who achieved ASAS20 in the dose group and the placebo group in the 16th week after administration was used as the primary efficacy endpoint analysis, and the proportion of subjects such as ASAS40, ASAS5/6, and BASDAI, BASFI, and BASMI scores after 16 weeks of administration were used.
  • Z-test, random-effects model (MMRM) or analysis of covariance (ANCOVA) were used for analysis, and safety, pharmacokinetics, and immunogenicity analyses were also carried out.
  • the clinical phase I efficacy evaluation results have shown that the 120mg or 240mg induction regimen of anti-IL-17A antibody has efficacy advantages. Based on this, it can be expected that the 120mg or 240mg induction regimen (Q2W) combined with the maintenance regimen (Q4W) will improve subjects. The trend of axial spondyloarthritis, and the efficacy is sustained, and it has good safety and tolerability; within 16 weeks, the response rate of ASAS20 and ASAS40 in the dose group is expected to be higher than that in the placebo group.

Abstract

抗IL-17抗体治疗自身免疫性疾病和炎症的方法。具体而言，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周一次的给药频率向患者施用抗IL-17抗体或其抗原结合片段；进一步地，包括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。该治疗方法方案简单，给药频率低，可有效减轻患者的治疗负担，提高患者治疗顺应性。

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抗体治疗自身免疫性疾病和炎症，如强直性脊柱炎的方法。
背景技术
白介素-17(IL-17)家族的细胞因子被分别命名为白介素-17A(IL-17A)到白介素-17F，这些IL-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IL-17A。迁移到机体受感染或损伤处的淋巴细胞会分泌IL-17A。一方面，IL-17A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，IL-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IL-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，IL-17A是高表达的，过高的IL-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，IL-17A的缺失或者IL-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)。
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 PCTCN2022078917-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 PCTCN2022078917-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。
强直性脊柱炎(ankylosing spondylitis,AS)是一种慢性炎症性疾病，发病较为隐匿，患者多为逐渐出现腰背部或骶髂部疼痛和/或晨僵。本疾病主要侵犯骶髂关节、脊柱骨突、脊柱旁软组织及外周关节，严重者可发生脊柱畸形和强直。AS亦可伴发胸廓、肺、心脏、虹膜等多系统的关节外表现。全球AS患病率范围为0.1～1.4％，我国AS的患病率在0.3％左右，男女之比约2～3:1。本疾病发病年龄通常在13-31岁，高峰年龄为20-30岁，大多 数患者为青壮年，对患者的身心健康造成巨大影响，为社会带来巨大负担。
为此，开发新的治疗自身免疫疾病和验证的临床方案是本领域亟需解决的问题。本公开提供了具有优势的IL-17抗体(例如抗IL-17A抗体)及其治疗自身免疫疾病和炎症(例如，强直性脊柱炎)的临床给药方案。
发明内容
本公开(The disclosure)提供了一种治疗、预防疾病或病症的方法，其包括诱导方案；或包括a)诱导方案和b)维持方案。所述a)诱导方案和b)维持方案均包括向有需要的受试者施用抗IL-17抗体。一些实施方案中，b)维持方案是在a)诱导方案后进行的。
一些实施方案中，提供了一种治疗、预防疾病或病症的方法，包括：诱导方案，在所述诱导方案期间向有需要的受试者施用抗IL-17抗体；其中所述诱导方案包括以每2周一次或每3周一次的给药频率向有需要的受试者施用抗IL-17抗体。
一些实施方案中，提供了一种治疗、预防疾病或病症的方法，包括：a)诱导方案，在所述诱导方案期间向有需要的受试者施用抗IL-17抗体；其中所述诱导方案包括以每2周一次或每3周一次的给药频率向有需要的受试者施用抗IL-17抗体，以及，所述方法进一步包含在后的b)维持方案，在维持方案期间向所述有需要的受试者施用抗IL-17抗体。
