Methods of treating radio-negative axial spondyloarthritis using interleukin 17 (il-17) antagonists

Abstract

To provide a method for treating X-ray negative axial spondyloarthritis (nr-axSpA) patients and inhibiting the progression of structural damage in these patients.SOLUTION: Methods of treating nr-axSpA patients with an IL-17 antagonist, e.g., secukinumab, to inhibit progression of structural damage in these patients are provided. Also provided are uses of IL-17 antagonists, e.g., IL-17 antibodies, such as secukinumab, for treating nr-axSpA patients and inhibiting the progression of structural damage in these patients, as well as medicaments, dosing regimens, pharmaceutical formulations, dosage forms, and kits for use in the disclosed uses and methods.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application is incorporated herein by reference in its entirety. This application claims priority to U.S. Provisional Patent Application No. 62 / 243,381, filed October 19, 2019. That is why.

[0002] The present disclosure provides a method for treating x-ray-negative axial leukemia using an IL-17 antagonist, e.g., secukinumab. Treating patients with non-rx spondyloarthritis (nr-axSpA) and preventing structural damage to the joints in these patients The present invention relates to a method for inhibiting the progression of [Background technology]

[0003] Axial spondyloarthritis (axSpA) is a rheumatoid arthritis that shares common features of spinal inflammation and inflammatory back pain. Patients with chronic back pain (onset before age 45) are considered to meet the criteria for clinical International Spondyloarthritis Evaluation Study for axSpA if the floor arm or imaging arm is met Assessment of Spondyloarthritis International Society (ASAS) classification criteria Classified according to (Rudwaleit et al 2009, Ann Rheum Dis; 68:770-76). Based on the presence or absence of sacroiliitis on photographs, patients with axSpA were classified as having radiographically negative axSpA. It is subclassified into ankylosing spondylitis (AS) and non-ankylosing spondylitis (nr-axSpA). 1984 modified New York diagnostic criteria (van der Linden Radiographic evidence of sacroiliitis (Arthritis Rheum; 27:361-8) Patients are classified as having AS whereas X-rays show no sacroiliitis but MRI Patients who can show evidence of sacroiliitis are classified as having nr-axSpA.

[0004] Radiographic sacroiliac joint inflammation by including both X-ray and MRI as imaging modalities To establish criteria applicable to patients with and without axSpA, The ASAS classification criteria were introduced in 2009. The diagnosis of nr-axSpA based on imaging is now in up to 88 % specificity and 67% sensitivity can be achieved, but based on clinical parameters alone The diagnosis can achieve a specificity of approximately 83% and a sensitivity of 57% (Sieper and van d er Heijde 2013, Arthritis Rheum; 65:543-51). Differentiation of patients with AS and non-r-axSpA In addition to identifying, the ASAS criteria identify those with unmet medical needs and those in the United States who have Clinical trials for the treatment of non-rapid stenosis (nr-axSpA), a disease for which there are no approved therapies, (Sieper 2012, Nat Rev Rheumatol; 8:280-87).

[0005] Trial and registry data suggest that patients with nr-axSpA have similar levels of disease to patients with AS. have been shown to have impaired activity, pain, and health-related quality of life (Wallis et al. 2013, J Rheumatol; 40:2038-41). Etiological and pathogenesis characteristics of AS and nr-axSpA Common features of the natural history are the subject of ongoing research. Disease parameters and tumor necrosis factors Response rates to treatment with tumor necrosis factor (TNF) antagonists were significantly higher in non-rx-SpA and AS patients. This is similar in patients with axSpA, suggesting that axSpA is one common disease with different stages. The concept is supported (Song et al 2013, Ann Rheum Dis; 72:823-25). Progression from SpA to AS occurred in approximately 12% of non-r-axSpA patients over a 2-year period (Poddubnyy et al 2011, Ann Rheum Dis; 70:1369-74). However, patients with nr-axSpA It is estimated that 10-15% of patients will not develop radiographically visible sacroiliitis ( Sieper and van der Heijde 2013, Arthritis Rheum; 65:543-51).

[0006] Nonsteroidal anti-inflammatory drugs (NSAIDs) are the first line of treatment for all patients with axSpA. It is considered the treatment of choice. Conventional disease-modifying antirheumatic drugs (DMARDs) are not effective in treating axSpA. F drugs are useful for patients with AS who continue to have active disease despite NSAIDs. In Europe, several anti-TNF drugs are approved for the treatment of non-rx-SpA. However, it has been approved for the treatment of adalimumab or etanercept. Over 60% of non-r-axSpA patients achieved an ASAS40 response in randomized clinical trials. (Sieper et al 2013, Ann Rheum Dis; 72:815-22; Dougados et al 2014, Arth Rheum; 66:2091-2102). Furthermore, inhibition of TNF has been shown to result in long-term remission of axSpA. Responders usually relapse within a few weeks after treatment discontinuation (Baraliakos et al. 200 5, Arthritis Res Ther; 7: R439-R444). It is effective in treating inflammatory symptoms, but agonists have been primarily tested in AS to treat structural joint damage in axSpA. (van der Heijde et al 2008a, Arthritis Rheum; 58:3063-70; van der H eijde et al 2008b, Arthritis Rheum; 58:1324-31). Summary of the Invention [Means for solving the problem]

[0007] Secukinumab (AIN457) is a high-affinity recombinant fully human monoclonal antibody of the IgG / κ class. Secukinumab is a monoclonal anti-human interleukin-17A antibody. IL-17A binds to and neutralizes the biological activity of this cytokine in several animal models. Inflammatory It is a key lymphokine of a newly defined subset of T cells (Th17). 17A is produced primarily by memory CD4+ and CD8+ T lymphocytes and mediates immune responses. It is recognized as one of the major inflammatory cytokines in inflammatory diseases.

[0008] Secukinumab in axSpA (ankylosing spondylitis; AS) Phase III study (0, 1, 2 and 150 mg SC in weeks 1 and 3, then the same dose every 4 weeks) The ASAS40 response rate was 0.1%. Clinically meaningful differences in ASAS40 response were evident as early as week 1. In the Phase II study, MRI scans were performed at baseline and at weeks 6 and 28. showed a reduction in inflammation after 6 weeks that was maintained through 28 weeks. This was especially evident in patients with higher baseline MRI scores (Baraliak os et al 2011, Arthritis Rheum 63 (Suppl 10):2486D).

[0009] Currently, there are no FDA-approved therapies available in the US for non-rapid stenosis (nr-axSpA). Potential role of Th17 cells in inflammatory infiltrates in spondyloarthritis, early Inflammatory activity in various stages of the disease (such as non-r-axSpA), TNF in the treatment of AS Equivalence of secukinumab with the alpha inhibitors certolizumab and etanercept, and Given the early reduction in inflammation revealed by MRI during AS trials of cukinumab, Long-term structural changes in the axial joint may be modulated by IL-17 antagonism. .

[0010] Thus, disclosed herein are IL-17 antagonists for use in treating patients in need thereof. and administering the drug to patients with radio-negative axial spondyloarthritis (nr-axSpA). Further disclosed herein are methods of treating patients with IL-17 antagonists. in patients with non-rxSpA, including administering This is a method to inhibit the progression of structural damage caused by the disease.

[0011] In some embodiments of the disclosed uses, methods and kits, an IL-17 antagonist The antibody is an IL-17 antibody or an antigen-binding fragment thereof. In some embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises: a) Leu74 ,Tyr85,His86,Met87,Asn88,Val124,Thr125,P Epitopes of IL-17 including ro126, Ile127, Val128, and His129 a) an IL-17 antibody or an antigen-binding fragment thereof that binds to Tyr43, Tyr44, and Arg; IL-17 antibody that binds to epitopes of IL-17 including 46, Ala79, and Asp80 or an antigen-binding fragment thereof, c) an IL-17 homozygote having two mature IL-17 protein chains. It binds to a dimeric epitope, which is located at Leu74, Tyr85, and His86, Met87, Asn88, Val124, Thr125, Pro126, I Ile127, Val128, His129 and Tyr43, Tyr44, Ar on the other chain IL-17 antibody or antigen-binding fragment thereof, comprising g46, Ala79, and Asp80; d)2 binds to an epitope of the IL-17 homodimer having two mature IL-17 protein chains, The epitope is located at Leu74, Tyr85, His86, Met87, As on one chain. n88, Val124, Thr125, Pro126, Ile127, Val128, H Tyr43, Tyr44, Arg46, Ala79, Asp8 on is129 and other chains K of approximately 100-200 pM, including 0 D It has an in vivo half-life of approximately 23 to 35 days. and e) an IL-17 antibody or antigen-binding fragment thereof having the structure shown as SEQ ID NO: 8. The immunoglobulin heavy chain variable domain (V) containing the amino acid sequence H ), ii) SEQ ID NO: 1 The immunoglobulin light chain variable domain (V) containing the amino acid sequence shown as L ), iii ) Immunoglobulin V comprising the amino acid sequence shown as SEQ ID NO: 8 H Domain and sequence number Immunoglobulin V containing the amino acid sequence shown as No. 10 L domain, iv) sequence number 1, immunoglobulin V comprising the hypervariable regions shown as SEQ ID NO:2 and SEQ ID NO:3 H Domestic v) an immunogen comprising the hypervariable regions shown as SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6; Globulin V L domains, vi) the domains shown as SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:13; Immunoglobulin V containing the hypervariable region H domain, vii) SEQ ID NO: 1, SEQ ID NO: 2 and immunoglobulin V comprising the hypervariable region shown as SEQ ID NO:3 H Domains and sequences Immunoglobulin V comprising the hypervariable regions shown as SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 L domain, viii) the hyperstable nucleotide sequences shown as SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:13; Immunoglobulin V containing variable regions H Domains and SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 Immunoglobulin V containing hypervariable regions designated as L domain, ix) SEQ ID NO: 14 x) an immunoglobulin light chain comprising the amino acid sequence shown as SEQ ID NO: 15; xi) an immunoglobulin heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 14; an immunoglobulin light chain comprising the amino acid sequence shown as SEQ ID NO: 15; The antibody is selected from the group consisting of an IL-17 antibody or an antigen-binding fragment thereof comprising a globulin heavy chain. In some embodiments of the disclosed uses, methods and kits, an IL-17 antibody or its The antigen-binding fragment is secukinumab. [Brief explanation of the drawings]

[0012] [Figure 1] Figure 2 shows the 2009 ASAS classification criteria for axial SpA. [Figure 2A] 16A-B are graphs showing that improvement from baseline in mean Berlin SI total joint edema score was greater for both secukinumab doses compared to the placebo group at week 16. Improvement was sustained through week 52. [Figure 2B] 10A-10C show that subjects randomized to secukinumab 10 mg / kg IV → 150 mg sc had lower mean baseline Berlin Spine Scores than the secukinumab 10 mg / kg IV → 75 mg sc and placebo groups, and the improvement in mean Berlin Spine Score at week 16 was greater for both secukinumab doses compared to the placebo group. Improvements were sustained through week 52. [Figure 3A] 1 is a graph showing that subjects who were switched from placebo to secukinumab at weeks 16 and 24 showed improvement in Berlin SI total joint edema score at week 52 from their respective week 16 scores. [Figure 3B] 1 is a graph showing that subjects who were switched from placebo to secukinumab at weeks 16 and 24 showed improvement in Berlin Spine Score at week 52 from their respective week 16 scores. DETAILED DESCRIPTION OF THE INVENTION

[0013] As used herein, IL-17 refers to interleukin 17A (IL-17A ) refers to

[0014] Treatment of X-ray-negative axial spondyloarthritis with IL-17 antagonists, such as secukinumab It is an object of the present disclosure to provide methods of treating patients with (nr-axSpA). 17 antagonists, e.g., secukinumab, in patients with nr-axSpA It is another object of the present disclosure to provide a method for inhibiting cardiac damage (e.g., bone and joint damage). .

