TW202246329A - Method of treating autoimmune diseases and inflammation with anti-il-17 antibody - Google Patents

Abstract

The present disclosure relates to a method of treating autoimmune diseases and inflammation with anti-IL-17 antibody. Specifically, it includes: (a) administering an anti-IL-17 antibody or its antigen binding fragment to the patient during the induction protocol, wherein the induction protocol includes administering an anti-IL-17 antibody or an antigen binding fragment thereof to a patient at a dosing frequency of once every 2 weeks or once every 3 weeks, further, it includes (b) thereafter administering an anti-IL-17 antibody or an antigen binding fragment thereof to the patient during the maintenance protocol. The treatment scheme is simple and the administration frequency is low, which can effectively reduce the treatment burden of patients and improve the treatment compliance of patients.

Description

Methods of treating autoimmune diseases and inflammation with anti-IL-17 antibodies

The disclosure relates to a method for 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 to mediate different inflammatory response.

The most representative member of this family is IL-17A. Lymphocytes that migrate to infected or injured sites in the body secrete IL-17A. On the one hand, IL-17A can induce the expression of inflammatory factors and chemokines, thereby recruiting more immune cells to reach the inflammatory site and aggravate the inflammatory response; on the other hand, IL-17A can also induce the expression of some tissue repair-related factors, thereby Accelerates body recovery. Although 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. The level of -17A has a worsening effect on pathological development because it can induce the expression of many inflammatory factors. Many animal experiments have also proved that the absence of IL-17A or IL-17A is neutralized by antibodies, which can effectively inhibit the pathological extent of various autoimmune diseases. There is evidence to target IL-17 signaling for the treatment of autoimmune diseases including rheumatoid arthritis (RA), psoriasis, Crohn's disease, multiple sclerosis (MS), psoriatic diseases, asthma and lupus erythematosus, both have certain curative effects (see eg Aggarwal et al., J. Leukoc. Biol., 71(1): 1-8 (2002); Lubberts et al.).

Anti-IL-17 drugs that have been developed and marketed, especially humanized monoclonal antibodies against IL-17 include: Ixekizumab (Eli Lilly), Secukinumab (Novartis) and Burro Brodalumab (SILIQ ^™ ). Cosentyx® has been approved by the U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA), Japan and Brazil for use in adults with plaque psoriasis, ankylosing spondylitis and psoriasis diseased arthritis. Ixekizumab (Taltz®) is FDA/EMA approved for the treatment of moderate to severe plaque psoriasis in adults. Brodalumab (SILIQ ^™ ), an IL-17 receptor monoclonal antibody, was developed and approved by AstraZeneca/Valeant for patients with moderate to severe plaque psoriasis.

Ankylosing spondylitis (AS) is a chronic inflammatory disease with relatively insidious onset. Most patients gradually develop low back or sacroiliac pain and/or morning stiffness. The disease mainly invades sacroiliac joints, spinal condyles, paraspinal soft tissues and peripheral joints, and severe cases may cause spinal deformity and stiffness. AS can also be accompanied by extra-articular manifestations of multiple systems such as the thorax, lung, heart, and iris. The prevalence of AS in the world 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 onset age of this disease is usually 13-31 years old, and the peak age is 20-30 years old. Most patients are young adults, which has a huge impact on the physical and mental health of patients and a huge burden on society.

For this reason, the development of new clinical solutions for the treatment of autoimmune diseases and verification is an urgent problem to be solved in this field. The present disclosure provides advantageous IL-17 antibodies (such as anti-IL-17A Antibodies) and clinical dosing regimens thereof for the treatment of autoimmune diseases and inflammation (eg, ankylosing spondylitis).

The disclosure provides a method for treating or preventing a disease or condition, which includes an induction regimen; or includes 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 a) the induction regimen.

In some embodiments, a method of treating or preventing a disease or disorder is provided, comprising: an induction regimen, during which an anti-IL-17 antibody is administered to a subject in need; wherein the induction regimen includes Anti-IL-17 antibodies are administered to subjects in need thereof at a dosing frequency of once or every 3 weeks.

In some embodiments, a method for treating or preventing a disease or disorder is provided, comprising: a) an induction regimen, during which an anti-IL-17 antibody is administered to a subject in need; wherein the induction regimen includes Administration of the anti-IL-17 antibody to a subject in need at a dosing frequency of once every 2 weeks or once every 3 weeks, and the method further comprises a subsequent b) maintenance regimen during which the subject in need Subjects were administered anti-IL-17 antibodies.

In some embodiments, 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.

In some specific embodiments, in the aforementioned method, a) during the induction regimen, administer 40 to 300 mg of anti-IL-17 antibody to subjects in need at a dosing frequency of once every 2 weeks from the zeroth week, and give The number of times of medicine is 1 to 5 times, for example, 3 times.

In some specific embodiments, in the aforementioned method, a) during the induction regimen, starting from the zeroth week, administering the anti-IL- 17 Antibodies, the administration frequency is 1 to 5 times, such as 2, 3, 4 times.

In some embodiments, a method for treating or preventing a disease or condition is provided, comprising: a) during the induction regimen, administering 120 mg or 240mg of anti-IL-17 antibody, the administration frequency is 1~5 times, such as 2, 3, 4 times; and, in the latter b) during the maintenance program, once every 4 weeks, every 8 weeks, every 12 weeks 120 mg or 240 mg of anti-IL-17 antibody was administered to subjects in need thereof at a dosing frequency of once or once every 16 weeks.

In some embodiments, a method for treating or preventing a disease or condition is provided, comprising: a) during the induction regimen, administering 120 mg or 240 mg of anti-IL-17 antibody administered three times; and, following b) during the maintenance regimen, 120 mg or 240 mg of anti-IL was administered to subjects in need at a dosing frequency of once every 4 weeks -17 antibody.

The present disclosure provides a method for treating and preventing a disease or condition, comprising:

a) an induction regimen during which an anti-IL-17 antibody is administered to a subject in need; and, thereafter b) a maintenance regimen during which an anti-IL-17 antibody is administered to a subject in need thereof 17 antibody, wherein the maintenance regimen includes administering the anti-IL-17 antibody to a subject in need at a dose of 120 mg or 240 mg.

In some embodiments, the method includes:

a) an induction regimen during which an anti-IL-17 antibody is administered to a subject in need;

b) a maintenance regimen during which an anti-IL-17 antibody is administered to a subject in need, wherein the maintenance regimen comprises once every 4 weeks, once every 8 weeks, once every 12 weeks, or once every 16 weeks The anti-IL-17 antibody was administered to subjects in need at a dosage of 120 mg or 240 mg at a dosing frequency of one time.

In the above embodiments, according to the type and severity of the disease, the body weight of the subject in need and the drug tolerance of the subject in need, the dosage of the maintenance regimen and the induction regimen can be selected or adjusted.

In some specific embodiments, the dosage of the anti-IL-17 antibody in the maintenance regimen is 40-300 mg, for example, 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, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, for example 80mg, 120mg, 160mg, 200mg or 240mg, for example 120mg or 240mg.

In some specific embodiments, the dose of anti-IL-17 antibody in the induction scheme can be 40-300 mg, for example, 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 , 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, for example 80mg, 120mg, 160mg, 200mg or 240mg.