一些实施方案中，所述抗IL-17抗体是以治疗有效量向有需要的受试者施用。另一些实施方案中，所述抗IL-17抗体是以预防有效量向有需要的受试者施用。
一些具体实施方案中，前述方法中，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有需要的受试者施用40～300mg的抗IL-17抗体，给药次数为1～5次，例如3次。
一些具体实施方案中，前述方法中，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有需要的受试者施用给药剂量为120mg或240mg的抗IL-17抗体，给药次数为1～5次，例如2、3、4次。
一些实施方案中，提供了一种治疗、预防疾病或病症的方法，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有需要的受试者施用120mg或240mg的抗IL-17抗体，给药次数为1～5次，例如2、3、4次；以及，在后的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有需要的受试者施用120mg或240mg的抗IL-17抗体。
一些实施方案中，提供了一种治疗、预防疾病或病症的方法，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有需要的受试者施用120mg或240mg的抗IL-17抗体，给药次数为3次；以及，在后的b)在维持方案期间，以每4周一次的给药频率向有需要的受试者施用120mg或240mg的抗IL-17抗体。
本公开提供了一种治疗、预防疾病或病症的方法，其包括：
a)诱导方案，在所述诱导方案期间向有需要的受试者施用抗IL-17抗体；以及，在后的b)维持方案，在所述维持方案期间向有需要的受试者施用抗IL-17抗体，其中所述维持方案包括以120mg或240mg的给药剂量向有需要的受试者施用抗IL-17抗体。
一些实施方案中，所述方法包括：
a)诱导方案，在所述诱导方案期间向有需要的受试者施用抗IL-17抗体；
b)维持方案，在所述维持方案期间向有需要的受试者施用抗IL-17抗体，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120mg或240mg的给药剂量向有需要的受试者施用抗IL-17抗体。
以上实施方案中，根据疾病的类型、严重性、有需要的受试者的体重和有需要的受试者对药物耐受性，可选择或调整维持方案和诱导方案的给药剂量。
一些具体实施方案中，维持方案中抗IL-17抗体的给药剂量为40～300mg，例如选自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，例如80mg、120mg、160mg、200mg或240mg，例如120mg或240mg。
一些具体实施方案中，诱导方案中抗IL-17抗体的给药剂量可为40～300mg，例如选自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，例如80mg、120mg、160mg、200mg或240mg。
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。
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。
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。
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。
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，一些实施方案中的诱导方案包括如从第零周开始(如在第0/1/2/3周或第0/1/2/3/4/5周)向所述有需要的受试者使用40～300mg(如40mg、60mg、80mg、120mg、160mg、200mg或240mg)剂量的前述抗IL-17抗体。
一些实施方案中，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)向所述有需要的受试者使用40～300mg(如40mg、60mg、80mg、120mg、160mg、200mg或240mg)剂量的前述抗IL-17抗体。
一些实施方案中，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)向所述有需要的受试者使用40～300mg(如40mg、60mg、80mg、120mg、160mg、200mg或240mg)剂量的前述抗IL-17抗体。
一些实施方案中，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)向所述有需要的受试者使用40～300mg(如40mg、60mg、80mg、120mg、160mg、200mg或240mg)剂量的前述抗IL-17抗体。
另一方面，本公开所述治疗、预防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。
一些实施方案中，维持方案包括向有需要的受试者施用40～300mg(如40mg、60mg、80mg、120mg、160mg、200mg或240mg)剂量的抗IL-17抗体，给药频率每4周一次。
一些实施方案中，维持方案包括向有需要的受试者施用40～300mg(如40mg、60mg、80mg、120mg、160mg、200mg或240mg)剂量的抗IL-17抗体，给药频率每月一次。
一些实施方案中，维持方案包括向有需要的受试者施用40～300mg(如40mg、60mg、80mg、120mg、160mg、200mg或240mg)剂量的抗IL-17抗体，给药频率每6周一次。