[0015] The term "comprising" is used interchangeably with "including" and "consisting of." ", for example, a composition "comprising" X may consist solely of X. It may also contain one or another, for example X+Y.

[0016] As used herein, the phrase "inhibiting the progression of structural damage" includes the phrase "inhibiting the progression of structural damage." This is synonymous with "preventing the progression of bone and joint damage" and is intended to reduce bone and joint damage associated with non-rx-SpA. It is used to mean to reduce, eliminate or slow down. , which includes pathogenic new bone formation in patients with nr-axSpA, bone and / or This means a reduction in the level and / or rate of progression of joint damage. X-rays and magnetic resonance imaging Magnetic resonance imaging (MRI) is particularly useful for analyzing bone and joint damage associated with axSpA. Various methods for imaging and scoring axial spondyloarthritis are described, for example, in Braun and Baraliakos (2011) Ann Rheum Dis 70 (Suppl 1):i97-i103; Rudwaleit (2009) Ann. Rhe um. Dis. 68:1520-7; and IH Song et al. Ann Rheum Dis. 2011 Jul;70(7):1257-63 A preferred method for scoring spine and SIJ MRI images is described in Berl et al. in MRI spine score (Lukas C, et al. J Rheumatol. 2007;34:862-70), Berl in SIJ score (Hermann KG, et al. Radiologe. 2004;44:217-28, Song et al. 20 00, supra), Ankylosing Spondylitis Disease Activity Spine MRI Scoring System (ASspiMRI-a) and "Berlin modification of ASspiMRI-a" (Lukas C et al (2007) J. Rheumato l; 34(4):862-70; Rudwaleit et al. (2008) Arthritis Rheum 67:1276-1281; Rudwaleit et al (2005) [abstract] Arthritis Rheum 50:S211). The SI joint is Spondyloarthritis Research Consortium of Canada (S PARCC) scoring system (Maksymowych et al. (2005) Arthritis Rheum. 53:703-09) Inhibition can also be scored using a control, e.g., a disclosed IL-17 antagonist. Patients who were not treated with steroids or who had a known rate of progression (e.g., mean, median, or This can be confirmed by comparing the

[0017] The term "about" in reference to a numerical value x means, for example, + / - 10%. When used before a list of numbers, the term "about" applies to each number in the series. For example, the phrase "about 1 to 5" should be interpreted as "about 1 to about 5", or For example, the phrase "about 1, 2, 3, 4" should be interpreted as "about 1, about 2, about 3, about 4, etc." It is.

[0018] The term "substantially" does not exclude "completely." For example, if Y is "substantially free of" The composition may be completely free of Y. Where necessary, the word "substantially" , may be excluded from the definition of this disclosure.

[0019] The term "antibody" as referred to herein includes whole antibodies and antigen-binding portions thereof or single chains. A naturally occurring "antibody" is a molecule that contains at least two amino acids linked together by disulfide bonds. It is a glycoprotein containing two heavy (H) chains and two light (L) chains. Each heavy chain contains a heavy chain variable region (herein V H The heavy chain constant region is composed of a heavy chain constant region. The constant region consists of three domains, CH1, CH2 and CH3. It is composed of a chain variable region (abbreviated as VL herein) and a light chain constant region. The light chain constant region is comprised of one domain, CL. H and V L The area is The ultrastructure is interspersed with more conservative regions called framework regions (FRs). They can be further subdivided into regions of hypervariability called variable regions or complementarity-determining regions (CDRs). Each V H and V L are arranged in the following order from amino to carboxy terminus: It consists of three CDRs and four FRs: FR1, CDR1, FR2, and CD R2, FR3, CDR3, FR4. The variable regions of the heavy and light chains form the binding domains that interact with the antigen. The constant region of an antibody binds to various cells of the immune system (e.g., effector cells) and Binding of immunoglobulins to host tissues or factors, including the first component (C1q) of the classical complement system Some embodiments of the disclosed methods, regimens, kits, processes, uses and compositions may mediate In some embodiments, an antibody to IL-17 or an IL-17 receptor, preferably IL-17 Antibodies against, for example, secukinumab, are used.

[0020] The term "antigen-binding fragment" of an antibody, as used herein, refers to a fragment that binds to an antigen (e.g., It refers to a fragment of an antibody that retains the ability to specifically bind to IL-17. It has been shown that the function can be performed by fragments of a full-length antibody. Examples of binding fragments included in the term are V L , V H , CL and CH1 domains Fab fragments are monovalent fragments linked by disulfide bridges in the hinge region. F(ab)2 fragment, a bivalent fragment containing two Fab fragments, V H and CH1 domain Fd fragment consisting of V of one arm of the antibody L and V H Fv fragment consisting of domains, V H Domain dAb fragments consisting of CDRs (Ward et al., 1989 Nature 341, 544-546) and isolated CDRs. Exemplary antigen-binding sites are shown in SEQ ID NOS: 1 to 6 and 11 to 13 (Table 1). The CDRs of secukinumab, preferably the heavy chain CDR3, are also known. The two domains of V L and V H are encoded by separate genes, but they are L and V H Single protein chains (single-chain Fvs) in which the domains pair to form monovalent molecules Fv), see, for example, Bird et al., 1988 Science 242:423-426, and Husto (See, e.g., N et al., 1988 Proc. Natl. Acad. Sci. Vol. 85, pp. 5879-5883). Such single chain antibodies can be linked by recombinant methods using synthetic linkers that allow the Single chain antibodies and antigen-binding portions thereof are also intended to be included within the scope of the term "antibody." It may be obtained using conventional techniques known to those skilled in the art.

[0021] An "isolated antibody," as used herein, is an antibody that is isolated from other antibodies having different antigen specificities. An isolated antibody that specifically binds IL-17 refers to an antibody that is substantially free of IL-17. (Substantially free of antibodies that specifically bind to antigens other than IgG-17) " or "monoclonal antibody composition," as used herein, refers to a single The term "human antibody" as used herein refers to a preparation of antibody molecules of the same molecular composition. Thus, both the framework and CDR regions have variable regions derived from sequences of human origin. A "human antibody" includes an antibody produced by a human, human tissue, or human cells. Human antibodies of the present disclosure may contain amino acid residues that are not encoded by human sequences (e.g., For example, antibody genes can be engineered by random or site-directed mutagenesis in vitro. by the addition of an N-nucleotide at the binding site upon in vivo recombination, or The disclosed techniques may include mutations introduced by in vivo somatic mutation. In some embodiments of the processes and compositions, the IL-17 antibody is a human antibody, an isolated antibody, or a human antibody. and / or monoclonal antibodies.

[0022] The term "IL-17" refers to IL-17A, formerly known as CTLA8. The wild-type IL-17A, IL-17A, and IL-17A from various species (e.g., human, mouse, and monkey) The functional equivalents of IL-17A according to the present disclosure include polymorphic variants and functional equivalents of IL-17A. Equivalents preferably have at least a partial homology with wild-type IL-17A (e.g., human IL-17A). Approximately 65%, 75%, 85%, 95%, 96%, 97%, 98% or even 99% full distribution It has sequence identity and substantially retains the ability to induce IL-6 production by human dermal fibroblasts. I have it.

[0023] "K D The term "K" refers to the dissociation rate of a particular antibody-antigen interaction. D " as used herein means K d and K. a (i.e., K d / K a ) and expressed as a molar concentration (M). K D The value can be determined using methods well established in the art. Body K D Methods for determining .alpha. are by using surface plasmon resonance or by using Biocor By using a biosensor system such as the e® system. In some embodiments, an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab has a K of approximately 100-250 pM D It binds to human IL-17.

[0024] The term "affinity" refers to the strength of the interaction between an antibody and an antigen at a single antigenic site. Within each antigenic site, the variable regions of the antibody "arms" weakly interact with the antigen at multiple sites. They interact through binding forces. The stronger the interaction, the stronger the affinity. For example, ELISA A, Binding affinity of antibodies to IL-17 in various species, including Western blot and RIA. Standard assays for assessing potency are known in the art. For example, binding affinity) can also be determined using methods publicly known in the art, such as Biacore® analysis. This can be assessed by known standard assays.

[0025] These IL-17 functions measured by methods known in the art and described herein. properties (e.g., biochemical, immunochemical, cellular, physiological, or other biological activity or the like) An antibody that "inhibits" one or more of the following (or unrelated) substances will inhibit the activity of the antibody in its absence (or in an unrelated Statistically significant increase in specific activity compared to that observed in the presence of a control antibody of the same specificity It is understood that antibodies that inhibit IL-17 activity are associated with a significant decrease in the measured parameters. Statistically significant in at least about 10%, at least 50%, 80%, or 90% of the parameters In certain embodiments of the disclosed methods and compositions, the IL-1 7 antibodies may inhibit 95%, 98%, or 99% or more of IL-17 functional activity.

[0026] "Inhibiting IL-6," as used herein, refers to the production of IL-6 from primary human dermal fibroblasts. IL-17 antibodies or antigen-binding fragments thereof (e.g., sec- numab) ability to stimulate IL-6 production in primary human (skin) fibroblasts. 17 (Hwang et al., (2004) Arthritis Res Ther, vol. 6, pp. R120-128). Human dermal fibroblasts were incubated with various concentrations of IL-17 binding molecules or human IL-17 bearing the Fc region. Stimulated by recombinant IL-17 in the presence of the IL-17 receptor. Chimeric anti-CD25 antibody S Imulect® (basiliximab) is conveniently used as a negative control. After 16 hours of stimulation, the supernatant was collected and assayed for IL-6 by ELISA. The IL-17 antibody or antigen-binding fragment thereof, for example, secukinumab, is When tested as described above, i.e., induced by hu-IL-17 in human skin fibroblasts, When the inhibitory activity against the production of IL-6 was measured, it was found to be about 50 nM or less (for example, Inhibition of IL-6 production (approximately 0.01 to approximately 50 nM) in the presence of 1 nM human IL-17 Harm IC 50 In some embodiments of the disclosed methods and compositions, In the present invention, an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab, and its function The soluble derivatives are less than about 20 nM, more preferably less than about 10 nM, more preferably less than about 5 nM IL-1 as defined above at or below about 2 nM, more preferably at or below about 1 nM IC for inhibition of 6 production 50 It has.