In some embodiments, the induction regimen and the maintenance regimen are administered at the same dose. In some alternatives, different doses are administered for the induction and maintenance regimens.

The induction regimen (loading) in this disclosure refers to the administration of anti-IL-17 antibody at a high dosing frequency (compared to the dosing frequency of maintenance therapy) at the initial stage of treatment to treat a disease or condition. The high dosing frequency may be once a week starting from the zeroth week, or once every two weeks starting from the zeroth week, or once every three weeks starting from the zeroth week, or a longer period of time.

Further, the number of administrations in the induction regimen described in this disclosure is at least 1 time, including but not limited to 1 time, 2 times, 3 times, 4 times, 5 times or more.

In some embodiments, the induction regimen comprises weekly dosing starting at week zero for 3 doses.

In some embodiments, the induction regimen comprises weekly dosing starting at week zero for 4 doses.

In some embodiments, the induction regimen comprises weekly dosing starting at week zero for 5 doses.

In some embodiments, the induction regimen comprises dosing once every 2 weeks starting at week zero for 3 doses.

In some embodiments, the induction regimen comprises administration once every 2 weeks starting at week zero for 4 administrations.

In some embodiments, the induction regimen comprises administration once every 2 weeks starting at week zero for 5 administrations.

In some embodiments, the induction regimen comprises dosing once every 3 weeks starting at week zero, for 3 doses.

In some embodiments, the induction regimen comprises administration once every 3 weeks starting at week zero for 4 administrations.

In some embodiments, the induction regimen comprises administration every 3 weeks starting at week zero for 5 administrations.

In some embodiments, the induction regimen comprises dosing every 4 weeks (or once a month) starting from week 0, for 3 doses.

In some embodiments, the induction regimen comprises administration once every 4 weeks starting at week zero, for 4 administrations.

In some embodiments, the induction regimen comprises administration every 4 weeks starting at week zero for 5 administrations.

Further, the induction regimen in some embodiments includes, for example, starting from week zero (such as at week 0/1/2/3 or week 0/1/2/3/4/5) to the subject in need. The tester used the aforementioned anti-IL-17 antibody at a dose of 40-300 mg (such as 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg or 240 mg).

In some embodiments, the induction regimen includes administering 40 to 300 mg (such as 40 mg , 60mg, 80mg, 120mg, 160mg, 200mg or 240mg) dose of the aforementioned anti-IL-17 antibody.

In some embodiments, the induction regimen includes administering 40 to 300 mg (e.g., 40 mg , 60mg, 80mg, 120mg, 160mg, 200mg or 240mg) dose of the aforementioned anti-IL-17 antibody.

In some embodiments, the induction regimen includes administering 40-300 mg (such as 40 mg , 60mg, 80mg, 120mg, 160mg, 200mg or 240mg) dose of the aforementioned anti-IL-17 antibody.

On the other hand, in the methods for treating and preventing diseases or diseases described in the present disclosure, the administration frequency during maintenance treatment is selected from once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, and once every 12 weeks Once, every 14 weeks, or every 16 weeks or less frequently.

In some embodiments, the maintenance regimen includes administering a dose of 40-300 mg (such as 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg or 240 mg) of anti-IL-17 antibody to a subject in need, and the dosing frequency is once every 4 weeks .

In some embodiments, the maintenance regimen includes administering a dose of 40-300 mg (such as 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg or 240 mg) of anti-IL-17 antibody to a subject in need, and the dosing frequency is once a month.

In some embodiments, the maintenance regimen includes administering 40 to 300 mg (such as 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg or 240 mg) of an anti-IL-17 antibody to a subject in need, and the dosing frequency is once every 6 weeks .

In some embodiments, the maintenance regimen includes administering 40 to 300 mg (such as 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg or 240 mg) of an anti-IL-17 antibody to a subject in need, and the dosing frequency is once every 8 weeks .

In some embodiments, the maintenance regimen includes administering a dose of 40-300 mg (such as 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg or 240 mg) of anti-IL-17 antibody to a subject in need, and the dosing frequency is once every 2 months .

In some embodiments, the maintenance regimen includes administering a dose of 40 to 300 mg (such as 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg or 240 mg) of anti-IL-17 antibody to a subject in need, and the dosing frequency is once every 12 weeks .

In some embodiments, the maintenance regimen includes administering a dose of 40-300 mg (such as 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg or 240 mg) of anti-IL-17 antibody to a subject in need, and the dosing frequency is once every 3 months .

In some embodiments, the maintenance regimen includes administering 40 to 300 mg (such as 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg or 240 mg) of an anti-IL-17 antibody to a subject in need, and the dosing frequency is once every 4 months .

In some embodiments, the method for treating or preventing a disease or condition disclosed herein comprises: a) administering 160 mg or 240 mg of an anti-IL-17 antibody to a subject in need once a week starting from week 0 during the induction regimen , administered 3 or 5 times; and, following b) administering 160 mg or 240 mg of IL-17 antibody to subjects in need during the maintenance regimen once every 4 weeks or every 8 weeks.

In some embodiments, the method for treating or preventing a disease or condition disclosed herein includes: a) administering 120 mg or 240 mg of anti-IL-17 to a subject in need every 2 weeks starting from the zeroth week during the induction regimen Antibody, administered 3 or 5 times; and, following b) 120 mg or 240 mg of IL-17 antibody was administered to subjects in need every 4 weeks or every 8 weeks during the maintenance regimen.

In some embodiments, the method for treating or preventing a disease or condition disclosed herein comprises: a) administering 120 mg or 240 mg of the drug to a subject in need at a dosing frequency of once every 2 weeks starting from the zeroth week during the induction regimen Anti-IL-17 antibody, the number of administrations is 1 to 5 times, such as 3 times; and, later b) during the maintenance program, administer 120 mg or 240 mg to subjects in need at a dosing frequency of once every 4 weeks anti-IL-17 antibody.

In some embodiments, the method for treating or preventing a disease or condition disclosed herein comprises: a) administering 120 mg of anti-IL to a subject in need at a dosing frequency of once every 2 weeks starting from week 0 during the induction regimen -17 antibody, administered 3 times; and, following b) administering 120 mg of anti-IL-17 antibody to subjects in need at a dosing frequency of once every 4 weeks during the maintenance regimen, administered at least 6 times (eg 6, 7, 8, 9, 10, 11, 12 times).

In some embodiments, the method of treating or preventing a disease or condition disclosed herein comprises: a) administering 240 mg of anti-IL to a subject in need at a dosing frequency of once every 2 weeks starting from week 0 during the induction regimen -17 antibody, administered 3 times; and, following b) during the maintenance regimen, administer 240 mg of anti-IL-17 antibody to subjects in need at a dosing frequency of once every 4 weeks, administered at least 6 times (eg 6, 7, 8, 9, 10, 11, 12 times).

The treatment method of the present disclosure carries out one or more treatment cycles, and a treatment cycle refers to a period of continuous administration from the first administration according to a specific dosage regimen. For example, in the present disclosure, a treatment cycle includes the total duration of the induction regimen and the maintenance regimen. In some embodiments, 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. In some embodiments, each treatment cycle is 6 weeks to 52 weeks, such as 16 to 48 weeks, such as 16 weeks to 32 weeks.