一些实施方案中，维持方案包括向有需要的受试者施用40～300mg(如40mg、60mg、80mg、120mg、160mg、200mg或240mg)剂量的抗IL-17抗体，给药频率每8周一次。
一些实施方案中，维持方案包括向有需要的受试者施用40～300mg(如40mg、60mg、80mg、120mg、160mg、200mg或240mg)剂量的抗IL-17抗体，给药频率每2月一次。
一些实施方案中，维持方案包括向有需要的受试者施用40～300mg(如40mg、60mg、80mg、120mg、160mg、200mg或240mg)剂量的抗IL-17抗体，给药频率每12周一次。
一些实施方案中，维持方案包括向有需要的受试者施用40～300mg(如40mg、60mg、80mg、120mg、160mg、200mg或240mg)剂量的抗IL-17抗体，给药频率每3月一次。
一些实施方案中，维持方案包括向有需要的受试者施用40～300mg(如40mg、60mg、80mg、120mg、160mg、200mg或240mg)剂量的抗IL-17抗体，给药频率每4月一次。
一些实施方案中，本公开的治疗、预防疾病或病症的方法包括：a)在诱导方案期间从第零周开始每周给药一次向有需要的受试者施用160mg或240mg的抗IL-17抗体，给药3或5次；以及，在后的b)在维持方案期间以每4周或每8周一次向有需要的受试者施用160mg或240mg的IL-17抗体。
一些实施方案中，本公开的治疗、预防疾病或病症的方法包括：a)在诱导方案期间从第零周开始每2周给药一次向有需要的受试者施用120mg或240mg的抗IL-17抗体，给药3或5次；以及，在后的b)在维持方案期间以每4周或每8周一次向有需要的受试者施用120mg或240mg的IL-17抗体。
一些实施方案中，本公开的治疗、预防疾病或病症的方法包括：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有需要的受试者施用120mg或240mg的抗IL-17抗体，给药次数为1～5次，例如3次；以及，在后的b)在维持方案期间以每4周一次的给药频率向有需要的受试者施用120mg或240mg的抗IL-17抗体。
一些实施方案中，本公开的治疗、预防疾病或病症的方法包括：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有需要的受试者施用120mg的抗IL-17抗体，给药3次；以及，在后的b)在维持方案期间以每4周一次的给药频率向有需要的受试者施用120mg的抗IL-17抗体，至少给药6次(例如6、7、8、9、10、11、12次)。
一些实施方案中，本公开的治疗、预防疾病或病症的方法包括：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有需要的受试者施用240mg的抗IL-17抗体，给药3次；以及，在后的b)在维持方案期间以每4周一次的给药频率向有需要的受试者施用240mg的抗IL-17抗体，至少给药6次(例如6、7、8、9、10、11、12次)。
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。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。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16周至32周。
一些实施方案中，前述本公开方法中的疾病或病症是自身免疫性疾病或炎症。
一些实施方案中，前述本公开方法中的疾病或病症是脊柱关节炎，例如中轴型脊柱关节炎或外周型脊柱关节炎，以及强制性脊柱炎、银屑病关节炎、肠病性关节炎，例如中度至重度强制性脊柱炎。
一些实施方案中，前述本公开方法中的中轴型脊柱关节炎的实例包括但不限于强制性脊柱炎、非放射性中轴性脊柱关节炎(nr-axSpA)。
一些实施方案中，前述本公开方法中的疾病或病症是活动性强制性脊柱炎，例如中度至重度活动性强制性脊柱炎。
一些实施方案中，前述本公开方法中的疾病或病症是Graves眼病、斑块状银屑病。
一些实施方案中，本公开方法中的有需要的受试者经诊断患有前述疾病或病症，或预期患有前述疾病或病症。
一些实施方案中，所述有需要的受试者为先前经至少一种非甾体抗炎药(NSAID)治疗而应答不足的，或者所述有需要的受试者对NSAID有禁忌症或不耐受。非甾体抗炎 药的实例包括但不限于阿司匹林、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、罗非昔布和塞来昔布。
一些实施方案中，所述有需要的受试者以前述本公开的治疗方法施用抗IL-17抗体后，向所述有需要的受试者进一步施用NSAID，对乙酰氨基酚，弱阿片类药物，改善病情抗风湿药(DMARD)例如甲氨碟呤，柳氮磺胺吡啶，或糖皮质激素例如泼尼松龙。
一些实施方案中，在用前述本公开的治疗方法进行抗IL-17抗体治疗之前，所述有需要的受试者先前未用一种或多种选自以下的治疗剂治疗：TNF-α抑制剂、IL-6抑制剂、IL-1抑制剂、抗CD20抗体、细胞毒T淋巴细胞相关抗原4抗体、IL-23抑制剂和其他IL-17抑制剂。
一些实施方案中，在用前述本公开的治疗方法进行抗IL-17抗体治疗之前，所述有需要的受试者先前已经用一种或多种选自以下的治疗剂治疗：TNF-α抑制剂、IL-6抑制剂、IL-1抑制剂、抗CD20抗体、细胞毒T淋巴细胞相关抗原4抗体、IL-23抑制剂和其他IL-17抑制剂。
一些实施方案中，TNF-α抑制剂的实例包括但不限于阿达木单抗、英夫利昔单抗，赛妥珠单抗、戈利木单抗或依那西普；IL-6抑制剂的实例包括但不限于托珠单抗(Tocilizumab)或Sarilumab；IL-1抑制剂例如是阿那白滞素；抗CD20抗体例如是利妥昔单抗；细胞毒T淋巴细胞相关抗原4抗体例如是阿巴西普；IL-23抑制剂的实例包括但不限于替拉珠单抗或Guselkunab；或者其他IL-17抑制剂的实例包括但不限于苏金单抗(Secukinumab)、依奇珠单抗(Ixekizumab)或布罗达单抗(Brodalumab)。