[0027] The term "derivative" refers to amino acid sequence variants as well as to compounds that are in accordance with the present disclosure, unless otherwise indicated. IL-17 antibodies or antigen-binding fragments thereof, e.g., secukinumab, e.g., Covalent modifications (e.g., pegylation, deamidation, hydrolysis) of sequences (e.g., variable domains) "Functional derivatives" are used to define the functional groups of the disclosed Functional derivatives include molecules that have the same qualitative biological activity as the IL-17 antibody. Fragments and peptide analogs of the IL-17 antibodies disclosed herein are included. The polypeptides disclosed herein include, for example, regions within the sequence of a specified sequence. Functional derivatives of the L-17 antibody (e.g., functional derivatives of secukinumab) are preferably V of the IL-17 antibodies and antigen-binding fragments thereof disclosed herein H and / or V L Arrays (e.g. For example, V in Table 1 H and / or V L sequence) and at least about 65%, 75%, 85%, 95%, V with 96%, 97%, 98% or even 99% overall sequence identity H and / or V L domain, which binds to human IL-17 or inhibits, for example, IL-17-induced human skin inflammation It substantially retains its ability to inhibit IL-6 production in fibroblasts.

[0028] The phrase "substantially the same" refers to a sequence of related amino acids or nucleotides (e.g., V H or V L domains) are the same or have minor differences compared to a particular reference sequence ( Minor differences are those that occur within a specified region (e.g., by conservative amino acid substitutions). , V H or V L A few amino acids, such as one or two substitutions in the five amino acid sequence of the domain In the case of antibodies, the second antibody has the same specificity and a lower affinity for the same. at least 50% of the sequence disclosed herein. In some embodiments, the derived sequences are also part of the present application. IL-17 antibodies (e.g., derivatives of secukinumab, e.g., secukinumab biosimilars) The sequence identity of the antibody to the disclosed sequence is about 90% or more, e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher It could be.

[0029] "Identity" in relation to naturally occurring polypeptides and functional derivatives thereof is used herein to mean: Align the sequences and introduce gaps, if necessary, to achieve the maximum percent identity. and then the corresponding native polypeptide, without considering conservative substitutions as part of the sequence identity. It is defined as the percentage of amino acid residues in a candidate sequence that are identical to the residues in the N- or C-terminal extension. Neither lengthening nor insertion shall be construed as reducing identity. Percent identity can be determined using standard alignment algorithms, e.g., Al Basic Lo described by Tshul et al. ((1990) J. Mol. Biol., Vol. 215, pp. 403-410) cal Alignment Search Tool (BLAST), Needleman et al. Algorithm ((1970) J. Mol. Biol., vol. 48, pp. 444-453) or the algorithm of Meyers et al. ((1988) Comput. Appl. Biosci., Vol. 4, pp. 11-17). The parameters are a gap penalty of 12, a gap extension penalty of 4, and a frameshift penalty of 1. Blosum 62 scoring matrix with a gap penalty of 5 The percent identity between two amino acid or nucleotide sequences is PAM120 AL using a weighted residue table, a gap length penalty of 12, and a gap penalty of 4 The application of E. Meyers and W. Miller to the IGN program (version 2.0) It can also be calculated using the algorithm ((1989) CABIOS, Vol. 4, pp. 11-17).

[0030] "amino acid(s)" refers to all naturally occurring L-α-amino acids; Also included are, for example, D-amino acids. The phrase "amino acid sequence variant" is used in accordance with the present disclosure. refers to molecules that have slight differences in their amino acid sequence compared to the specified sequence. The amino acid sequence variants of the antibodies according to the present disclosure bind to human IL-17, or For example, the ability to inhibit IL-17-induced human dermal fibroblast IL-6 production remains unclear. Amino acid sequence variants include substitution variants (where at least one amino acid residue is removed). and a different amino acid sequence inserted at the same position in a polypeptide according to the present disclosure. insertion mutants (those with a specific amino acid at a specific position in a polypeptide according to the present disclosure); (having one or more amino acids inserted immediately adjacent to the amino acid(s) in question), deletion mutations and the like, including polypeptides in which one or more amino acids in a polypeptide according to the present disclosure have been removed. nothing.

[0031] The term "pharmaceutically acceptable" refers to a compound that is pharmaceutically acceptable and that is capable of maintaining the effectiveness of the biological activity of the active ingredient(s). It means a non-toxic substance that does not inhibit.

[0032] The term "administering" in reference to a compound, e.g., an IL-17 binding molecule or other agent The term is used to refer to delivery of the compound to a patient by any route.

[0033] As used herein, a "therapeutically effective amount" is an amount that is effective to treat a disorder or a recurring disorder. , prevent, prevent its onset, cure, delay, reduce its severity, to improve at least one symptom of, or as expected in the absence of such treatment One or more doses to a patient (e.g., human) to extend the patient's survival beyond the normal life span. IL-17 antagonists, e.g., IL-17 binding molecules, that are effective in a single dose. (e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) or IL IL-17 receptor-binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof) Individual active ingredients administered alone (e.g., IL-17 antagonists, e.g., When applied to a single agent (secukinumab), the term refers to that agent only. When applied to combinations The term refers to any combination of compounds that provide a therapeutic effect, whether administered in combination, sequentially or simultaneously. This refers to the total amount of active ingredient delivered.

[0034] The term "treatment" or "treating" refers to prophylactic or preventative treatment as well as reducing the risk of contracting a disease. Patients who are ill or suspected of having a disease or medical condition This includes the treatment of patients diagnosed with the disease, and includes curative or disease-modifying treatment, including the prevention of clinical recurrence. It refers to both the prevention, cure, and delay of the onset of a disorder or recurring disorder. to reduce the severity of, or ameliorate one or more symptoms thereof, or prolongs patient survival beyond that expected in the absence of such treatment Therefore, treatment may be administered to patients who have or may eventually develop a medical disorder. can.

[0035] As used herein, "a patient who has not previously received treatment with a TNF antagonist" means a patient who has not previously received treatment with a TNF antagonist. The terms "TNF-naive" and "TNF-naive" refer to the use of TNF for nr-axSpA. This refers to patients with non-rxSpA who have not previously received treatment with an F alpha inhibitor. As used herein, "previously treated with a TNF antagonist" and " The phrase "TNF-experienced" refers to TNF-alpha inhibitors (e.g., infliximab, etanercept, Previously treated with rituximab (Estradiol, adalimumab, certolizumab, golimumab) - refers to axSpA patients, which are refractory to TNF-alpha inhibitor treatment or Patients who have had an inadequate response and who are no longer receiving TNF-alpha inhibitors due to safety or tolerability As used herein, "TNF-alpha antagonist" includes patients who have discontinued treatment with had a previous unresponsive or inadequate response to treatment with an antagonist, The terms "TNF-inadequate responder" and "TNF-IR" refer to TNF-IR for nr-axSpA. F alpha inhibitors (e.g., infliximab, etanercept, adalimumab, ceritinib, have previously been treated with rituximab, rituximab, or golimumab, but the symptoms (e.g., bone and / or nr-axSp in which joint symptoms were not adequately controlled by TNF-alpha inhibitors A patient (e.g., at least 2 weeks, 4 weeks, or at least 1 week) with approved doses of anti-TNF agents at least 8 weeks, at least 3 months, at least 14 weeks, or at least 4 months of treatment (Patients with active nr-axSpA regardless of disease progression) In some embodiments of the methods, the uses, the kits and the pharmaceutical compositions, the patient is had a previous non-response or inadequate response to treatment with an inhibitor;

[0036] As used herein, "anti-inflammatory drug (NSAID) therapy" means a The phrase "had a previous non-response or inadequate response to nr-axS" is used to describe One or more NSAIDs (e.g., COX-1 or COX-2 inhibitors) for pA If you have previously received treatment and your symptoms (e.g., pain, bone and / or joint symptoms) are not due to an NSAID Patients with nr-axSpA who were not adequately controlled by NSAIDs (e.g., At least 2 weeks, 4 weeks, at least 8 weeks, at least 3 months, or Active non-rxSpA despite at least 14 weeks of treatment or at least 4 months of treatment Some of the disclosed methods, regimens, uses, kits and pharmaceutical compositions In some embodiments, the patient is taking one or more nonsteroidal anti-inflammatory drugs (NSAIDs) had a previous non-response or inadequate response to treatment with

[0037] As used herein, "select" and "selected" with respect to a patient are used to refer to a specific Based on the patient having predetermined criteria, a particular patient It is used to mean specifically selected from a larger group of patients. "Selective treatment" refers to the treatment of specific diseases and individual patients with predetermined criteria. Providing treatment to patients who are specifically selected from a larger group of patients on the basis that they Similarly, "selectively administering" means that an individual patient is administered a predetermined standard of administering a drug to a patient specifically selected from a larger group of patients on the basis of having Selecting, selectively treating, and selectively administering refer to administering to a patient. provides a standard treatment regimen based solely on the patient's membership in a larger group. rather, the patient's personal history (e.g., prior therapeutic interventions, e.g., biologics) prior treatment), biology (e.g., certain genetic markers), and / or symptoms (e.g., certain This means that individuals will be offered individualized treatment based on their condition (or lack of condition) and whether they meet the diagnostic criteria. As used herein in relation to methods of treatment, the incidental occurrence of a patient with certain criteria. It does not mean treatment, but treatment for patients based on the patient having certain criteria. Therefore, selective treatment / administration is based on the patient's personal history, Prescribing a specific drug to all patients with a specific disease, regardless of disease manifestation and / or biology In some embodiments, the standard of care / administration provided is different from that of the axSpA Patients simultaneously met radiological criteria according to the modified New York diagnostic criteria for ankylosing spondylitis. However, patients are selected for treatment if they meet the ASAS axSpA criteria. Patients with these characteristics are classified as having "axial spondyloarthritis without radiographic evidence of ankylosing spondylitis." The disclosed subject is referred to herein as having "nr-axSpA" or simply "nr-axSpA." In some embodiments of the methods, regimens, uses, kits and pharmaceutical compositions, the patient is Axial spondyloarthritis (axSpA) without radiographic evidence of orthotopic spondylitis (nr-ax SpA).

[0038] At least Grade II or higher bilaterally or Grade III or IV unilaterally Radiographic changes of the sacroiliac joint are considered to be diagnostic criteria for AS according to the modified New York criteria. These changes are necessary (Van der Linden et al. (1984) Arthritis Rheum 27:361-8). The term "radiological criteria according to the modified New York diagnostic criteria for ankylosing spondylitis" is used herein. and "radiographic evidence of ankylosing spondylitis."