In some embodiments, the disease or condition of the aforementioned methods of the present disclosure is an autoimmune disease or inflammation.

In some embodiments, the aforementioned disease or condition of the disclosed methods is arthritis of the spine, such as axial spondyloarthritis or peripheral spondyloarthritis, as well as ankylosing spondylitis, psoriatic arthritis, enteropathic arthritis , such as moderate to severe ankylosing spondylitis.

In some embodiments, examples of axial spondyloarthritis in the aforementioned methods of the present disclosure include, but are not limited to, ankylosing spondylitis, non-radioactive axial spondyloarthritis (nr-axSpA).

In some embodiments, the disease or condition of the aforementioned methods of the present disclosure is active ankylosing spondylitis, eg, moderately to severely active ankylosing spondylitis.

In some embodiments, the aforementioned disease or condition in the methods of the present disclosure is Graves ophthalmopathy, plaque psoriasis.

In some embodiments, a subject in need thereof in a method of the present disclosure has been diagnosed with, or is expected to have, the aforementioned disease or disorder.

In some embodiments, the subject in need thereof is previously underresponsive to at least one non-steroidal anti-inflammatory drug (NSAID) therapy, or the subject in need thereof has a contraindication to or intolerance to an NSAID. Examples of NSAIDs include, but are not limited to, aspirin, ibuprofen, acetaminophen, indomethacin, naproxen, naproxen, diclofenac, nimesulide, rofecoxib, and Lecoxib.

In some embodiments, after the subject in need is administered the anti-IL-17 antibody with the treatment method disclosed above, the subject in need is further administered with NSAID, acetaminophen, weak opioid , disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, sulfasalazine, or corticosteroids such as prednisolone.

In some embodiments, prior to anti-IL-17 antibody treatment with the aforementioned treatment methods of the present disclosure, the subject in need thereof has not previously been treated with one or more therapeutic agents selected from the group consisting of TNF-α inhibitors, IL-17 -6 inhibitors, IL-1 inhibitors, anti-CD20 antibodies, cytotoxic T lymphocyte-associated antigen 4 antibodies, IL-23 inhibitors and other IL-17 inhibitors.

In some embodiments, prior to anti-IL-17 antibody treatment with the aforementioned treatment methods of the present disclosure, the subject in need has previously been treated with one or more therapeutic agents selected from the group consisting of TNF-α inhibitors, IL-17 -6 inhibitors, IL-1 inhibitors, anti-CD20 antibodies, cytotoxic T lymphocyte-associated antigen 4 antibodies, IL-23 inhibitors and other IL-17 inhibitors.

In some embodiments, examples of TNF-α inhibitors include, but are not limited to, adalimumab, infliximab, certolizumab, golimumab, or etanercept; IL-6 inhibitors Examples include, but are not limited to, Tocilizumab or Thalimumab; IL-1 inhibitors such as Anakinra; anti-CD20 antibodies such as Rituximab; cytotoxic T lymphocyte-associated antigen 4An example of an antibody is abatacept; examples of IL-23 inhibitors include but are not limited to tira Zizumab or Guselkunab; or examples of other IL-17 inhibitors include, but are not limited to, Secukinumab, Ixekizumab or Brodalumab.

The present disclosure also provides a method for treating and preventing the aforementioned diseases or conditions (such as ankylosing spondylitis), the method comprising administering to a subject in need an effective amount of the aforementioned anti-IL-17 antibody of the present disclosure, and the administration frequency Every 4-16 weeks, including but not limited to 4, 6, 8, 10, 12, 14, or 16 weeks.

Further, in an alternative embodiment, the treatment method of the present disclosure with a dosing frequency of once every 4-12 weeks may or may not include an induction regimen (loading). For example, the induction protocol is as described previously.

In some embodiments, the aforementioned anti-IL-17 antibody is an anti-IL-17A and/or anti-IL-17F antibody.

In some embodiments, the anti-IL-17A antibody comprises one or more CDR region sequences selected from the following or amino acid sequences having at least 95% sequence identity thereto:

Antibody heavy chain HCDR sequences: respectively shown in the amino acid sequences of SEQ ID NO: 5, 6 and 7; antibody light chain LCDR sequences: respectively shown in the amino acid sequences of SEQ ID NO: 8, 9 and 10.

In some embodiments, 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:

In some embodiments, the anti-IL-17A antibody is selected from recombinant antibodies of murine antibodies, chimeric antibodies, and humanized antibodies.

In some embodiments, the light chain and heavy chain FR region sequences of the light chain and heavy chain variable regions of the humanized anti-IL-17A antibody are respectively derived from human germline light chain and heavy chain or mutant sequences thereof.

In some embodiments, the anti-IL-17A antibody contains a heavy chain framework region or a variant thereof whose amino acid sequence is shown in SEQ ID NO: 1, and the variant is preferably relative to the heavy chain shown in SEQ ID NO: 1. The chain 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 whose amino acid sequence is shown in SEQ ID NO: 2 Framework region or its variant, the variant preferably has a sequence of 0-10 amino acid changes relative to the light chain framework region shown in SEQ ID NO: 2, especially with amino acid back mutations F71Y, K49Y, Y36F and/or L47W.

In some embodiments, the anti-IL-17A antibody contains a heavy chain variable region with the amino acid sequence shown in SEQ ID NO:3 and a light chain variable region with the amino acid sequence shown in SEQ ID NO:4.

In some embodiments, the anti-IL-17A antibody comprises HCDR1, HCDR2, and HCDR3 with the amino acid sequences shown in SEQ ID NOs: 5, 6, and 7, respectively, and the amino acid sequences shown in SEQ ID NOs: 8, 9, and 10, respectively. LCDR1, LCDR2, LCDR3 of the amino acid sequence.

In some embodiments, the light chain sequence of the anti-IL-17 antibody is shown in SEQ ID NO:11, and the heavy chain sequence is shown in SEQ ID NO:12.

Human germline heavy chain variable region (VH1-18)

SEQ ID NO：1

SEQ ID NO: 1

Human germline light chain variable region (A10)

EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSLHWYQQKPDQSPKLLIKYASQSFSGVPSRFSGSGSGTDFLTINSLEAEDAATYYCHQSSSLP SEQ ID NO: 2

heavy chain variable region

SEQ ID NO：3

SEQ ID NO: 3

light chain variable region

SEQ ID NO：4

SEQ ID NO: 4

Humanized antibody design also takes into account factors such as Q1E mutations to eliminate the formation of N-terminal pyroglutamic acid, and mutations that maintain consistency within the selected VH family to maintain the typical structure of the CDR and VH /VL interface, which can avoid the N-glycosylation pattern (N-{P}-S/T) in the humanized structure, etc.

Immunoglobulins can be derived from any of the generally known isotypes, including but not limited to IgA, secretory IgA, IgG, and IgM. IgG subclasses are also well known to those of ordinary skill in the art and include, but are not limited to, IgGl, IgG2, IgG3, and IgG4. "Isotype" refers to the Ab class or subclass (eg, IgM or IgGl) encoded by the heavy chain constant region genes. In some alternative embodiments, the anti-IL-17 antibody of the present disclosure comprises a heavy chain constant region of a human IgG1, IgG2, IgG3 or IgG4 isotype, for example comprising a heavy chain constant region of an IgG1 isotype.