本公开还提供了一种治疗、预防前述疾病或病症(例如强直性脊柱炎)的方法，该方法包括向有需要的受试者施用有效量的前述本公开的抗IL-17抗体，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。
一些实施方案中，前述抗IL-17抗体为抗IL-17A和/或抗IL-17F抗体。
一些实施方案中，所述抗IL-17A抗体包含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：分别如SEQ ID NO：5、6和7氨基酸序列所示；抗体轻链LCDR序列：分别如SEQ ID NO：8、9和10氨基酸序列所示。
一些实施方案中抗IL-17A抗体重链可变区(VH)和轻链可变区(VL)中CDR序 列如下表所示：
Figure PCTCN2022078917-appb-000003
一些实施方案中，所述抗IL-17A抗体选自鼠源抗体、嵌合抗体、人源化抗体的重组抗体。
一些实施方案中，所述人源化抗IL-17A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。
一些实施方案中，所述抗IL-17A抗体含有氨基酸序列如SEQ ID NO：1所示的重链框架区或其变体，所述变体优选相对于SEQ ID NO：1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/或T71A；所述抗IL-17抗体含有氨基酸序列如SEQ ID NO：2所示的轻链框架区或其变体，所述变体优选相对于SEQ ID NO：2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/或L47W。
一些实施方案中，所述抗IL-17A抗体含有氨基酸序列如SEQ ID NO：3所示的重链可变区和氨基酸序列如SEQ ID NO：4所示的轻链可变区。
一些实施方案中，所述抗IL-17A抗体包含分别如SEQ ID NO：5、6和7所示氨基酸序列的HCDR1、HCDR2、HCDR3，和分别如SEQ ID NO：8、9和10所示氨基酸序列的LCDR1、LCDR2、LCDR3。
一些实施方案中，所述抗IL-17抗体的轻链序列如SEQ ID NO：11所示，重链序列如SEQ ID NO：12所示。
人种系重链可变区(VH1-18)
Figure PCTCN2022078917-appb-000004
人种系轻链可变区(A10)
Figure PCTCN2022078917-appb-000005
重链可变区
Figure PCTCN2022078917-appb-000006
轻链可变区
Figure PCTCN2022078917-appb-000007
人源化抗体设计，也考虑到如下等因素，Q1E突变以消除N-末端焦谷氨酸的形成，突变也包括那些保持所选VH家族内一致性的突变，以维持CDR的典型结构和VH/VL界面，可避免N-糖基化模式(N-{P}-S/T)在人源化结构中出现等。
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。
一些实施方案中，所述抗IL-17A抗体包含κ或λ轻链恒定区。
一些实施方案中，所述人源化抗IL-17A抗体的轻链包含或为SEQ ID NO：11所示的氨基酸序列，重链包含或为SEQ ID NO：12所示的氨基酸序列，
轻链
Figure PCTCN2022078917-appb-000008
重链
Figure PCTCN2022078917-appb-000009
Figure PCTCN2022078917-appb-000010
本公开中抗IL-17抗体的给药途径可以为经口给药、胃肠外给药，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。
一些实施方案中，本公开的抗IL-17抗体以注射的方式给药，例如皮下或静脉注射，注射前需将抗IL-17抗体配制成可注射的形式的药物组合物。例如，抗IL-17抗体的可注射形式是注射液或冻干粉针，其包含抗IL-17抗体、缓冲剂、稳定剂，可选地，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，所述聚氧乙烯山梨醇酐脂肪酸酯例如为聚山梨酯20、40、60或80，例如聚山梨酯20。抗IL-17抗体的可注射形式的pH值范围可以在5.0至7.0之间，例如5.4至6.2、5.8至6.0。
一些实施方案中，本公开提供包含前述抗IL-17抗体的药物组合物，所述药物组合物包含前述抗IL-17抗体可注射形式，任选地，还包含药学上可接受的盐或载体。
一些实施方案中，本公开的含有抗IL-17抗体的药物组合物中包含前述抗IL-17抗体、组氨酸盐酸盐缓冲剂、蔗糖和聚山梨醇酯80。一些具体实施方案中，抗IL-17抗体的药物组合物包含约80mg/mL的前述抗IL-17抗体、约10mM组氨酸盐酸盐、约76mg/mL蔗糖、和约0.6mg/mL聚山梨醇酯80，pH为约5.8。此处全文引入CN201610739134.4中的抗IL-17A抗体及其药物组合物的方案。
本公开提供了前述任意抗IL-17抗体或含有所述抗IL-17抗体的药物组合物在制备治疗前述疾病或病症(例如自身免疫性疾病和炎症，又例如脊柱关节炎、中轴型脊柱关节炎、外周型脊柱关节炎、强制性脊柱炎、非放射性中轴性脊柱关节炎(nr-axSpA)、银屑病关节炎、肠病性关节炎、中度至重度强制性脊柱炎、Graves眼病、斑块状银屑病)的药物中用途，包括向有需要的受试者以前述本公开提供的任意的治疗方法或给药方案施用所述抗IL-17抗体或其药物组合物。
本公开提供了前述任意抗IL-17抗体或含有所述抗IL-17抗体的药物组合物，及其用于治疗前述疾病或病症(例如自身免疫性疾病和炎症，又例如脊柱关节炎、中轴型脊柱关节炎、外周型脊柱关节炎、强制性脊柱炎、非放射性中轴性脊柱关节炎(nr-axSpA)、 银屑病关节炎、肠病性关节炎、中度至重度强制性脊柱炎、Graves眼病、斑块状银屑病)，包括向有需要的受试者以前述本公开提供的任意的治疗方法或给药方案施用所述抗IL-17抗体或其药物组合物。一些实施方案中，所述抗IL-17抗体或其药物组合物给药频率为每4-16周一次，例如每4、6、8、10、12、14或16周一次。