[0039] Spondyloarthritis (SpA) is a group of arthritis / inflammatory bowel disease-associated conditions including ankylosing spondylitis, reactive arthritis, and inflammatory bowel disease. It is a group of related disorders that includes spondylitis, arthritis / spondylitis associated with psoriasis, and unclassified spondyloarthritis. SpA patients with predominantly axial skeletal symptoms are said to have axial SpA (axSpA). The International Society for the Assessment of Spondyloarthritis (ASAS) criteria are used to define radiographic axial SpA and nr -axSpA as a classification criterion for axial spondyloarthritis (axSpA) (Rudwaleit et al. (2009) Ann. Rheum. Dis. 68:777-83, in its entirety (These criteria are incorporated herein by reference.) The ASAS axSpA criteria are shown in Figure 1. Specifically, they are: a) radiographic (modified New York criteria for radiographic sacroiliac arthritis); Presence of sacroiliitis by MRI or MRI, plus at least one SpA feature (image imaging arm); or b) the presence of HLA-B27 and at least two SpA features (clinical arm). "Characteristics of SpA" are inflammatory back pain, elevated CRP (inflammatory back pain and associated with HIV-1 infection, HLA-B27 positivity, family history of SpA, good response to NSAIDs, Includes Rohn's disease / ulcerative colitis, psoriasis, dactylitis, uveitis, enthesitis (heel) and arthritis. Meets ASAS axSpA criteria but , X-ray sacral according to the modified New York criteria Ileitis do not have Patients were diagnosed with radio-negative axial spondyloarthritis (nr-axSpA). Called.

[0040] As used herein, the presence of an HLA-B27 antigen or allele as determined by laboratory testing. When the identity of the individual is revealed (e.g., using flow cytometry or PCR genotyping), In this case, the patient is "HLA-B27 positive."

[0041] As used herein, the phrase "inflammatory back pain" refers to non-mechanical back pain. These include, for example, gradual onset, persistence of at least 3 months, and onset at a relatively young age. Alternating buttock pain, morning stiffness lasting more than 30 minutes, nighttime pain, relief with rest It is characterized by a lack of quality, etc. It is not caused by strain or damage and develops rapidly. It tends to be symptomatic or has variable onset and can be diagnosed by a skilled physician.

[0042] As used herein, "active nr-axSpA" is defined as any active schizophrenia on a scale of 0 to 10. 4 or higher total Bath Ankylosing Spondylitis Dis Symptoms of illness consistent with the BASDAI score Some embodiments of the disclosed methods, regimens, uses, kits and pharmaceutical compositions In some embodiments, the patient has active nr-axSpA. In some embodiments of the uses, kits and pharmaceutical compositions, the patient has Total BASDAI ≥ 4cm (0-10cm) at baseline, BASDAI questionnaire #2 ≥ 4cm (0-10cm) spinal pain and baseline VA Have total back pain measured by S≧40mm (0-100mm).

[0043] As used herein, "severe nr-axSpA" and "moderate to severe nr- "axSpA" means signs and symptoms of a disease that requires treatment with a biological therapy. "ASAS Recommendations for the Use of Anti-TNF Agents in Patients with Axial Spondyloarthritis" According to der Heijde et al (2011) Ann Rheum Dis. 2011 Jun;70(6):905-8), Unless otherwise specified, at least two sessions of NSAID therapy at the maximum recommended dose for a total of 4 weeks After a total of 4 or higher on a scale of 0 to 10, Activity with ndylitis Disease Activity Index score Patients with nr-axSpA require biologic therapy if they present with chronic disease. In some embodiments of the methods, regimens, uses, kits and pharmaceutical compositions, a patient has severe nr-axSpA.

[0044] As used herein, "elevated CRP and / or objective signs of inflammation by MRI" means The phrases "signs of inflammation" and "objective signs of inflammation by CRP and / or MRI" refer to the sacroiliac joint. (SIJ) MRI evidence of inflammation, elevated C-reactive protein (CRP), or both. In some embodiments of the disclosed methods, regimens, uses, kits and pharmaceutical compositions The patient had no radiographic evidence of ankylosing spondylitis but had M of sacroiliac joint (SIJ) inflammation. Evidence of RI and / or objective signs of inflammation as elevated C-reactive protein (CRP) Patients with axSpA (e.g., severe, moderate-to-severe, active) with other objective signs of inflammation A sign is inflammation of the spine, which can be seen by MRI. Spinal inflammation is associated with disease activity. Ankylosing Spondylitis Spine MRI Scoring System (ASspiMRI-a) and ASspi Berlin modification of MRI-a" (Lukas C et al (2007) J. Rheumatol;34(4):862-70; Rudwaleit et al. (2008) Arthritis Rheum 67:1276-1281; Rudwaleit et al. (2005) [ab stract] Arthritis Rheum 50:S211).

[0045] Recent MRI methods have demonstrated the ability to visualize the SIJ, spine, and spinal cord in patients with axSpA and normal radiographic findings. and other skeletal elements (e.g., Rudwaleit et al. (2009) ) Ann. Rheum Dis. 68:1520-7; Braun et al 1994, Arthritis Rheum 37:1039-45; Oostv een et al 1999, J. Rheumatol. 26:1953-58; Heuft-Dorenbosch et al 2006, Ann. Rheu m. Dis. 65:804-08; Heuft-Dorenbosch et al. 2006 Arthritis Res. Ther. 8:R11; Brau n and Baraliakos (2011) Ann Rheum Dis 70 (Suppl 1):i97-i103, and for reviews See Ambak et al. 2012 Arthrits Res. & Therapy 14:R55 for more information), and the SIJ and This allows for the depiction of both acute inflammatory lesions and chronic / structural changes in the spine. MRI highly suggestive of sacroiliac joint inflammation, which we call "MRI evidence of sacroiliac joint (SIJ) inflammation" There are various scoring methods that can be used to clarify the evidence. The preferred MRI scoring system used is the Berlin SIJ score (Hermann KG , et al. Radiologe. 2004;44:217-28). The disclosed methods, regimens, uses, kits and medicines In some embodiments of the pharmaceutical composition, the patient has MRI evidence of SIJ inflammation.

[0046] As used herein, "elevated CRP" refers to the measurement of CRP by the assay laboratory. Higher than normal CRP levels are associated with increased risk of heart disease, according to the 2010 ACR / EU As defined in the LAR criteria (Aletaha et al. (2010) Ann. Rheum. Dis. 69:1580-88) According to the 2010 ACR / EULAR criteria, normal / abnormal CRP is determined by the local facility's criteria. Each local facility uses its own unique method to calculate normal maximum CRP. A cutoff value for abnormal (high) CRP is used based on a set rule. The local facility will order a CRP test and the individual facility will use the data used to calculate normal CRP. Normal or abnormal (low or high) CRP values ​​are reported using established rules. The facility simply reports that CRP is above the "upper limit of normal (ULN)." Unless the context indicates otherwise, what is considered a normal CRP value may vary between laboratories and assays. Therefore, as used herein, "elevated CRP" refers to a specific value. In some embodiments of the present disclosure, CRP is detected using a highly sensitive assay. The elevated CRP (i.e., hsCRP) by this assay is, for example, >approx. 3mg / L (e.g., 3mg / L), >approximately 10mg / L (e.g., 10mg / L), >approximately 20 mg / L (e.g., 20 mg / L) or > about 30 mg / L (e.g., 30 mg / L) CRP levels, when assessed at baseline, can be considered "baseline CRP." An elevated level of CRP at baseline is called "baseline CRP." The disclosed methods, regimens, uses, kits and pharmaceutical compositions In some embodiments, the patient has elevated baseline CRP or hsCRP. .

[0047] IL-17 antagonist The various disclosed methods, kits, uses and methods involve the use of IL-17 antagonists, e.g. IL-17 binding molecules (e.g., soluble IL-17 receptors, IL-17 antibodies, or antigens thereof) binding fragments, e.g., secukinumab) or IL-17 receptor binding molecules (e.g., IL-1 In some embodiments, an IL-7 receptor antibody or antigen-binding fragment thereof is utilized. The IL-17 antagonist is an IL-17 binding molecule, preferably an IL-17 antibody or its anti- It is the original binding fragment.

[0048] In one embodiment, the IL-17 antibody or antigen-binding fragment thereof comprises the hypervariable region CDRs 1. At least one immunoglobulin heavy chain variable domain (V) comprising CDR2 and CDR3 H ), wherein the CDR1 has the amino acid sequence SEQ ID NO: 1 and the CDR2 has the amino acid sequence The CDR1 has the amino acid sequence SEQ ID NO: 2, and the CDR2 has the amino acid sequence SEQ ID NO: 3. In some embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises a hypervariable region CDR1′, a CD4 domain, a CD5 domain, a CD6 domain, a CD7 domain, a CD8 domain, a CD9 domain, a CD10 domain, a CD11 domain, a CD12 domain, a CD13 domain, a CD14 domain, a CD15 domain, a CD16 domain, a CD17 domain, a CD18 domain, a CD20 domain, a CD21 domain, a CD2 at least one immunoglobulin light chain variable domain (V) comprising CDR2' and CDR3' L’ ), wherein the CDR1' has the amino acid sequence SEQ ID NO: 4, and the CDR2' has the amino acid sequence SEQ ID NO: The CDR3' has the amino acid sequence SEQ ID NO: 5, and the CDR3' has the amino acid sequence SEQ ID NO: 6. In one embodiment, the IL-17 antibody or antigen-binding fragment thereof comprises the hypervariable region CDR1-x at least one immunoglobulin heavy chain variable domain comprising CDR2-x and CDR3-x N(V H ), wherein the CDR1-x has the amino acid sequence SEQ ID NO: 11, and the CDR 2-x has the amino acid sequence SEQ ID NO: 12, and said CDR3-x has the amino acid sequence SEQ ID NO: It has number 13.

[0049] In one embodiment, the IL-17 antibody or antigen-binding fragment thereof comprises at least one Immunoglobulin V H domain and at least one immunoglobulin V L Includes the domain, a) Immunoglobulin V H The domains may be (e.g., in order): i) hypervariable region CDR1; CDR CDR1 has the amino acid sequence SEQ ID NO: 1 and CDR2 has the amino acid sequence SEQ ID NO: 2. the CDR3 has the amino acid sequence SEQ ID NO: 3) or ii) hypervariable regions CDR1-x, CDR2-x and CDR3-x (wherein CDR1-x is The CDR2-x has the amino acid sequence SEQ ID NO: 12. wherein said CDR3-x has the amino acid sequence SEQ ID NO: 13; and b) an immunoglobulin Rin V L The domains are (e.g., in order) hypervariable regions CDR1', CDR2' and CDR3 '(the CDR1' has the amino acid sequence SEQ ID NO: 4, and the CDR2' has the amino acid sequence The CDR3' comprises the amino acid sequence SEQ ID NO: 5, and the CDR3' comprises the amino acid sequence SEQ ID NO: 6).

[0050] In one embodiment, the IL-17 antibody or antigen-binding fragment thereof comprises: a) An immunoglobulin heavy chain variable domain (V) comprising the amino acid sequence set forth as SEQ ID NO: 8 H ) b) an immunoglobulin light chain variable domain comprising the amino acid sequence set forth as SEQ ID NO: 10 (V L ), c) immunoglobulin V comprising the amino acid sequence shown as SEQ ID NO: 8 H Domain and immunoglobulin V comprising the amino acid sequence shown as SEQ ID NO: 10. L domain, d ) Immunoglobulins comprising the hypervariable regions shown as SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 N V H domain, e) hypervariable regions shown as SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 immunoglobulin V, including L domain, f) SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 Immunoglobulin V containing hypervariable regions designated as H domain, g) SEQ ID NO: 1, SEQ ID NO: Immunoglobulin V comprising the hypervariable regions shown as SEQ ID NO:2 and SEQ ID NO:3 H Domain and Immunoglobulins comprising hypervariable regions shown as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 V L domain, or h) the superfamily shown as SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 Immunoglobulin V containing the variable region H Domain and SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: Immunoglobulin V containing the hypervariable region designated as 6 L domain.