In some embodiments, the anti-IL-17A antibody comprises a kappa or lambda light chain constant region.

In some embodiments, the light chain of the humanized anti-IL-17A antibody comprises or is the amino acid sequence shown in SEQ ID NO: 11, and the heavy chain comprises or is the amino acid sequence shown in SEQ ID NO: 12 ,

light chain

SEQ ID NO：11

SEQ ID NO: 11

heavy chain

SEQ ID NO：12

SEQ ID NO: 12

The administration route of the anti-IL-17 antibody in the present disclosure can be oral administration or parenteral administration, and the parenteral administration includes but not limited to intravenous injection, subcutaneous injection, and intramuscular injection.

In some embodiments, the anti-IL-17 antibody of the present disclosure is administered by injection, such as subcutaneous or intravenous injection, and the anti-IL-17 antibody needs to be formulated into an injectable pharmaceutical composition before injection. For example, the injectable form of anti-IL-17 antibody is injection solution or lyophilized powder, which contains anti-IL-17 antibody, buffer, stabilizer, and optionally, a surfactant. The buffer is a histidine-hydrochloride system; the stabilizer can be selected from sugars or amino acids, such as disaccharides, such as sucrose, lactose, trehalose, maltose. Surfactant is selected from polyoxyethylene hydrogenated sesame oil, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, and this polyoxyethylene sorbitan fatty acid ester is for example polysorbate 20, 40, 60 or 80, For example polysorbate 20. The injectable form of the anti-IL-17 antibody may have a pH range between 5.0 and 7.0, eg 5.4 to 6.2, 5.8 to 6.0.

In some embodiments, the present disclosure provides a pharmaceutical composition comprising the aforementioned anti-IL-17 antibody, the pharmaceutical composition comprising an injectable form of the aforementioned anti-IL-17 antibody, and optionally, a pharmaceutically acceptable salt or carrier.

In some embodiments, the anti-IL-17 antibody-containing pharmaceutical composition disclosed herein comprises the aforementioned anti-IL-17 antibody, histidine hydrochloride buffer, sucrose, and polysorbate 80. In some embodiments, the pharmaceutical composition of 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 poly Sorbitan ester 80, pH about 5.8. The scheme of the anti-IL-17A antibody and its pharmaceutical composition in CN201610739134.4 is introduced here in its entirety.

The present disclosure provides any of the aforementioned anti-IL-17 antibodies or pharmaceutical compositions containing the anti-IL-17 antibodies in the preparation of the treatment of the aforementioned diseases or conditions (such as autoimmune diseases and inflammation, such as spondyloarthritis, axial spinal joints) arthritis, peripheral spondylitis, ankylosing spondylitis, nonradioactive axial spondyloarthritis (nr-axSpA), psoriatic arthritis, enteropathic arthritis, moderate to severe ankylosing spondylitis, Graves ophthalmopathy, Plaque psoriasis), including administering the anti-IL-17 antibody or its pharmaceutical composition to a subject in need with any of the treatment methods or dosage regimens provided in the foregoing disclosure.

The disclosure provides any of the aforementioned anti-IL-17 antibodies or a pharmaceutical composition containing the anti-IL-17 antibody, and its use in the treatment of the aforementioned diseases or conditions (such as autoimmune diseases and inflammation, such as spondyloarthritis, axial Spinal arthritis, peripheral spondylitis, ankylosing spondylitis, non-radioactive axial spondyloarthritis (nr-axSpA), psoriatic arthritis, enteropathic arthritis, moderate to severe ankylosing spondylitis , Graves ophthalmopathy, plaque psoriasis), including administering the anti-IL-17 antibody or its pharmaceutical composition to a subject in need with any treatment method or dosage regimen provided in the foregoing disclosure. In some embodiments, the anti-IL-17 antibody or its therapeutic The administration frequency of the pharmaceutical composition is once every 4-16 weeks, such as once every 4, 6, 8, 10, 12, 14 or 16 weeks.

The aforementioned anti-IL-17A antibody provided by this disclosure has the characteristics of high affinity, rapid onset of action and low toxicity, so the anti-IL-17 antibody can be used in low frequency to treat diseases or diseases.

Figure 1: Histogram of ASAS20 response rate at week 16 of the treatment period (FAS)

Figure 2: Line chart (FAS) of changes in NRS, BASFI, BASDAI and ASDAS scores relative to baseline at each time point during the treatment period, where Figure 2A, Figure 2B, Figure 2C, and Figure 2D are NRS, BASFI, BASDAI, and ASDAS respectively score.

the term

Unless otherwise explained, terms in this disclosure have the following meanings:

The term "IL-17A" generally refers to native or recombinant human IL-17A, as well as non-human homologues of human IL-17A. Molar concentrations of IL-17A were calculated using the molecular weight of the homodimer of IL-17A (eg, 30 KDa for human IL-17A) unless otherwise indicated.

The antibody described in this disclosure refers to immunoglobulin, which is a tetrapeptide chain structure formed by two identical heavy chains and two identical light chains connected by interchain disulfide bonds. The amino acid composition and sequence of the constant region of the immunoglobulin heavy chain are different, so their antigenicity is also different. Accordingly, immunoglobulins can be divided into five classes, or isotypes, of immunoglobulins, namely IgM, IgD, IgG, IgA, and IgE. According to the amino acid composition of the hinge region and the number and position of the heavy chain disulfide bonds of the same class of Ig Differences can be divided into different subclasses, such as IgG can be divided into IgG1, IgG2, IgG3, IgG4. Light chains are classified as kappa or lambda chains by difference in the constant region.

The sequence of about 110 amino acids near the N-terminus of the heavy and light chains of the antibody 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 3 hypervariable regions (HVR) and 4 framework regions (FR) with relatively conserved sequences. Three hypervariable regions determine the specificity of antibodies, also known as complementarity determining regions (CDR). Each light chain variable region (VL) and heavy chain variable region (VH) consists of 3 CDR regions and 4 FR regions, and the sequence from the amino terminal to the carboxyl terminal is: FR1, CDR1, FR2, CDR2 , FR3, CDR3, FR4. The three CDR regions of the light chain refer to LCDR1, LCDR2, and LCDR3; the three CDR regions of the heavy chain refer to HCDR1, HCDR2, and HCDR3. The "antigen-binding fragment" in this disclosure refers to a Fab fragment, Fab' fragment, F(ab')2 fragment, or a single Fv fragment with antigen-binding activity. Fv antibody is the smallest antibody fragment that contains antibody heavy chain variable region, light chain variable region, but no constant region, and has all antigen-binding sites. Typically, Fv antibodies also contain a polypeptide linker between the VH and VL domains and are capable of forming the structures required for antigen binding.

The "humanized antibody" mentioned in this disclosure, also known as CDR-grafted antibody (CDR-grafted antibody), refers to the antibody variable region framework grafted with mouse CDR sequences to humans, that is, different types Antibodies generated from human germline antibody framework sequences. It can overcome the strong antibody variable antibody response induced by chimeric antibodies due to carrying 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. For example, the germline DNA sequences of the human heavy and light chain variable region genes can be found in the "VBase" human germline sequence database (on the Internet at www.mrccpe.com.ac.uk /vbase), and found in Kabat, E.A. et al., 1991 Sequences of Proteins of Immunological Interest, 5th edition.