前述本公开提供的抗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抗IL-17抗体治疗疾病或病症。
附图说明
图1：治疗期第16周ASAS20应答率情况柱状图(FAS)
图2：治疗期各时间点NRS、BASFI、BASDAI及ASDAS评分相对于基线的变化情况折线图(FAS)，其中，图2A、图2B、图2C、图2D分别为NRS、BASFI、BASDAI、ASDAS评分。
术语
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)。本公开的“抗体”涵盖“抗原结合片段”，例如“抗IL-17抗体”涵盖“抗IL-17抗体的抗原结合片段”。
“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。
本公开的抗IL-17抗体的有效性评估涵盖多个方面：包括对AS症状体征的改善、疾病活动性、生理功能、脊柱活动度、周围关节炎和肌腱端炎、生活质量及反映炎症变化的实验室指标(CRP和ESR)的评估。
1、ASAS评分系统
国际脊柱关节炎评估工作组(Assessment of SpondyloArthritis International Society，ASAS)制定的评分系统包括：
1)受试者整体状况评价VAS评分(0-100mm)；
2)夜间痛和总背痛VAS评分(0-100mm)；
3)身体功能(BASFI)；
4)晨僵(BASDAI中最后两项和晨僵有关的VAS平均得分)；
5)CRP；
6)脊柱活动度(同BASMI中腰椎侧弯)。
“ASAS20”表示在上述1-4项指标中至少3项指标与基线相比有20％的改善，并且改善幅度至少10个单位(在0-100mm VAS的量表上)，且剩余的一项指标恶化程度＜20％且＜10个单位(在0-100mm VAS的量表上)。
“ASAS40”表示在上述1-4项指标中至少3项指标与基线相比有40％的改善，并且改善幅度至少20个单位(在0-100mm VAS的量表上)，且剩余的一项指标与基线相比无恶化。
“ASAS5/6”表示上述1-6项指标中至少有5项改善幅度≥20％。
2、夜间痛和总背痛VAS评分
受试者将用一个0表示没有疼痛，100表示最严重的疼痛的100mmVAS对疼痛的严重程度进行评分，受试者将在VAS上做一个标记指明疼痛的强度。
BASDAI：Bath强直性脊柱炎疾病活动指数(BASDAI)是一个由受试者关于评价疾病活动性的综合指标，由6个与AS的5个主要症状相关的问题组成。
BASFI：Bath强直性脊柱炎功能指数(BASFI)是一个由受试者评价的关于功能能力的指标，它由10个问题组成。根据10个与功能解剖学和应对能力相关的问题评价身体功能，总分介于0-10分之间，采用VAS(视觉模拟评分)进行受试者自我评价。分数越高，功能损害越严重。
BASMI：Bath强直性脊柱炎衡量指数(BASMI)是一个由医生来实施的评价脊柱活动性的指标，对中轴脊柱的活动能力进行量化，并对脊柱运动的临床显著变化进行客观评估。总分介于0-10分之间，为5个指标评价之和。包括：腰椎侧弯、耳壁距、腰椎延展、颈部旋转、踝间距。
MASES：Maastricht强直性脊柱炎肌腱端炎评分(Maastricht Ankylosing Spondylitis Enthesitis Score，MASES)是对AS的起止点炎程度进行评价，包括13个部位：左右第一肋软骨关节(a)、左右第七肋软骨关节(b)、左右髂前上棘(c)、左右髂嵴(d)、左右髂后上棘(e)、第五腰椎棘突(f)、左右足跟肌腱近端关节连接处(g)。每个部位分别评为0分或1分，其中0分表示该部位无炎症，1分表示有炎症。总评分最多为13分。对按压疼痛的位置，需进行超声确认。
3、44个肿胀及压痛关节计数
在V2(W0)、V7(W16)、V11(W32)需要评估44个外周关节是否存在压痛和/或肿胀的关节。人工关节不予评价。滑膜液和/或软组织肿胀，而不是骨过度生长代表关节肿胀计数阳性结果。若4周内关节内注射过皮质激素或透明质酸的关节直接计算在肿胀和压痛关节计数内。
4、胸廓扩张度
测量时，受试者双手抱头，在第4前肋间(一般情况：男性乳头；女性乳房下缘)测量深吸气、呼气时的胸围。每次测量时，需测量2次，取胸围差值大者进行报告。胸廓活动度＝吸气时的胸围-呼气时的胸围。
5、ASQoL
强直性脊柱炎生活质量问卷(Ankylosing Spondylitis Quality of Life，ASQoL)将评估AS受试者的生活质量。问卷由18个是/否问题组成。每回答一个“是”，就会得到1分，总分在0到18分之间，分数越低表示生活质量越好。
6、SF-36量表
健康调查简表(36-item Short Form Health Survey，SF-36)包含36个项目，对总体健康状态进行评测。该调查对以下8类总体健康概念进行测定：躯体功能、躯体角色、躯体疼痛、总体健康、活力、社交功能、情感角色和心理健康。
7、ASDAS-CRP
AS病情活动度评分(ASDAS)-CRP是一个综合受试者主观评价及CRP的病情活动评分系统。ASDAS-CRP计算公式：
ASDAS-CRP＝0.121×腰背痛+0.110×受试者总体评价+0.073×外周关节疼痛/肿胀+0.058×晨僵持续时间+0.579×Ln(CRP+1)；Ln(CRP+1):CRP(单位：mg/L)+1的自然对数。
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方案设计和初步效果评价
1、受试抗体
抗IL-17A抗体，重、轻链的序列如本公开中SEQ ID NO：11和SEQ ID NO：12；80mg/mL，每瓶1mL；或者120mg预充针。
2、入组标准
中轴型脊柱关节炎入组标准：
(1)符合2009年国际脊柱关节炎评价工作组(The Assessment of SpondyloArthritis
international Society，ASAS)中轴型脊柱关节炎(AxSpA)分类标准；