[0051] For ease of reference, the values ​​are based on the Kabat definition, measured by X-ray analysis, and C Ultrastructural characterization of secukinumab monoclonal antibody using the approach of hothia and collaborators The amino acid sequences of the variable regions are shown in Table 1 below.

[0052] [Table 1]

[0053] In a preferred embodiment, the constant region domains are also preferably, e.g., "Sequences of Proteins of Immunological Interest”, Kabat EA et al., US Department of Health and Human Services, Public Health Service, National Institute of Health The DNA encoding the VL of secukinumab is sequenced. Number 9 shows the V of secukinumab. H The DNA encoding this is shown in SEQ ID NO:7.

[0054] In some embodiments, an IL-17 antibody or antigen-binding fragment thereof (e.g., numab) comprises the three CDRs of SEQ ID NO: 10. In another embodiment, the IL-17 antibody In another embodiment, the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 8. The IL-17 antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 10 and the CDR of SEQ ID NO: 8. The CDRs of SEQ ID NO:8 and SEQ ID NO:10 can be found in Table 1. The free cysteine ​​in the light chain (CysL97) can be seen in SEQ ID NO: 6. .

[0055] In some embodiments, the IL-17 antibody or antigen-binding fragment thereof is SEQ ID NO: 14 In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises a light chain of SEQ ID NO: In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises a heavy chain of In some embodiments, the IL-11 comprises a light chain of SEQ ID NO: 14 and a heavy chain of SEQ ID NO: 15. The -17 antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 14. wherein the IL-17 antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 15. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises the triplet of SEQ ID NO: 14. and the three CDRs of SEQ ID NO: 14 and SEQ ID NO: 15. R can be found in Table 1.

[0056] The hypervariable regions are preferably of human origin, but any type of framework region may be used. Suitable framework regions can be associated with the nucleotide sequences described in Kabat EA et al., supra. A preferred heavy chain framework is a human heavy chain framework, e.g., The heavy chain framework of the Numab antibody is, in order, for example, FR1 (SEQ ID NO: 8) FR2 (amino acids 36 to 49 of SEQ ID NO: 8), FR3 (amino acids 1 to 30 of SEQ ID NO: 8) 8) and FR4 (amino acids 67-98 of SEQ ID NO: 8) regions Considering the defined hypervariable regions of secukinumab by X-ray analysis, other preferred heavy chain The framework is, in order, FR1-x (amino acids 1 to 25 of SEQ ID NO: 8), FR2-x ( FR3-x (amino acids 36 to 49 of SEQ ID NO: 8), FR3-x (amino acids 61 to 95 of SEQ ID NO: 8), and and FR4 (amino acids 119 to 127 of SEQ ID NO: 8) regions. The workpiece is, in order, FR1' (amino acids 1 to 23 of SEQ ID NO: 10), FR2' (amino acids 1 to 23 of SEQ ID NO: 10), FR3' (amino acids 36 to 50 of SEQ ID NO: 10), FR3' (amino acids 58 to 89 of SEQ ID NO: 10), and FR4' ' (amino acids 99 to 109 of SEQ ID NO: 10) region.

[0057] In one embodiment, an IL-17 antibody or antigen-binding fragment thereof (e.g., Seckinumab) is administered. a) a variable domain comprising, in order, hypervariable regions CDR1, CDR2 and CDR3; and immunoglobulin heavy chains or fragments thereof containing the constant region of a human heavy chain or a fragment thereof (see above). CDR1 has the amino acid sequence SEQ ID NO: 1, and CDR2 has the amino acid sequence SEQ ID NO: 2 wherein the CDR3 has the amino acid sequence SEQ ID NO: 3), and b) a hypervariable region a variable domain comprising CDR1', CDR2' and CDR3' and a constant region of a human light chain, or An immunoglobulin light chain or a fragment thereof containing the fragment (the CDR1' has the amino acid sequence No. 4, said CDR2' having the amino acid sequence SEQ ID NO: 5, and said CDR3' having having the amino acid sequence SEQ ID NO:6).

[0058] In one embodiment, the IL-17 antibody or antigen-binding fragment thereof comprises: a) a hypervariable region, a first domain comprising domains CDR1, CDR2 and CDR3 (the CDR1 domain has the amino acid sequence the CDR2 has the amino acid sequence SEQ ID NO: 2, and the CDR3 has , having the amino acid sequence SEQ ID NO: 3), and b) the hypervariable regions CDR1′, CDR2 a second domain comprising CDR1' and CDR3' (said CDR1' having the amino acid sequence SEQ ID NO: 4); wherein the CDR2' has the amino acid sequence SEQ ID NO:5 and the CDR3' has the amino acid sequence having the sequence SEQ ID NO: 6), and c) the N-terminus of the first domain and the C or a peptide linker linked to the C-terminus of the first domain and the N-terminus of the second domain. The antibody is selected from single chain antibodies or antigen-binding fragments thereof, each of which comprises an antigen-binding site containing a cross-linker.

[0059] Alternatively, the IL-17 antibody or antigen-binding fragment thereof used in the disclosed methods may be identified by its sequence as These may include derivatives of the IL-17 antibodies described herein (e.g., pegylated versions of secukinumab). Alternatively, the V of the IL-17 antibody or antigen-binding fragment thereof used in the disclosed methods H or V L The domains are the V H or V L domains (e.g., those shown in SEQ ID NOS: 8 and 10) V is substantially the same as H or V L The human leukocytes disclosed herein may have domains. The human IL-17 antibody has a heavy chain and a nucleotide sequence substantially identical to that shown as SEQ ID NO: 15. and / or a light chain substantially the same as that shown as SEQ ID NO: 14. The human IL-17 antibody disclosed herein has a heavy chain comprising SEQ ID NO: 15 and a nucleotide sequence comprising SEQ ID NO: 14. The human IL-17 antibodies disclosed herein may comprise a light chain comprising: a) a light chain comprising the amino acid sequence shown in SEQ ID NO: 8; and a constant region of a human heavy chain having substantially the same amino acid sequence as that of a human heavy chain. and b) a heavy chain comprising substantially the same amino acid sequence as set forth in SEQ ID NO:10. The antibody may comprise one light chain comprising a variable domain having a constant region of a human light chain and a variable domain having a constant region of a human light chain.

[0060] Alternatively, the IL-17 antibody or antigen-binding fragment thereof for use in the disclosed methods may be an IL-17 antibody or antigen-binding fragment thereof that is a Cys The present invention relates to an IL-17 antibody that is an IL-17 antibody having an IL-17 sequence variant of the present invention. The present disclosure also provides the V H or V L domain (excluding CysL97) or is a sequence of multiple amino acid residues, generally only a small number (e.g., 1-10), but e.g., Mutations in the DNA sequence of the IL-1 gene, e.g., altered by site-directed mutagenesis, 7. Antibodies or antigen-binding fragments thereof (e.g., secukinumab), including all derivatives and variants thereof. In all such cases, the IL-17 antibody or antigen-binding fragment thereof has a cytotoxicity of about 50 nM or less. , about 20 nM or less, about 10 nM or less, about 5 nM or less, about 2 nM or less, or more preferably about The activity of human IL-17 at a concentration of 1 nM or less was suppressed by approximately 50 ng / ml (=30 ng / ml). 0% inhibition, and the inhibitory activity was measured in accordance with the method described in WO 2006 / 013107. Induced by hu-IL-17 in human dermal fibroblasts as described in Example 1 It is measured based on IL-6 production.

[0061] In some embodiments, an IL-17 antibody or antigen-binding fragment thereof, e.g., Numab binds to Leu74, Tyr85, His86, Met87, Asn88, and Val12 4, containing Thr125, Pro126, Ile127, Val128, and His129 In some embodiments, the IL-17 antibody binds to an epitope on mature human IL-17. For example, secukinumab contains Tyr43, Tyr44, Arg46, Ala79, and As In some embodiments, the present invention binds to an epitope of mature human IL-17, including p80. IL-17 antibodies, such as secukinumab, are IL-17 antibodies that contain two mature human IL-17 chains. 17 homodimeric epitope, which is located at Leu74 on one chain, T yr85, His86, Met87, Asn88, Val124, Thr125, Pro 126, Ile127, Val128, His129 and Tyr43, Tyr on the other chain These epitopes include Arg44, Arg46, Ala79, and Asp80. The residue numbering scheme used is such that one is the residue that is the first amino acid of the mature protein ( That is, IL-17A lacks the 23 amino acid N-terminal signal peptide and begins with glycine. The sequence of immature IL-17A is based on Swiss-Prot entry Q16 In some embodiments, the IL-17 antibody is about 100-2 00pM K D In some embodiments, the IL-17 antibody has a IgG antibody binding affinity of about 0.67 IC of approximately 0.4 nM for in vitro neutralization of the biological activity of nM human IL-17A 50 With In some embodiments, the absolute activity of subcutaneously (SC) administered IL-17 antibodies is The bioavailability ranges from about 60 to about 80%, for example, about 76%. In some embodiments, the IL-17 antibody, such as secukinumab, provides a therapeutic effect for about 4 weeks (e.g., about 23 Some have an elimination half-life of about 25 to about 35 days, about 23 to about 30 days, for example, about 30 days. In embodiments, the IL-17 antibody (e.g., secukinumab) has a T of about 7-8 days. max It has.

[0062] Particularly preferred IL-17 antibodies or antigen-binding fragments thereof for use in the disclosed methods are human IL-17 antibodies or antigen-binding fragments thereof. Antibodies, in particular those described in Examples 1 and 2 of WO 2006 / 013107 Secukinumab is currently in clinical trials for the treatment of immune-mediated inflammatory conditions. Currently available recombinant high-affinity fully human monoclonal antibody of the IgG1 / kappa isotype Secukinumab (e.g., secukinumab) is an anti-interleukin-17A (IL-17A, IL-17) antibody. For example, International Publication No. 2006 / 013107 and International Publication No. 2007 / 11 (See brochure No. 7749) has a very high affinity for IL-17, i.e., approximately K of 100-200 pM D and about 0.4 nM of about 0.67 nM of human IL-17A. IC of in vitro neutralization of antimicrobial activity 50 Therefore, secukinumab has a Secukinumab inhibits the antigen at a molar ratio of 1:1. This high binding affinity makes it suitable for therapeutic applications. Furthermore, secukinumab is a particularly suitable antibody for lifelong disease, such as non-rx-axSpA. Long periods between doses are an especially attractive feature when treating chronic disorders that can last for many years. It has been confirmed that it has a very long half-life, i.e., about 4 weeks, which is possible.