The "mouse antibody" mentioned in this disclosure is a monoclonal antibody against human IL-17 prepared according to the knowledge and skills in this field. In preparation, test subjects are injected with IL-17 antigen, and fusionomas expressing antibodies with desired sequence or functional properties are isolated. In one embodiment of the present disclosure, the murine anti-IL-17 antibody or antigen-binding fragment thereof may further comprise the light chain constant region of the murine κ, λ chain or variant thereof, or further comprise the murine IgG1, IgG2, Heavy chain constant region of IgG3 or variants thereof.

The "chimeric antibody" mentioned in this 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 establish a chimeric antibody, it is necessary to first establish a fusion tumor that secretes a mouse-derived specific monoclonal antibody, then select and clone the variable region gene from the mouse fusion tumor cell, and then clone the constant region gene of the human antibody according to the need, and then clone the variable region gene of the mouse. The region gene is connected with the human constant region gene to form a chimeric gene and then inserted into an expression vector, and finally the chimeric antibody molecule is expressed in a eukaryotic system or a prokaryotic system.

The sequence of the heavy chain or light chain variable region of the anti-IL-17 antibody or its antigen-binding fragment sequence described in this disclosure is analyzed using Molecular Operating Environment (MOE, Molecular Operating Environment) database software and translated into an amino acid sequence. On the other hand, 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 an amino acid sequence (see J. Methods Mol Biol, 2012, 882, 605-633). However, when using database software such as MOE or IMGT to provide antibody sequences or structures, it should be noted that different databases encode or interpret the same antibody sequence in different ways.

The "effective amount or effective dose" mentioned in the present disclosure includes an amount sufficient to improve or prevent the symptoms or conditions of a medical condition. Effective amount or effective dose also means sufficient to allow or facilitate diagnosis quantity. Effective amounts 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 dosage may be the maximum dosage or dosage regimen that avoids significant side effects or toxic effects.

"Treatment" means the administration of a therapeutic agent, internally or externally, 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 to have therapeutic effect effect. Generally, a therapeutic agent is administered in a patient or population to be treated in an amount effective to alleviate one or more symptoms of the disease, either by inducing regression of such symptoms or inhibiting the progression of such symptoms to any clinically measured extent. The amount of a therapeutic agent effective to alleviate the symptoms of any particular disease (also referred to as a "therapeutically effective amount") will 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.

The term "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. Examples of binding fragments encompassed by the term "antigen-binding portion" of an antibody include Fab fragments, a monovalent fragment consisting of VL, VH, CL and CH1 domains; F(ab')2 fragments, comprising two Fab fragments at the hinge region Bivalent fragments connected by disulfide bridges; Fd fragments consisting of VH and CH1 domains; Fv fragments consisting of VL and VH domains of antibody single arms; dAb fragments (Ward et al., 1989 Nature 341:544-546), which consist of 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".

"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example, "Optional To comprise 1-3 antibody heavy chain variable regions" means that antibody heavy chain variable regions of the specified sequence may but not necessarily be present, and when present may be 1, 2 or 3.

The step of transforming host cells with recombinant DNA described in this disclosure can be performed by conventional techniques well known to those skilled in the art. The obtained transformant can be cultured by conventional methods, and the transformant expresses the polypeptide encoded by the gene disclosed herein. The medium used in the culture can be selected from various conventional media according to the host cells used. The culture is carried out under conditions suitable for the growth of the host cells.

Antibodies or antigen-binding fragments engineered in the present disclosure can be prepared and purified using conventional methods. For example, cDNA sequences encoding heavy and light chains can be cloned and recombined into GS expression vectors. The recombinant immunoglobulin expression vector can stably transfect CHO cells. As a more recommended prior art, mammalian expression systems lead to glycosylation of antibodies, especially at the highly conserved N-terminal site of the Fc region. Stable strains were obtained by expressing antibodies that specifically bind human IL-17. Positive strains were expanded in serum-free medium in bioreactors for antibody production. The culture fluid from which the antibody has been secreted can be purified by conventional techniques. For example, use an A or G Sepharose FF column with adjusted buffer for purification. Wash away non-specifically bound components. Then, the combined antibody was eluted by pH gradient method, and the antibody fragments were detected by SDS-PAGE and collected. Antibodies can be concentrated by filtration using conventional methods. Soluble mixtures and aggregates can also be removed by conventional methods such as molecular sieves and ion exchange. The obtained product needs to be immediately frozen, such as -70°C, or freeze-dried.

"Affinity" refers to the degree of interaction between an antibody and an antigen at a single antigenic site. Within each antigenic site, the variable region of the antibody "arm" interacts with the antigen at many sites through weak non-covalent forces, and the more interactions, the stronger the affinity.

The "homology" mentioned in this disclosure refers to the sequence similarity between two polynucleotide sequences or between two polypeptides. When the positions in the two compared sequences are replaced by the same base or amino acid monomer When subunits are occupied, for example, if every position in two DNA molecules is occupied by an adenine, then the molecules are homologous at that position. The percent homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences divided by the number of compared positions x 100. For example, when the sequences are optimally aligned, if 6 of the 10 positions in the two sequences match or are homologous, then the two sequences are 60% homologous; if 95 of the 100 positions in the two sequences match Or homologous, then the two sequences are 95% homologous. In general, comparisons are made when two sequences are aligned to yield the greatest percent homology.

The effectiveness evaluation of the anti-IL-17 antibody disclosed in this disclosure covers many aspects: including the improvement of AS symptoms and signs, disease activity, physiological function, spinal mobility, peripheral arthritis and tendinitis, quality of life and reflection of inflammatory changes Evaluation of laboratory indicators (CRP and ESR).

1. ASAS scoring system

The scoring system developed by the Assessment of Spondylo Arthritis International Society (ASAS) includes:

1) VAS score (0-100mm) for the overall condition evaluation of the subject;

2) Night pain and total back pain VAS score (0-100mm);

3) Body function (BASFI);

4) Morning stiffness (average VAS score of the last two items in BASDAI related to morning stiffness);

5) CRP;

6) Spinal mobility (same as lumbar scoliosis in BASMI).

"ASAS20" means that at least 3 of the above 1-4 indicators have an improvement of 20% compared with the baseline, and the improvement range is at least 10 units (on the scale of 0-100mm VAS), and the remaining one Index deterioration <20% and <10 units (on the 0-100mm VAS scale).

"ASAS40" means that at least 3 of the above 1-4 indicators have improved by 40% compared with the baseline, and the improvement range is at least 20 units (on the scale of 0-100mm VAS), and the remaining one Indicators showed no deterioration from baseline.

20%。 "ASAS5/6" means that at least 5 of the above 1-6 indicators have improved

20%.

2. Nocturnal pain and total back pain VAS score

Subjects will rate the severity of pain using a 100 mm VAS with 0 representing no pain and 100 representing the worst pain, and subjects will make a mark on the VAS indicating the intensity of the pain.