(2)Bath强直性脊柱炎病情活动指数(Bath Ankylosing Spondylitis-Disease Activity Index，BASDAI)≥4；随机前至少使用一种非甾体类抗炎药(NSAID)而疗效不佳或不耐受，即随机前使用1种NSAID治疗≥4周或随机前使用≥2种NSAIDs治疗，每种NSAID治疗≥2周，而疗效不佳或不耐受；
(3)服用NSAID或口服皮质类固醇激素的受试者，随机前2周及整个研究期间应保持稳定剂量，每日口服皮质类固醇激素剂量≤10mg的强的松或等效剂量的其他类似物。
强制性脊柱炎入组标准：(1)符合活动性AS诊断，具有放射学证据记录符合1984年修订的强直性脊柱炎改良纽约分类标准；
(2)在筛选期和随机前被确诊为活动性AS(活动性AS定义为：BASDAI≥4分(0-10分总表)，总背痛VAS评分≥4分(0-10分总表)；
(3)对非甾体抗炎药(NSAID)反应欠佳(定义为：≥2种NSAIDs推荐剂量下共治疗≥4周且每种NSAID不少于2周的推荐剂量的治疗反应欠佳)；或对NSAID有禁忌症或不耐受；
(4)如受试者正在口服NSAID或其它镇痛药(如对乙酰氨基酚或弱阿片类药物)，随机前需要稳定剂量持续≥2周；如受试者未稳定剂量口服上述药物，随机前至少停药≥2周；
(5)如受试者正在口服使用甲氨蝶呤(MTX)(7.5-25mg/周)或柳氮磺胺吡啶(≤3g/日)的患者允许继续使用药物，但随机前需要持续治疗≥3个月，且稳定剂量持续≥4周；如受试者未稳定剂量口服上述药物，随机前至少停药≥4周；
(6)如受试者正在口服糖皮质激素，剂量需≤10mg/日泼尼松龙(或等效剂量的其它糖皮质激素)，且随机前需要稳定剂量持续≥4周；如受试者未口服糖皮质激素，随机前至少停药≥4周。
3、治疗方案
方案1：抗IL-17A抗体，固定剂量20mg，皮下注射，每2周1次，给药3次；
方案2：抗IL-17A抗体，固定剂量40mg，皮下注射，每2周1次，给药3次；
方案3：抗IL-17A抗体，固定剂量80mg，皮下注射，每2周1次，给药3次；
方案4：抗IL-17A抗体，固定剂量160mg，皮下注射，每2周1次，给药3次；
方案5：抗IL-17A抗体，固定剂量240mg，皮下注射，每2周1次，给药3次；
方案6：抗IL-17A抗体，诱导剂量120mg，皮下注射，每2周1次，给药3次，此后固定剂量120mg，皮下注射，每4周1次，给药6次；
方案7：抗IL-17A抗体，诱导剂量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，给药6次；
安慰剂组：不接受任何积极治疗。
4、结果
研究结果表明：1)抗IL-17A抗体20mg、40mg、80mg、160mg、240mg Q2W连续3次皮下注射在中轴型脊柱炎患者中安全且耐受性良好；2)20-240mg剂量范围内，抗IL-17A抗体血清暴露量与剂量呈线性比例关系；3)16周内，40～240mg Q2W*3剂量组ASAS20、ASAS40应答率均较安慰剂组有较大幅度升高，对中轴型脊柱关节炎均有一定程度的改善，且起效迅速，疗效持续。
实施例2安全性评价
在接受实施例1的方案1～方案5(20～240mg)的抗IL-17A抗体皮下注射给药的35例中轴型脊柱关节炎受试者中，共有28例(80％)受试者发生138例次TEAE；安慰剂组共有10例(100％)受试者发生19例次TEAE。抗IL-17A抗体各剂量组TEAE的严重程度大多均 为轻度，中度TEAE发生11例(31.4％)，发生未见重度TEAE；其中，与试验药物相关的中度TEAE发生6例(17.1％)，分别为20mg剂量组1例，160mg剂量组3例，240mg剂量组2例。本研究仅160mg剂量组的1例受试者发生3例次SAE(肾积水、肾石症和输尿管结石)，研究者判断均与试验药物“可能无关”。整个研究无导致死亡及导致退出的TEAE发生。
综上所述，中轴型脊柱关节炎受试者每2周一次(Q2W)接受20～240mg抗IL-17A抗体皮下注射给药的安全性、耐受性良好。
实施例3临床I期药效
针对实施例1的方案1～方案5进行临床药效分析，其中35例中轴型脊柱关节炎受试者接受方案1～方案5(20～240mg)的抗IL-17A抗体皮下注射给药，10例受试者接受安慰剂给药。
1、ASAS20应答率
以第16周达到ASAS20的受试者比例作为主要疗效指标。
如图1所示，第16周时，各剂量组与安慰剂组比较，ASAS20应答率数值上均有升高，除20mg剂量组应答率为44.4％外，其余剂量组应答率均高达71％以上。
2、ASAS40应答率
安慰剂组仅有1例(10％)受试者在第6周时达到ASAS40，其余各周均无受试者有ASAS40应答。与安慰剂组相比，抗IL-17A抗体所有剂量组均显现出持续的ASAS40应答，除20mg剂量组自第4周(2次给药后)起出现ASAS40应答外，其余各组均在第2周(即首次给药后)起出现ASAS40应答。如表1所示，第16周时，80mg和240mg剂量组ASAS40应答率明显增加，分别为66.7％和57.1％。
表1治疗期和随访期各时间点ASAS40应答受试者情况
Figure PCTCN2022078917-appb-000011
(备注：安慰剂组1例受试者提前退出研究，未获得12、16周疗效数据；抗IL-17A抗体160mg组1例受试者提前退出研究，未获得第4周及之后访视的疗效数据；抗IL-17A抗体160mg组1例受试者提前退出研究，未获得第8周及之后访视的疗效数据。未获得疗效数据按评估周无应答处理。)
3、NRS、BASFI、BASDAI、BASMI及ASDAS评分
第16周时，与安慰剂相比，40-240mg剂量组患者疼痛自我评分及医生对患者疼痛评分较基线数值上均有降低，见图2A。
第16周时，各剂量组与安慰剂组比较，BASFI平均评分较基线数值上均有降低。20-240mg剂量组BASFI平均评分(SD)变化数值分别为-0.66(3.21)、-2.30(0.98)、-1.47(0.72)、-2.33(1.77)及-1.80(1.98)，见图2B。
第16周时，各剂量组与安慰剂组比较，BASDAI平均评分较基线数值上均有降低。20-240mg剂量组BASDAI平均评分(SD)变化数值分别为-1.83(2.13)、-2.50(1.03)、-3.29(1.69)、-3.04(1.68)及-2.21(1.93)，见图2C。