[0063] Other preferred IL-17 antibodies for use in the disclosed methods, kits and regimens include those U.S. Pat. No. 8,057,794, which is incorporated herein by reference in its entirety. , 8,003,099, 8,110,191 and 7,838,6 38 and U.S. Patent Application Publication Nos. 20120034656 and 2011 It is an IL-17 antibody described in the specification of Patent Publication No. 0027290.

[0064] Methods for treating nr-axSpA and uses of IL-17 antagonists The disclosed IL-17 antagonists, e.g., IL-17 binding molecules (e.g., IL- 17 antibody or antigen-binding fragment thereof, e.g., secukinumab) or IL-17 receptor-binding molecule The antibody (e.g., an IL-17 receptor antibody or an antigen-binding fragment thereof) can be used in vitro, ex vivo, It can be used in vivo or incorporated into a pharmaceutical composition and administered in vivo. , treating a nr-axSpA patient (e.g., a human patient) and / or patients with non-TNF-alpha inhibitors, e.g., those with nr-axSpA who have not previously been treated with TNF-alpha inhibitors (TNF-naive patients), those previously treated with TNF-alpha inhibitors Patients with nr-axSpA who have received treatment with, for example, TNF-alpha inhibitors, Patients who had an inadequate response (e.g., failure or less than desirable response) to (TNF-IR patients), and those who had previously received treatment with NSAIDs but had not responded adequately to it. nr-axSpA patients who had an inadequate response (e.g., failure or less than desirable response) It can inhibit the progression of structural damage in patients.

[0065] IL-17 antagonists, e.g., IL-17 binding molecules (e.g., IL-17 antibodies or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor-binding molecule ( For example, the IL-17 antibody or antigen-binding fragment thereof may be mixed with a pharmaceutically acceptable carrier. Such a composition can be used as a pharmaceutical composition. In addition to the antagonist, carriers, various diluents, fillers, salts, buffers, stabilizers, solubilizers, and and other materials well known in the art. The characteristics of the carrier will depend on the route of administration. The pharmaceutical compositions used in the disclosed methods may also contain additional therapeutic agents for the treatment of specific target disorders. For example, the pharmaceutical composition may also include an anti-inflammatory agent. The factor / agent may be used to produce a synergistic effect with an IL-17 binding molecule or to bind to an IL-17 antigen. antagonists, e.g., IL-17 binding molecules (e.g., IL-17 antibodies or their antibodies); an IL-17 receptor binding fragment (e.g., secukinumab) or an IL-17 receptor binding molecule (e.g., IL- 17) to minimize side effects caused by antibodies or their antigen-binding fragments It can be included in a pharmaceutical composition.

[0066] Pharmaceutical compositions for use in the disclosed methods can be prepared by conventional methods. In this form, the pharmaceutical composition is provided as a lyophilized form. Dissolve in a suitable aqueous carrier, such as sterile water for injection or sterile buffered saline. It may be desirable to prepare a larger volume of solution for administration by injection rather than by bolus injection. If necessary, human serum albumin or the patient's own heparinized blood may be added to the saline solution at the time of preparation. The presence of excess such physiologically inactive proteins can be advantageous. This prevents loss of antibodies due to adsorption onto the walls of containers and tubing used with the infusion solution. If albumin is used, the appropriate concentration is 0.5 to 4.0 mg of saline solution. 5% by weight. Other formulations include liquid or lyophilized formulations.

[0067] Antibodies, e.g., antibodies against IL-17, are generally available in aqueous formulations ready for parenteral administration. The pharmaceutical composition may be formulated in a liquid form or as a lyophilizate for reconstitution with a suitable diluent prior to administration. In some embodiments of the disclosed methods and uses, an IL-17 antagonist, e.g. For example, an IL-17 antibody, e.g., secukinumab, is formulated as a lyophilizate. The dry formulation must be reconstituted with a small volume of liquid (e.g., 2 ml or less) to allow for subcutaneous administration. This can result in a solution with low levels of antibody aggregation. ® (trastuzumab), RITUXAN® (rituximab), SYNAGIS® The use of antibodies as active ingredients in pharmaceuticals, including palivizumab (Palivizumab), is now widely known. Techniques for purifying antibodies for pharmaceutical use are well known in the art. IL-17 antagonists, e.g., IL-17 binding molecules (e.g., IL-17 antibodies) or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor-binding molecule ( For example, when an IL-17 antibody or an antigen-binding fragment thereof is injected intravenously, cutaneously, or subcutaneously, In this case, the IL-17 antagonist is in the form of a pyrogen-free, parenterally acceptable solution. The pharmaceutical composition for intravenous, cutaneous or subcutaneous injection contains, in addition to the IL-17 antagonist: Sodium chloride, Ringer's solution, dextrose, dextrose and sodium chloride, milk An isotonic excipient such as acidified Ringer's solution or other excipients known in the art may be included.

[0068] The appropriate dose will depend, for example, on the specific IL-17 antagonist used, e.g., IL- IL-17 binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) mab) or IL-17 receptor binding molecule (e.g., IL-17 antibody or its antigen-binding fragment), the host, the method of administration, and the nature and severity of the condition being treated and any previous treatment the patient has received. Ultimately, the nature of the treatment will depend on the provider's own needs to treat each individual patient. In some embodiments, the healthcare provider determines the amount of IL-17 antagonist. can administer a low dose of an IL-17 antagonist and observe the patient's response. In other embodiments, the initial dose (single or multiple doses) of IL-17 antagonist administered to the patient The dose is then adjusted downward until signs of relapse occur. Higher doses of the IL-17 antagonist may be administered until an optimal therapeutic effect is achieved. and generally do not require further dose increases.

[0069] In practicing some of the methods of treatment or uses of the present disclosure, a therapeutically effective amount of IL-17 antigen is administered. antagonists, e.g., IL-17 binding molecules (e.g., IL-17 antibodies or their antibodies); an IL-17 receptor binding fragment (e.g., secukinumab) or an IL-17 receptor binding molecule (e.g., IL- 17 antibody or its antigen-binding fragment) to a patient, e.g., a mammal (e.g., a human). The disclosed methods use an IL-17 antagonist (e.g., secukinumab) It is understood that the present invention provides a treatment for patients with α-axSpA, which involves treating the patient with IL-17 antagonists. If the patient should ultimately be treated with an IL-17 antagonist, such IL-17 antagonist therapy This does not exclude that IL-17 antagonists are necessarily monotherapy. When selected for treatment with IL-17 antagonists (e.g., secukinumab), According to the disclosed methods, In combination with therapies, for example, immunosuppressants, disease-modifying antirheumatic drugs (DMARDs) (e.g., Sulfasalazine), pain management drugs, steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), Cytokine antagonists, bone anabolic agents, bone antiresorptive agents and combinations thereof (e.g., Administered in combination with at least one additional non-rapid-acting SpA medication, such as steroid therapy (double and triple therapy) When administered in combination with one or more additional non-rxSpA medications, IL The -17 antagonist can be administered simultaneously with the other agent or sequentially. If so, your doctor should advise you on the appropriate use of IL-17 antagonists in combination with other medications. Determine the appropriate sequence and appropriate doses for co-delivery.

[0070] Nonsteroidal anti-inflammatory drugs useful in combination with secukinumab for the treatment of patients with nr-axSpA NSAIDs and pain management drugs are propionic acid derivatives, acetic acid derivatives, and enolic acid derivatives. derivatives, fenamic acid derivatives, Cox inhibitors, e.g., lumiracoxib, ibuprofen, Enoprofen, ketoprofen, flurbiprofen, oxaprozin, indomethacin sulindac, etodolac, ketorolac, nabumetone, aspirin, naproxen, Rudecoxib, etoricoxib, MK0966, rofecoxib, acetaminophen, Celecoxib, diclofenac, tramadol, piroxicam, meloxicam, tenoxicam Cam, droxicam, lornoxicam, isoxicam, mefanamic acid, meclofenamic acid , flufenamic acid, tolfenamic, parecoxib, firocoxib IL-17 antagonists, e.g., secukinumab, for the treatment of patients with nr-axSpA DMARDs useful in combination with mab include methotrexate (MTX), antimalarials (e.g. (e.g., hydroxychloroquine and chloroquine), sulfasalazine, leflunomide, azathioprine Oprin, cyclosporine, gold salts, minocycline, cyclophosphamide, D-penicilla Min, minocycline, auranofin, tacrolimus, myocrisin, chlorambucil IL-17 antagonists, e.g., cerebrospinal fluid (ES)-1, for the treatment of patients with nr-axSpA. Steroids (e.g., glucocorticoids) useful in combination with cukinumab include prednisolone. Ron, prednisone, dexamethasone, cortisol, cortisone, hydrocortisone, Methylprednisolone, betamethasone, triamcinolone, beclomethasone, fludroco including, but not limited to, lutizone, deoxycorticosterone, and aldosterone .

[0071] IL-17 antagonists, e.g., secukinumab, for the treatment of patients with nr-axSpA A biologic agent that may be useful in combination with a mab is adalimumab (Humira®). )), etanercept (Enbrel®), infliximab (Remica de®; TA-650), certolizumab pegol (Cimzia® ; CDP870), golimumab (Simponi®; CNTO148), ximab (Rituxan®; MabThera®), abatacept (Orencia®), tocilizumab (RoActemAS / Actemr a (registered trademark), integrin antagonist (TYSABRI (registered trademark) (Natari Illumina (Ilaris), IL-1 antagonist (ACZ885, canakinumab (Ilaris) (registered trademark), anakinra (Kineret®), CD4 antagonists, etc. IL-17 antagonists (LY2439821, ixekizumab, RG4934, A MG827, brodalumab, SCH900117, R05310074, MEDI-57 1, CAT-2200), IL-23 antagonist, IL-20 antagonist, IL -6 antagonists, other TNF alpha antagonists (e.g., other TNF alpha antagonists or TNF alpha receptor antagonists, such as pegsunercept, ), BLyS antagonists (e.g., atacicept, Benlysta® / LymphoStat-B® (belimumab), a P38 inhibitor, CD20 antagonist agonists (ocrelizumab, ofatumumab (Arzerra®)), Terferon gamma antagonist (hontolizumab) or biologics Includes follow-on products.

[0072] IL-17 antagonists, e.g., IL-17 binding molecules (e.g., IL-17 antibodies or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor-binding molecule (e.g., , IL-17 receptor antibody or antigen-binding fragment thereof) can be administered parenterally, for example, intravenously (e.g., It is conveniently administered intramuscularly (e.g., into the antecubital or other peripheral vein), intramuscularly, or subcutaneously. The duration of intravenous (IV) therapy using the indicated pharmaceutical compositions will depend on the severity of the disease being treated and The effectiveness of the subcutaneous (subcutaneous) administration of the pharmaceutical composition of the present disclosure will vary depending on the condition and personal response of each patient. IV or SC therapy using the pharmaceutical compositions of the present disclosure is also contemplated. Determine the appropriate duration of the law and the timing of the implementation of the therapy.

[0073] Preferred Dosing and Treatment Regimen for Treating Patients with nr-axSpA (Induction and Maintenance) The present invention relates to a method for treating rheumatoid arthritis (including both rheumatoid arthritis and rheumatoid arthritis), ... and a method for treating rheumatoid arthritis (including both rheumatoid arthritis and rheumatoid arthritis). This is presented in application number PCT / US2011 / 064307.