BASDAI: The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) is a comprehensive index for assessing disease activity by subjects, consisting of 6 questions related to the 5 main symptoms of AS.

BASFI: The Bath Ankylosing Spondylitis Functional Index (BASFI) is a subject-assessed measure of functional ability that consists of 10 questions. Physical function was assessed based on 10 questions related to functional anatomy and coping ability, with a total score ranging from 0 to 10, and self-evaluation by subjects using VAS (Visual Analogue Scale). The higher the score, the more severe the functional impairment.

BASMI: The Bath Ankylosing Spondylitis Measure Index (BASMI) is a physician-administered spinal mobility index that quantifies axial spine mobility and provides an objective assessment of clinically significant changes in spinal motion. The total score ranges from 0 to 10 and is the sum of the evaluations of the five indicators. Including: lumbar scoliosis, ear wall distance, lumbar extension, neck rotation, ankle distance.

MASES: Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) is used to evaluate the degree of inflammation of the starting and ending points of AS, including 13 parts: left and right first costochondral joints (a), left and right seventh ribs Cartilaginous joints (b), left and right anterior superior iliac spines (c), left and right iliac crests (d), left and right posterior superior iliac spines (e), fifth lumbar spinous process (f), proximal junction of left and right heel tendons ( g). Each site is rated as 0 or 1, where 0 indicates no inflammation at the site and 1 indicates inflammation. The total score is a maximum of 13 points. Ultrasonographic confirmation is required for the location of compression pain.

3. Count 44 swollen and tender joints

At V2 (W0), V7 (W16), and V11 (W32), 44 peripheral joints were evaluated for tender and/or swollen joints. Artificial joints are not evaluated. Synovial fluid and/or soft tissue swelling, but not bone overgrowth, is indicative of a positive joint swelling count. Joints that received intra-articular injections of corticosteroids or hyaluronic acid within 4 weeks were directly counted in the count of swollen and tender joints.

4. Chest expansion

During the measurement, the subject held his head with both hands, and measured the bust during deep inhalation and exhalation in the 4th anterior intercostal space (general situation: male nipple; female breast lower edge). For each measurement, two measurements are required, and the one with the largest bust difference will be reported. Thoracic mobility = chest girth during inhalation - chest girth during exhalation.

5. ASQoL

Ankylosing Spondylitis Quality of Life (ASQoL)

To assess the quality of life of AS subjects. The questionnaire consists of 18 yes/no questions. Each "yes" answer is awarded 1 point on a scale of 0 to 18, with lower scores indicating better quality of life.

6. SF-36 Scale

The 36-item Short Form Health Survey (SF-36) contains 36 items to evaluate the overall health status. The survey examines the following 8 categories of general health Concepts were measured: physical functioning, physical roles, physical pain, general health, vitality, social functioning, emotional roles, and mental health.

7. ASDAS-CRP

AS Disease Activity Scale (ASDAS)-CRP is a disease activity scoring system that integrates subjects' subjective evaluation and CRP. ASDAS-CRP calculation formula:

ASDAS-CRP=0.121×lower back pain+0.110×subject’s overall evaluation+0.073×peripheral joint pain/swelling+0.058×morning stiffness duration+0.579×Ln(CRP+1); Ln(CRP+1):CRP (Unit: mg/L)+1 natural logarithm.

The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.

Example 1 Scheme design and preliminary effect evaluation

1. Test antibody

For the anti-IL-17A antibody, the sequences of the heavy and light chains are as shown in SEQ ID NO: 11 and SEQ ID NO: 12 in this disclosure; 80 mg/mL, 1 mL per bottle; or 120 mg pre-filled syringe.

2. Inclusion criteria

Inclusion criteria for axial spondyloarthritis:

(1) Meet the 2009 classification criteria for axial spondyloarthritis (AxSpA) of the Assessment of Spondylo Arthritis international Society (ASAS);

4；隨機前至少使用一種非甾體類抗炎藥(NSAID)而療效不佳或不耐受，即隨機前使用1種NSAID治療

4 週或隨機前使用

2種NSAIDs治療，每種NSAID治療

2週，而療效不佳或不耐受； (2) Bath Ankylosing Spondylitis-Disease Activity Index (BASDAI)

4. At least one non-steroidal anti-inflammatory drug (NSAID) was used before randomization, but the curative effect was poor or intolerable, that is, one NSAID was used for treatment before randomization

Use 4 weeks or before randomization

2 NSAIDs treatment, each NSAID treatment

2 weeks, and the curative effect is poor or intolerable;

10mg的僵的松或等效劑量的其他類似物。 (3) Subjects taking NSAID or oral corticosteroids should maintain a stable dose 2 weeks before randomization and throughout the study period, and the daily dose of oral corticosteroids

10 mg of stromatisone or equivalent dose of other analogues.

Inclusion criteria for ankylosing spondylitis: (1) meet the diagnosis of active AS, have radiological evidence records, and meet the modified New York classification criteria for ankylosing spondylitis revised in 1984;

4分(0-10分總表)，總背痛VAS評分

4分(0-10分總表)； (2) Diagnosed with active AS during the screening period and before randomization (active AS is defined as: BASDAI

4 points (0-10 points total scale), total back pain VAS score

4 points (0-10 points total table);

2種NSAIDs推薦劑量下共治療

4週且每種NSAID不少於2週的推薦劑量的治療反應欠佳)；或對NSAID有禁忌症或不耐受； (3) Poor response to non-steroidal anti-inflammatory drugs (NSAIDs) (defined as:

Co-treatment with 2 NSAIDs at the recommended dose

suboptimal response to treatment at recommended doses of 4 weeks and not less than 2 weeks for each NSAID); or contraindications or intolerance to NSAIDs;

2週；如受試者未穩定劑量口服上述藥物，隨機前至少停藥

2週； (4) If the subject is taking oral NSAID or other analgesics (such as acetaminophen or weak opioids), a stable dose should be continued before randomization

2 weeks; if the subject does not take the above drugs orally in a stable dose, the drug should be stopped at least before randomization

2 weeks;

3g/日)的患者允許繼續使用藥物，但隨機前需要持續治療

3個月，且穩定劑量持續

4週；如受試者未穩定劑量口服上述藥物，隨機前至少停藥

4週； (5) If the subject is taking methotrexate (MTX) (7.5-25mg/week) or sulfasalazine (

3g/day) patients are allowed to continue to use the drug, but continuous treatment is required before randomization

3 months, and the stable dose continues

4 weeks; if the subject does not take the above drugs orally in a stable dose, the drug should be stopped at least before randomization

4 weeks;

10mg/日潑尼松龍(或等效劑量的其它糖皮質激素)，且隨機前需要穩定劑量持續

4週；如受試者未口服糖皮質激素，隨機前至少停藥

4週。 (6) If the subject is taking oral glucocorticoids, the dosage needs to be

10mg/day prednisolone (or equivalent dose of other glucocorticoids), and stable doses need to be continued before randomization

4 weeks; if the subject did not take oral glucocorticoids, at least stop the drug before randomization

4 weeks.