第16周时，安慰剂组及20-240mg剂量组BASMI平均评分(SD)变化数值分别为-0.7(1.9)、-0.4(1.0)、-0.2(1.0)、0(0.9)、-1.2(1.1)及0(0.8)。
第16周时，各剂量组与安慰剂组比较，ASDAS评分(基于CRP及ESR)平均评分较基线数值上均显著降低，见图2D。
实施例4临床II/III期药效
参照实施例1的方案6～方案7开展随机、双盲、多中心、安慰剂对照的适应性无缝II/III期临床研究。在药物用法用量探索的第一阶段，剂量组：在第0周、第2周及第4周接受1次皮下给药120mg或240mg抗IL-17A抗体，共给药3次；接着从第4周起，每4周1次相同剂量皮下给药，共给药6次；末次疗效评估至治疗期结束后有20周的随访期。安慰剂组：不接受任何积极治疗。第一阶段16周后进行期中分析，为第二阶段选择最优剂量，确认最优剂量后进行与第一阶段相同的给药方案。
预计整个研究入组400至600例受试者。以给药后第16周剂量组与安慰剂组达到ASAS20的受试者比例作为主要疗效终点分析，以给药16周后ASAS40、ASAS5/6等受试者比例和BASDAI、BASFI、BASMI评分等作为次要和其它疗效终点分析，采用Z检验、随机效应模型(MMRM)或协方差分析(ANCOVA)等方法分析，同时还展开安全性、药代动力学、免疫原性的分析。
临床I期的有效性评价结果已经显示，抗IL-17A抗体的120mg或240mg诱导方案具有疗效优势，基于此，能够预期120mg或240mg诱导方案(Q2W)结合维持方案(Q4W)具有改善受试者中轴型脊柱关节炎的趋势，且疗效持续，同时具有良好安全性和耐受性；16周内，预计剂量组ASAS20、ASAS40应答率相较于安慰剂组会升高。

Claims (23)

  1. 一种治疗疾病或病症的方法，其包括：
    a)诱导方案，包括以每2周一次或每3周一次的给药频率向有需要的受试者施用抗IL-17抗体；
    优选地，还包括b)维持方案，包括向所述有需要的受试者施用抗IL-17抗体。
  2. 如权利要求1所述的方法，其中，a)诱导方案中抗IL-17抗体的给药剂量为40mg、80mg、120mg、160mg、200mg或240mg，优选120mg或240mg。
  3. 如权利要求1或2所述的方法，其中，a)诱导方案中抗IL-17抗体的给药次数为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有需要的受试者施用120mg或240mg的抗IL-17抗体，给药次数为1～5次，优选3次；
    优选地，还包括b)在维持方案期间向所述有需要的受试者施用120mg或240mg的抗IL-17抗体，优选在维持方案期间以每4周一次的给药频率向所述有需要的受试者施用120mg或240mg的抗IL-17抗体。
  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16周至32周。
  6. 一种治疗疾病或病症的方法，其包括：
    a)诱导方案，包括向有需要的受试者施用抗IL-17抗体；和在后的
    b)维持方案，包括向所述有需要的受试者施用抗IL-17抗体，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120mg或240mg的给药剂量向所述有需要的受试者施用抗IL-17抗体。
  7. 如权利要求1-6任一项所述的方法，其中给药方式为静脉或皮下给药。
  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，优选为脊柱关节炎，更优选中轴型脊柱关节炎，最优选为强直性脊柱炎。
  9. 如权利要求8所述的方法，所述强直性脊柱炎选自活动性强制性脊柱炎、中度至重度强直性脊柱炎，优选为中度至严重活动性强直性脊柱炎。
  10. 如权利要求1-9任一项所述的方法，其中所述抗IL-17抗体为抗IL-17A抗体。
  11. 如权利要求10所述的方法，所述抗IL-17A抗体包含氨基酸序列分别如SEQ ID NO：5、6和7所示的重链HCDR1、HCDR2和HCDR3；和氨基酸序列分别如SEQ ID NO：8、9和10所示的轻链LCDR1、LCDR2和LCDR3。
  12. 如权利要求1-11所述的方法，其中所述抗IL-17抗体为嵌合抗体或人源化抗体。
  13. 如权利要求12所述的方法，其中所述人源化抗IL-17抗体的轻链和重链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：1所示的重链框架区或其变体，所述变体优选相对于SEQ ID NO：1所示的重链框架区序列具有0-10个氨基酸突变，更优选具有A93T和/或T71A的氨基酸突变；所述抗IL-17抗体含有氨基酸序列如SEQ ID NO：2所示的轻链框架区或其变体，所述变体优选相对于SEQ ID NO：2所示的轻链框架区具有0-10个氨基酸突变，更优选具有F71Y、K49Y、Y36F和/或L47W的氨基酸突变。
  14. 如权利要求1-13所述的方法，其中所述抗IL-17抗体含有SEQ ID NO：3所示的重链可变区，和SEQ ID NO：4所示的轻链可变区。
  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；和/或，所述抗IL-17抗体包含κ或λ轻链恒定区。
  16. 如权利要求1-15任一项所述的方法，其中所述抗IL-17抗体包含SEQ ID NO：11所示的轻链，和SEQ ID NO：12所示的重链。
  17. 如权利要求16所述的方法，其中所述有需要的受试者为先前经至少一种非甾体抗炎药(NSAID)治疗而应答不足的，或者所述有需要的受试者对NSAID有禁忌症或不耐受。
  18. 如权利要求17所述的方法，其中所述有需要的受试者进一步施用NSAID，对乙酰氨基酚，弱阿片类药物，抗风湿药(DMARD)，柳氮磺胺吡啶，或糖皮质激素；抗风湿药优选甲氨碟呤，糖皮质激素优选泼尼松龙。