[0074] IL-17 antagonists, e.g., IL-17 binding molecules (e.g., IL-17 antibodies or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor-binding molecule (e.g., , IL-17 receptor antibody or its antigen-binding fragment) at approximately 10 mg every other week at weeks 0, 2, and 4 / kg intravenously (IV) to patients with non-rx-axSpA, followed by monthly Approximately 75 mg to approximately 300 mg (e.g., approximately 75 mg, approximately 150 mg, approximately 300 mg) This will be administered subcutaneously (SC) to patients at approximately 10 mg / kg at weeks 0, 2, and 4. IV administration, and then the patient receives approximately 75 mg to approximately 300 mg (e.g., 12 mg to 16 mg) at weeks 8, 12, 16, and 20. about 75 mg, about 150 mg, about 300 mg) of an IL-17 antagonist (e.g., , secukinumab) will be administered SC.

[0075] IL-17 antagonists, e.g., IL-17 binding molecules (e.g., IL-17 antibodies or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor-binding molecule (e.g., , IL-17 receptor antibody or antigen-binding fragment thereof) once a week at 0, 1, 2 and 3 weeks mg to approximately 300 mg (e.g., approximately 75 mg, approximately 150 mg, approximately 300 mg) administered SC to the patient Then, starting in the fourth week, approximately 75 mg to approximately 300 mg (e.g., approximately 75 mg) is administered once a month. The patient is given SC doses of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, , about 75 mg to about 300 mg (for example, about 7 weeks) at 2, 3, 4, 8, 12, 16, 20, etc. 5 mg, about 150 mg, about 300 mg) of an IL-17 antagonist (e.g., secukinumab Mab) is administered SC.

[0076] Alternatively, an IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., IL- 17 antibody or antigen-binding fragment thereof, e.g., secukinumab) or IL-17 receptor-binding molecule The compound (e.g., an IL-17 antibody or antigen-binding fragment thereof) can be administered to patients without a loading dose regimen. For example, the antagonist can be administered every four weeks (once a month) at a dose of about 75 mg to about 3 00 mg (e.g., about 75 mg, about 150 mg, about 300 mg) administered SC to patients. In this way, patients can receive approximately 75 mg to approximately 20 mg of the drug at weeks 0, 4, 8, 12, 16, and 20. 300 mg (e.g., about 75 mg, about 150 mg, about 300 mg) of IL-17 antagomir Administer an anti-inflammatory drug (e.g., secukinumab) SC.

[0077] Certain patients, for example, may be at increased risk of developing an IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., For example, an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) or an IL-1 IL-17 receptor-binding molecules (e.g., IL-17 receptor antibodies or antigen-binding fragments thereof) Dose escalation may be necessary for patients who show an inadequate response to treatment (e.g., induction). It will be understood that the SC dose of secukinumab is , about 75 mg to about 300 mg (SC) or more, for example, about 80 mg, about 100 mg, Approx. 125mg, approx. 175mg, approx. 200mg, approx. 250mg, approx. 350mg, approx. 400m g, etc. Similarly, an IV dose can be greater than about 10 mg / kg, for example, about 11 mg / kg. g / kg, 12mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30m g / kg, 35 mg / kg, etc. In certain patients, e.g., adverse events or IL-17 antagonists (e.g., IL-17 antibodies or antigen-binding fragments thereof, e.g., secukinumab Dose reductions may also be necessary for patients who experience adverse reactions to treatment with It will also be understood that the IL-17 antagonist may be administered in the induction and / or maintenance phases. The dose of a steroid (e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) is , about 75 mg to about 300 mg SC or less, for example, about 25 mg, about 50 mg, about 80 mg , about 100 mg, about 125 mg, about 175 mg, about 200 mg, 250 mg, etc. Similarly, IV doses may be less than about 10 mg / kg, e.g., about 9 mg / kg, 8 mg / kg , 5mg / kg, 4mg / kg, 3mg / kg, 2mg / kg, 1mg / kg, etc. In some embodiments, the IL-17 antagonist, e.g., IL-17 binding an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) or The IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody or an antigen-binding fragment thereof) Patients can be administered an initial dose of 75 mg delivered SC, followed by a 24-hour period as determined by a physician. Increase the dose to 150 mg or 300 mg if necessary, as advised.

[0078] The timing of administration is generally on the day of the first dose of secukinumab (also known as the "baseline"). However, healthcare providers should be aware of the dosage regimen as shown in Table 2. They often use different naming conventions to make it easier to

[0079] [Table 2]

[0080] Notably, week 0 is sometimes referred to as week 1 by some healthcare providers, while day 0 is sometimes referred to as Day 1 by some healthcare providers. Although they mentioned this, different doctors gave different treatments, for example, at week 3 / day 21, week 3 / day 22, and week 4. For consistency, the study may specify administration at week 4 / day 21 or week 4 / day 22. For purposes of this analysis, the first week of administration will be referred to herein as week 0, while the first day of administration shall be called Day 1. However, this naming convention is used solely for consistency. and should not be construed as limiting, i.e., a physician may refer to a particular week as "week 1" or "week 2." Whether or not it is referred to as "week 2," the once-weekly administration is in line with the once-weekly administration of IL-17 antibodies. Furthermore, in preferred dosing regimens, the antibody is administered in 0, 1, 2, 3, 4, 8, It is administered at weeks 12, 16, 20, etc. One provider recommends administering this regimen weekly for 5 weeks. 1 and then monthly (or every 4 weeks) thereafter, starting at week 8, While other providers administer this regimen once a week for four weeks and then start the fourth week. Thereafter, it may be called monthly (or every 4 weeks). Thus, weeks 0, 1, 2 and 3 Administering an injection to patients in the eye, followed by monthly dosing starting in week 4, is recommended. Patients will receive injections at weeks 2, 3, and 4, then monthly starting at week 8. It will be well understood by those skilled in the art that the above is the same as the above.

[0081] Disclosed herein are IL-17 antibodies or antigen-binding fragments thereof for use in treating IL-17-positive patients in need thereof. and a method for treating a patient with x-ray-negative axial spondyloarthritis, comprising administering to the patient: Therefore, the IL-17 antibody or antigen-binding fragment thereof has two mature IL-17 protein chains. The epitope of the IL-17 homodimer is located on one chain of Le u74, Tyr85, His86, Met87, Asn88, Val124, Thr12 5, Pro126, Ile127, Val128, His129 and Tyr4 on the other chain 3, Tyr44, Arg46, Ala79, Asp80, and an IL-17 antibody or its The antigen-binding fragment has a K of approximately 100-200 pM. D an IL-17 antibody or its antigen-binding The fragment has an in vivo half-life of about 4 weeks.

[0082] Further disclosed herein are methods for administering an IL-17 antibody or antigen-binding fragment thereof to a patient in need thereof. and the prevention of structural damage in patients with non-rx-axSpA, including administering The method of inhibiting progression of IL-17, wherein the IL-17 antibody or antigen-binding fragment thereof binds two mature IL-17 binds to an epitope of the IL-17 homodimer having the IL-17 protein chain, The fragment consists of Leu74, Tyr85, His86, Met87, Asn88, and Val124, Thr125, Pro126, Ile127, Val128, His12 9 and Tyr43, Tyr44, Arg46, Ala79, and Asp80 on the other chains. The IL-17 antibody or antigen-binding fragment thereof has a K of about 100 to 200 pM. D IL- The 17 antibody or antigen-binding fragment thereof has an in vivo half-life of approximately 4 weeks.

[0083] Further disclosed herein are methods for treating patients with nr-axSpA. IL-17 antagonists (e.g., IL-17 antibodies or antigen-binding fragments thereof, e.g., Sec. cukinumab), and an IL-17 antagonist (e.g., an IL-17 antibody or its The original binding fragment (e.g., secukinumab) contains two mature IL-17 protein chains. It binds to an epitope on the L-17 homodimer, the epitope being Leu74 on one chain. ,Tyr85,His86,Met87,Asn88,Val124,Thr125,P ro126, Ile127, Val128, His129 and Tyr43 on the other chain, T yr44, Arg46, Ala79, Asp80, and an IL-17 antibody or its antigen-binding site. The antibody or antigen-binding fragment thereof has a KD of approximately 100 to 200 pM. , with an in vivo half-life of approximately 4 weeks.

[0084] Further disclosed herein are methods for inhibiting the progression of structural damage in patients with nr-axSpA. IL-17 antagonists (e.g., IL-17 antibodies or their antigen-binding fragments, e.g., secukinumab), and IL-17 antagonists (e.g., IL-1 7 antibody or antigen-binding fragment thereof, e.g., secukinumab) binds to two mature IL-17 proteins. The present invention relates to a method for producing an IL-17 homodimer having a protein chain, the method comprising: Leu74, Tyr85, His86, Met87, Asn88, Val124 on the chain; Thr125, Pro126, Ile127, Val128, His129 and other chains It contains Tyr43, Tyr44, Arg46, Ala79, and Asp80 of the IL-17 antibody. The antibody or antigen-binding fragment thereof has a KD of about 100 to 200 pM, and The antigen-binding fragment of has an in vivo half-life of about 4 weeks.

[0085] Further disclosed herein are pharmaceuticals for treating patients with nr-axSpA. IL-17 antagonists (e.g., IL-17 antibodies or antigen-binding fragments thereof) used in the production of secukinumab), and an IL-17 antagonist (e.g., IL-17 The antibody or antigen-binding fragment thereof (e.g., secukinumab) binds to two mature IL-17 proteins. IL-17 homodimers having one chain, and the epitope is Leu74, Tyr85, His86, Met87, Asn88, Val124, T hr125, Pro126, Ile127, Val128, His129 and other sequences Contains Tyr43, Tyr44, Arg46, Ala79, and Asp80, and is an IL-17 antibody or an antigen-binding fragment thereof, has a KD of about 100 to 200 pM, and is an IL-17 antibody or an antigen-binding fragment thereof The antigen-binding fragment has an in vivo half-life of approximately 4 weeks.

[0086] Further disclosed herein are methods for inhibiting the progression of structural damage in patients with nr-axSpA. IL-17 antagonists (e.g., IL-17 antibodies or or an antigen-binding fragment thereof, e.g., secukinumab), and an IL-17 antagonist (e.g., For example, IL-17 antibodies or antigen-binding fragments thereof, such as secukinumab, bind to two mature IL-17 receptors. IL-17 homodimer having an IL-17 protein chain, The group consists of Leu74, Tyr85, His86, Met87, Asn88, and Val124, Thr125, Pro126, Ile127, Val128, His12 9 and Tyr43, Tyr44, Arg46, Ala79, and Asp80 on the other chains. The IL-17 antibody or antigen-binding fragment thereof has a KD of approximately 100 to 200 pM, and The 17 antibody or antigen-binding fragment thereof has an in vivo half-life of approximately 4 weeks.