3. Treatment plan

Scheme 1: Anti-IL-17A antibody, fixed dose 20mg, subcutaneous injection, once every 2 weeks, administered 3 times;

Scheme 2: Anti-IL-17A antibody, fixed dose 40mg, subcutaneous injection, once every 2 weeks, administered 3 times;

Scheme 3: Anti-IL-17A antibody, fixed dose 80mg, subcutaneous injection, once every 2 weeks, 3 times of administration;

Scheme 4: Anti-IL-17A antibody, fixed dose 160mg, subcutaneous injection, once every 2 weeks, administered 3 times;

Scheme 5: Anti-IL-17A antibody, fixed dose 240mg, subcutaneous injection, once every 2 weeks, administered 3 times;

Scheme 6: Anti-IL-17A antibody, induction dose 120mg, subcutaneous injection, once every 2 weeks, administered 3 times, then a fixed dose of 120mg, subcutaneous injection, once every 4 weeks, administered 6 times;

Scheme 7: Anti-IL-17A antibody, induction dose 240mg, subcutaneous injection, once every 2 weeks, administered 3 times, then a fixed dose of 240mg, subcutaneous injection, once every 4 weeks, administered 6 times;

Placebo group: did not receive any active treatment.

4. Results

The research results showed that: 1) 20mg, 40mg, 80mg, 160mg, 240mg Q2W three consecutive subcutaneous injections of anti-IL-17A antibody were safe and well tolerated in patients with axial spondylitis; The serum exposure of IL-17A antibody has a linear proportional relationship with the dose; 3) Within 16 weeks, the response rates of ASAS20 and ASAS40 in the 40-240mg Q2W*3 dose group were significantly higher than those in the placebo group Inflammation has been improved to a certain extent, and the onset of effect is rapid and the curative effect is sustained.

Example 2 Safety Evaluation

Among the 35 subjects with axial spondyloarthritis who received subcutaneous injections of anti-IL-17A antibodies in Scheme 1 to Scheme 5 (20-240 mg) of Example 1, a total of 28 (80%) subjects developed 138 TEAEs; 19 TEAEs occurred in 10 (100%) subjects in the placebo group. The severity of TEAEs in each dose group of anti-IL-17A antibody was mostly mild, with 11 cases (31.4%) of moderate TEAEs and no severe TEAEs; among them, 6 cases (17.1%) of moderate TEAEs related to the test drug occurred. %), 1 case in the 20mg dose group, 3 cases in the 160mg dose group, and 2 cases in the 240mg dose group. In this study, only 1 subject in the 160mg dose group had 3 SAEs (hydronephrosis, nephrolithiasis and ureteral calculi), all of which were judged by the investigator to be “possibly irrelevant” to the test drug. There were no TEAEs leading to death or withdrawal in the whole study.

In conclusion, subjects with axial spondyloarthritis who received subcutaneous injections of 20-240 mg anti-IL-17A antibody every 2 weeks (Q2W) were safe and well tolerated.

Example 3 Clinical phase I efficacy

Clinical pharmacodynamic analysis was carried out for schemes 1 to 5 of Example 1, wherein 35 subjects with axial spondyloarthritis received subcutaneous injections of anti-IL-17A antibodies from schemes 1 to 5 (20-240 mg), and 10 subjects received placebo.

1. ASAS20 response rate

The proportion of subjects who reached ASAS20 at week 16 was used as the main efficacy indicator.

As shown in Figure 1, at the 16th week, compared with the placebo group, the response rate of ASAS20 in each dose group increased numerically, except for the response rate of 20mg dose group, which was 44.4%, and the response rate of other dose groups was as high as 71%. above.

2. ASAS40 response rate

Only one subject (10%) in the placebo group achieved ASAS40 at week 6, and no subject had ASAS40 responses in the remaining weeks. Anti-IL-17A antibody compared with placebo All dose groups showed sustained ASAS40 responses, except for the 20mg dose group, which showed ASAS40 responses from week 4 (after 2 doses), all other groups showed ASAS40 from week 2 (i.e., after the first dose) answer. As shown in Table 1, at week 16, the ASAS40 response rates in the 80mg and 240mg dose groups increased significantly, being 66.7% and 57.1%, respectively.

Table 1 Situation of subjects responding to ASAS40 at each time point during the treatment period and follow-up period

3. NRS, BASFI, BASDAI, BASMI and ASDAS scores

At week 16, compared with placebo, patients in the 40-240 mg dose group had lower pain self-ratings and doctors' pain ratings compared with baseline values, as shown in Figure 2A.

At week 16, compared with the placebo group, the average BASFI score of each dose group was lower than the baseline value. The mean BASFI score (SD) changes in the 20-240 mg dose group 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.

At the 16th week, compared with the placebo group, the average BASDAI score of each dose group was lower than the baseline value. The BASDAI mean score (SD) changes in the 20-240 mg dose group 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.

At the 16th week, the BASMI mean score (SD) changes in the placebo group and the 20-240mg 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).

At week 16, compared with the placebo group, the average ASDAS score (based on CRP and ESR) in each dose group was significantly lower than the baseline value, as shown in Figure 2D.

Example 4 clinical phase II/III efficacy

A randomized, double-blind, multi-center, placebo-controlled adaptive seamless Phase II/III clinical study was carried out with reference to Scheme 6 to Scheme 7 of Example 1. In the first stage of drug usage and dosage exploration, dosage group: received 1 subcutaneous administration of 120 mg or 240 mg of anti-IL-17A antibody at week 0, week 2 and week 4, and administered 3 times in total; then from week 4 From the first week, the same dose was administered subcutaneously every 4 weeks, for a total of 6 times; there was a 20-week follow-up period from the last efficacy evaluation to the end of the treatment period. Placebo group: did not receive any active treatment. After 16 weeks of the first stage, an interim analysis was conducted to select the optimal dose for the second stage, and after confirming the optimal dose, the same dosing regimen as that of the first stage was carried out.

Between 400 and 600 subjects are expected to be enrolled in the entire study. The proportion of subjects who reached ASAS20 in the dose group and the placebo group at 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, BASMI scores, etc. were used 16 weeks after administration. As secondary and other efficacy endpoint analysis, Z test, random effect model (MMRM) or covariance analysis (ANCOVA) and other methods are used for analysis, and safety, pharmacokinetics, and immunogenicity are also analyzed.

The effectiveness evaluation results of clinical phase I have shown that the 120mg or 240mg induction regimen of anti-IL-17A antibody has a curative effect advantage. Based on this, it can be expected that the 120mg or 240mg induction regimen (Q2W) combined with the maintenance regimen (Q4W) can improve the efficacy of the subjects. Axial spondyloarthritis tends, and the efficacy is sustained, and it has good safety and tolerance; within 16 weeks, it is expected that the response rate of ASAS20 and ASAS40 in the dose group will increase compared with the placebo group.

<110> SUZHOU SUNCADIA BIOPHARMACEUTICALS CO.,LTD.) JIANGSU HENGRUI PHARMACEUTICALS CO., LTD.) Continental Shanghai Hengrui Pharmaceutical Co., Ltd. (SHANGHAI HENGRUI PHARMACEUTICAL CO.,LTD.)