  19. 如权利要求1-18任一项所述的方法，其中，在用抗IL-17抗体治疗之前，所述有需要的受试者先前未用或已经用一种或多种选自以下的治疗剂治疗：TNF-α抑制剂、IL-6抑制剂、IL-1抑制剂、抗CD20抗体、细胞毒T淋巴细胞相关抗原4抗体、IL-23抑制剂和其他IL-17抑制剂。
  20. 如权利要求19所述的方法，其中：
    所述TNF-α抑制剂选自阿达木单抗、英夫利昔单抗，赛妥珠单抗、戈利木单抗和依那西普；
    IL-6抑制剂选自托珠单抗和Sarilumab；
    IL-1抑制剂是阿那白滞素；
    抗CD20抗体是利妥昔单抗；
    细胞毒T淋巴细胞相关抗原4抗体是阿巴西普；
    IL-23抑制剂选自替拉珠单抗和Guselkunab；或者
    其他IL-17抑制剂选自苏金单抗、依奇珠单抗和布罗达单抗。
  21. 一种抗IL-17抗体，用于治疗疾病或病症，包括：根据权利要求1-20任一项所述的方法向有需要的受试者施用抗IL-17抗体；
    优选地，所述抗IL-17抗体为权利要求11-16中任一项所限定的。
  22. 一种包含抗IL-17抗体的药物组合物，用于治疗疾病或病症，包括：根据权利要求1-20任一项所述的方法向有需要的受试者施用抗IL-17抗体；
    优选地，所述抗IL-17抗体为权利要求11-16中任一项所限定的；
    优选地，所述药物组合物还包含药学上可接受的盐或载体，更优选地，所述药物组合物含有约80mg/mL的权利要求11-16中任一项所限定的抗IL-17抗体、约10mM组氨酸盐酸盐、约76mg/mL蔗糖、和约0.6mg/mL聚山梨醇酯80，pH为约5.8。
  23. 一种抗IL-17抗体或包含所述抗IL-17抗体的药物组合物在制备用于治疗疾病或病症的药物中的用途，包括：根据权利要求1-20任一项所述的方法向有需要的受试者施用抗IL-17抗体；
    优选地，所述抗IL-17抗体为权利要求11-16中任一项所限定的；
    优选地，所述药物组合物还包含药学上可接受的盐或载体，更优选地，所述药物组合物含有约80mg/mL的权利要求11-16中任一项所限定的抗IL-17抗体、约10mM组氨酸盐酸盐、约76mg/mL蔗糖、和约0.6mg/mL聚山梨醇酯80，pH为约5.8。
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103189074A (zh) * 2010-11-05 2013-07-03 诺华有限公司 使用il-17拮抗剂治疗类风湿性关节炎的方法
CN104936981A (zh) * 2013-11-18 2015-09-23 上海恒瑞医药有限公司 Il-17a结合物及其用途
CN106474470A (zh) * 2015-08-28 2017-03-08 江苏恒瑞医药股份有限公司 一种抗il‑17a抗体的组合物
CN107029234A (zh) * 2010-10-08 2017-08-11 诺华有限公司 利用il‑17拮抗剂治疗牛皮癣的方法
CN113164596A (zh) * 2018-09-24 2021-07-23 詹森生物科技公司 用抗il12/il23抗体治疗溃疡性结肠炎的安全且有效的方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107029234A (zh) * 2010-10-08 2017-08-11 诺华有限公司 利用il‑17拮抗剂治疗牛皮癣的方法
CN103189074A (zh) * 2010-11-05 2013-07-03 诺华有限公司 使用il-17拮抗剂治疗类风湿性关节炎的方法
CN104936981A (zh) * 2013-11-18 2015-09-23 上海恒瑞医药有限公司 Il-17a结合物及其用途
CN106474470A (zh) * 2015-08-28 2017-03-08 江苏恒瑞医药股份有限公司 一种抗il‑17a抗体的组合物
CN113164596A (zh) * 2018-09-24 2021-07-23 詹森生物科技公司 用抗il12/il23抗体治疗溃疡性结肠炎的安全且有效的方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BIOLOGICAL ABSTRACTS, 6 October 2010, Philadelphia, PA, US; HUEBER WOLFGANG, PATEL DHAVALKUMAR D, DRYJA THADDEUS, ET AL: "Effects of AIN457, a Fully Human Antibody to Interleukin-17A, on Psoriasis, Rheumatoid Arthritis, and Uveitis" XP002666877 *
VAN DER HEIJDE DÉSIRÉE, GENSLER LIANNE S, DEODHAR ATUL, BARALIAKOS XENOFON, PODDUBNYY DENIS, KIVITZ ALAN, FARMER MARY KATHERINE, B: "Dual neutralisation of interleukin-17A and interleukin-17F with bimekizumab in patients with active ankylosing spondylitis: results from a 48-week phase IIb, randomised, double-blind, placebo-controlled, dose-ranging study", ANNALS OF THE RHEUMATIC DISEASES, BRITISH MEDICAL ASSOCIATION, GB, vol. 79, no. 5, 1 May 2020 (2020-05-01), GB , pages 595 - 604, XP055963458, ISSN: 0003-4967, DOI: 10.1136/annrheumdis-2020-216980 *

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