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Claims (23)

A method of treating a disease or condition comprising: a) an induction regimen comprising administering an anti-IL-17 antibody to a subject in need at a dosing frequency of once every 2 weeks or once every 3 weeks; Preferably, b) a maintenance regimen is also included, comprising administering an anti-IL-17 antibody to the subject in need. The method according to claim 1, wherein, a) the dose of anti-IL-17 antibody in the induction scheme is 40 mg, 80 mg, 120 mg, 160 mg, 200 mg or 240 mg, preferably 120 mg or 240 mg. The method according to claim 1 or 2, wherein, a) the number of administrations of the anti-IL-17 antibody in the induction regimen is 1 to 6 times, preferably 2 to 4 times, more preferably 3 times. The method according to any one of claims 1 to 3, comprising: a) administering 120 mg or 240 mg of the antimicrobial drug to a subject in need at a dosing frequency of once every 2 weeks starting from week 0 during the induction regimen For IL-17 antibody, the number of administrations is 1 to 5 times, preferably 3 times; Preferably, it also includes b) administering 120 mg or 240 mg of anti-IL-17 antibody to the subject in need during the maintenance regimen, preferably at a dosing frequency of once every 4 weeks to the subject in need during the maintenance regimen. of subjects were administered 120 mg or 240 mg of anti-IL-17 antibody. The method according to any one of claims 1 to 4, wherein the method is carried out for one or more treatment cycles, wherein each treatment cycle is 6 weeks to 52 weeks, preferably 16 to 48 weeks, more preferably 16 weeks to 32 weeks . A method of treating a disease or condition comprising: a) an induction regimen comprising administering an anti-IL-17 antibody to a subject in need; and subsequent b) a maintenance regimen, comprising administering an anti-IL-17 antibody to the subject in need, wherein the maintenance regimen comprises once every 4 weeks, once every 8 weeks, once every 12 weeks, or once every 16 weeks, more The anti-IL-17 antibody is administered to the subject in need at a dosage of 120 mg or 240 mg, preferably once every 4 weeks. The method according to any one of claims 1 to 6, wherein the administration is intravenous or subcutaneous administration. The method according to any one of claims 1 to 7, wherein the disease or condition is selected from inflammatory or autoimmune diseases, preferably spondyloarthritis, more preferably axial spondyloarthritis, most preferably catalepsy spondylitis. The method according to claim 8, wherein the ankylosing spondylitis is selected from active ankylosing spondylitis, moderate to severe ankylosing spondylitis, preferably moderate to severe active ankylosing spondylitis. The method according to any one of claims 1 to 9, wherein the anti-IL-17 antibody is an anti-IL-17A antibody. The method according to claim 10, wherein the anti-IL-17A antibody comprises heavy chain HCDR1, HCDR2 and HCDR3 with amino acid sequences as shown in SEQ ID NO: 5, 6 and 7 respectively; and amino acid sequences as shown in Light chains LCDR1, LCDR2 and LCDR3 shown in SEQ ID NO:8, 9 and 10. The method according to any one of claims 1 to 11, wherein the anti-IL-17 antibody is a chimeric antibody or a humanized antibody. The method of claim 12, wherein the light chain and heavy chain framework regions of the humanized anti-IL-17 antibody are derived from human germline light chain and heavy chain or mutants thereof, respectively; Preferably, the anti-IL-17 antibody contains a heavy chain framework region or a variant thereof whose amino acid sequence is shown in SEQ ID NO: 1, and the variant is preferably relative to the heavy chain shown in SEQ ID NO: 1 The framework region sequence has 0-10 amino acid mutations, more preferably A93T and/or T71A amino acid mutations; the anti-IL-17 antibody contains a light chain whose amino acid sequence is shown in SEQ ID NO: 2 framework region Or a variant thereof, the variant preferably has 0-10 amino acid mutations relative to the light chain framework region shown in SEQ ID NO: 2, more preferably has the amino acids of F71Y, K49Y, Y36F and/or L47W mutation. The method according to any one of claims 1 to 13, wherein the anti-IL-17 antibody contains the heavy chain variable region shown in SEQ ID NO: 3, and the light chain variable region shown in SEQ ID NO: 4 Area. The method according to any one of claims 1 to 14, wherein the anti-IL-17 antibody comprises a heavy chain constant region of human IgG1, IgG2, IgG3 or IgG4 isotype, preferably a heavy chain constant region of IgG1 isotype region; and/or, the anti-IL-17 antibody comprises a kappa or lambda light chain constant region. The method according to any one of claims 1 to 15, wherein the anti-IL-17 antibody comprises the light chain shown in SEQ ID NO:11, and the heavy chain shown in SEQ ID NO:12. The method of claim 16, wherein the subject in need is previously underresponsive to at least one nonsteroidal anti-inflammatory drug (NSAID) treatment, or the subject in need has a contraindication to NSAID or intolerance. The method of claim 17, wherein the subject in need further administers NSAID, acetaminophen, weak opioid, antirheumatic drug (DMARD), sulfasalazine, or glucocorticoid; Antirheumatic drugs are preferably methotrexate, and glucocorticoids are preferably prednisolone. The method of any one of claims 1 to 18, wherein, prior to treatment with anti-IL-17 antibody, the subject in need has not previously been treated or has been treated with one or more therapeutic agents selected from : TNF-α inhibitors, 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 method of claim 19, wherein, The TNF-α inhibitor is selected from adalimumab, infliximab, certolizumab, golimumab and etanercept; The IL-6 inhibitor is selected from tocilizumab and sarilumab; The IL-1 inhibitor is anakinra; The anti-CD20 antibody is rituximab; Cytotoxic T lymphocyte-associated antigen 4 antibody is abatacept; The IL-23 inhibitor is selected from Tiragizumab and Guselkumab; or Other IL-17 inhibitors are selected from secukinumab, ixekizumab and brodalumab. An anti-IL-17 antibody for treating a disease or disorder, comprising: administering an anti-IL-17 antibody to a subject in need according to any one of claims 1 to 20; Preferably, the anti-IL-17 antibody is as defined in the method of any one of claims 11-16. A pharmaceutical composition comprising an anti-IL-17 antibody for treating a disease or a disease, comprising: administering the anti-IL-17 antibody to a subject in need according to the method described in any one of claims 1 to 20; Preferably, the anti-IL-17 antibody is as defined in the method of any one of claims 11 to 16; Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable salt or carrier, more preferably, the pharmaceutical composition contains about 80 mg/mL of the method as defined in any one of claims 11 to 16 Anti-IL-17 antibody, about 10 mM histidine hydrochloride, about 76 mg/mL sucrose, and about 0.6 mg/mL polysorbate 80, the pH is about 5.8. The use of an anti-IL-17 antibody or a pharmaceutical composition comprising the anti-IL-17 antibody in the preparation of a medicament for treating a disease or a disease, comprising: the method described in any one of claims 1 to 20 has Administration of anti-IL-17 antibodies to subjects in need; Preferably, the anti-IL-17 antibody is as defined in the method of any one of claims 11 to 16; Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable salt or carrier, more preferably, the pharmaceutical composition contains about 80 mg/mL of the method as defined in any one of claims 11 to 16 Anti-IL-17 antibody, about 10 mM histidine hydrochloride, about 76 mg/mL sucrose, and about 0.6 mg/mL polysorbate 80, the pH is about 5.8.

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