[0087] Further disclosed herein are pharmaceuticals for treating patients with nr-axSpA. IL-17 antagonists (e.g., IL-17 antibodies or antigen-binding fragments thereof) used in the production of a drug product, e.g., secukinumab), wherein the medicament is formulated to contain containers, each container containing: At least about 75 mg to about 300 mg (e.g., about 75 mg, about 150 mg) per unit dose g, about 300 mg) of an IL-17 antagonist (e.g., an IL-17 antibody or its antigen a sufficient amount of IL-17 antigen to allow subcutaneous delivery of a binding fragment thereof, e.g., secukinumab antagonist (e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) and further comprising an IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof). fragments (e.g., secukinumab) are IL-17 molecules that contain two mature IL-17 protein chains. The epitope binds to the homodimer, which is comprised of Leu74, Tyr on one chain, and 85, His86, Met87, Asn88, Val124, Thr125, Pro12 6, Ile127, Val128, His129, and Tyr43 and Tyr44 on the other chain , Arg46, Ala79, and Asp80, and the IL-17 antibody or antigen-binding fragment thereof and the IL-17 antibody or antigen-binding fragment thereof has a KD of approximately 100 to 200 pM. It has an in vivo half-life of between 100 and 150 mg / kg.

[0088] Further disclosed herein are methods for inhibiting the progression of structural damage in patients with nr-axSpA. IL-17 antagonists (e.g., IL-17 antibodies or or an antigen-binding fragment thereof, e.g., secukinumab), and the medicament is manufactured to include a container. Each container contains at least about 75 mg to about 300 mg (e.g., about 75 mg, about 150 mg, about 300 mg) of an IL-17 antagonist (e.g., IL- 17 sufficient to enable subcutaneous delivery of an antibody or antigen-binding fragment thereof, e.g., secukinumab a sufficient amount of an IL-17 antagonist (e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) and an IL-17 antagonist (e.g., The antibody or antigen-binding fragment thereof (e.g., secukinumab) binds two mature IL-17 proteins Binds to an epitope on an IL-17 homodimer having one or more chains, said epitope being present on one or more chains. Leu74, Tyr85, His86, Met87, Asn88, Val124, Th r125, Pro126, Ile127, Val128, His129 and T on other chains Contains yr43, Tyr44, Arg46, Ala79, and Asp80, and is an IL-17 antibody or The antigen-binding fragment has a KD of about 100 to 200 pM, and is an IL-17 antibody or an anti-IL-17 antibody thereof. The original binding fragment has an in vivo half-life of approximately 4 weeks.

[0089] As used herein, "a dosage that allows for the delivery of [specified dose] by [route of administration]" The phrase "prescribed in an amount" refers to a desired amount administered by a designated route of administration (e.g., SC or IV). a dose of an IL-17 antagonist, e.g., an IL-17 antibody, e.g., secukinumab, It is used to mean that a given pharmaceutical composition can be used to deliver Therefore, if the desired subcutaneous dose is 300 mg, the clinician should use a concentration of 150 mg / ml. 2 ml of IL-17 antibody preparation, 1 ml of IL-17 with a concentration of 300 mg / ml Use an antibody preparation, such as 0.5 ml of an IL-17 antibody preparation with a concentration of 600 mg / ml. In each such case, these IL-17 antibody preparations may be The concentration is high enough to allow subcutaneous delivery of the antibody. Subcutaneous delivery typically requires approximately 2 ml A preferred formulation requires delivery of a volume of less than about 2 ml, preferably about 1 ml or less. 5mg / mL to 150mg / mL secukinumab, approximately 10mM to 30mM histidine, pH 5 0.8, about 200 mM to about 225 mM trehalose, about 0.02% polysorbate 80, and The liquid pharmaceutical composition comprises about 2.5 mM to about 20 mM methionine.

[0090] As used herein, an amount of IL sufficient to allow delivery of the specified dose. The phrase "container having a -17 antagonist" refers to a predetermined container (e.g., a vial, pen, etc.). The volume of IL-17 antagonist that can be used to deliver the desired dose (e.g., syringe) to mean that an agonist (e.g., as part of a pharmaceutical composition) has been placed therein For example, if the desired dose is 150 mg, the clinician may administer 75 mg / m 2 ml of the IL-17 antibody formulation having a concentration of 150 mg / ml was dispensed from a container containing the IL-17 antibody formulation having a concentration of 150 mg / ml. 1 ml of the IL-17 antibody formulation having a concentration of 300 mg / ml is dispensed from a container containing the IL-17 antibody formulation having a concentration of 300 mg / ml. 0.5 ml or the like can be used from a container containing an IL-17 antibody formulation. In each case, these containers were filled with enough fluid to allow delivery of the desired 150 mg dose. The present invention has an adequate amount of an IL-17 antagonist.

[0091] In some embodiments of the disclosed uses, methods and kits, the patient has moderate to severe In some embodiments of the disclosed uses, methods and kits, In the present invention, the patient has severe non-r-axSpA. In some embodiments, the patient has active nr-axSpA.

[0092] In some embodiments of the disclosed uses, methods and kits, the patient has a total BASDA The disclosed uses, methods and kits have active nr-axSpA as assessed by I≧4. In some embodiments, the patient has a total BASDAI of ≥ 4c at baseline. m (0-10 cm), BASDAI question number 2 at baseline ≥ 4 cm (0-10 Spinal pain measured by VAS ≥ 40 mm (0-1 cm) at baseline 00mm).

[0093] In some embodiments of the disclosed uses, methods and kits, the patient is Some of the disclosed uses, methods and kits include: In some embodiments, a) the patient has been receiving steroid therapy for at least 3 months, preferably at least 6 months. b) the onset of the inflammatory back pain in a) occurred before the patient was 45 years old and c) patients have MRI evidence of sacroiliac joint inflammation and at least one feature of SpA. or patients are HLA-B27 positive and have at least two SpA characteristics .

[0094] In some embodiments of the disclosed uses, methods and kits, the patient is Elevated protein (CRP) and / or magnetic resonance imaging (MRI) evidence of sacroiliac joint inflammation Some embodiments of the disclosed uses, methods and kits include: In this condition, patients had sacroiliac joint (SIJ) scores according to the Berlin sacroiliac joint (SIJ) scoring system. and objective signs of inflammation as indicated by MRI evidence of nodal inflammation. In some embodiments of the kit, the patient is indicated by MRI evidence of inflammation of the spine. There are objective signs of inflammation.

[0095] In some embodiments of the disclosed uses, methods and kits, the patient has ankylosing spondylitis The radiological criteria according to the modified New York diagnostic criteria for pulmonary embolism were not met.

[0096] In some embodiments of the disclosed uses, methods and kits, the patient is Previously unresponsive or inadequate response to treatment with anti-inflammatory drugs (NSAIDs) In some embodiments of the disclosed uses, methods and kits, the patient is diagnosed with TN Previously unresponsive or inadequate response to treatment with F alpha inhibitors In some embodiments of the disclosed uses, methods and kits, the patient Subjects had not received prior treatment with TNF alpha antagonists (TNF medications). I have never received it).

[0097] In some embodiments of the disclosed uses, methods and kits, the patient further administers This means that cyclosporine, hydroxychloroquine, methotrexate, NSAIDs, Fasalazine, leflunomide, prednisolone, prodnisone, or methylprednisolone to the patient.

[0098] In some embodiments of the disclosed uses, methods and kits, from about 75 mg to about 300 mg mg of IL-17 antibody or its antigen-binding fragment was administered subcutaneously to the patients at weeks 0, 1, 2, and 3. The disclosed uses, methods and kits are administered to a subject, and then monthly starting in the fourth week. In some embodiments, 150 mg of an IL-17 antibody or antigen-binding fragment thereof is added to 0 Patients will receive subcutaneous injections on weeks 1, 2, and 3, then monthly starting on week 4. Give.

[0099] In some embodiments of the disclosed uses, methods and kits, an IL-17 antibody or its The antigen-binding fragment of i) an immunoglobulin heavy chain comprising the amino acid sequence shown as SEQ ID NO: 8 Variable domain (V H ii) an immunoglobulin comprising the amino acid sequence shown as SEQ ID NO: 10; Brine light chain variable domain (V L iii) containing the amino acid sequence shown as SEQ ID NO: 8 Immunoglobulin V H domain and an immunoglobulin comprising the amino acid sequence shown as SEQ ID NO: 10. Globulin V L Domains, iv) shown as SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 Immunoglobulin V containing hypervariable regions H Domain, v) SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: Immunoglobulin V containing the hypervariable region designated as No. 6 L domain, vi) SEQ ID NO: 11 , immunoglobulin V comprising the hypervariable regions shown as SEQ ID NO: 12 and SEQ ID NO: 13 H Do vii) comprising the hypervariable regions shown as SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3; Immunoglobulin V H domains and shown as SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 Immunoglobulin V containing the hypervariable region L domain, viii) SEQ ID NO: 11, SEQ ID NO: 12 and immunoglobulin V comprising the hypervariable region shown as SEQ ID NO: 13 H Domain list Immunoglobulins comprising the hypervariable regions shown as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 N V L Domain, ix) an immunoglobulin comprising the amino acid sequence shown as SEQ ID NO: 14 x) an immunoglobulin light chain comprising the amino acid sequence set forth as SEQ ID NO: 15; or x) an immunoglobulin heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 16. i) an immunoglobulin light chain comprising the amino acid sequence shown as SEQ ID NO: 14 and SEQ ID NO: 1 The disclosed uses, methods and In some embodiments of the kits, the IL-17 antibody or antigen-binding fragment thereof is It is kinumab.

[0100] Disclosed herein is a method for administering approximately 150 mg of secukinumab subcutaneously at weeks 0, 1, 2, and 3. Administered to patients by injection, followed by monthly administration starting at week 4, including tonic No radiographic evidence of spondylitis, but inflammation shown by CRP and / or MRI Treating patients with objectively symptomatic, severe, active axial spondyloarthritis (axSpA) It is also a way to do this.

[0101] Disclosed herein is a method for administering approximately 150 mg of secukinumab subcutaneously at weeks 0, 1, 2, and 3. of AS, including administering it to patients by injection and then monthly starting at week 4. Objective signs of inflammation by elevated CRP and / or MRI, but without radiographic evidence severe axS with a history of steroid use and a previous inadequate response to treatment with NSAIDs It is also a method of treating patients with pA.

[0102] Disclosed herein is a method for administering approximately 150 mg of secukinumab subcutaneously at weeks 0, 1, 2, and 3. of AS, including administering it to patients by injection and then monthly starting at week 4. Objective signs of inflammation by elevated CRP and / or MRI, but without radiographic evidence have had a previous inadequate response to or intolerance to treatment with NSAIDs It is also a way to treat patients with severe axSpA.

[0103] Disclosed herein is a method for administering approximately 150 mg of secukinumab subcutaneously at weeks 0, 1, 2, and 3. of AS, including administering it to patients by injection and then monthly starting at week 4. Objective signs of inflammation by elevated CRP and / or MRI, but without radiographic evidence have previously failed or inadequately responded to treatment with TNF-alpha inhibitors It is also a method of treating patients with severe axSpA who have had a response.

[0104] Disclosed herein is a method for administering approximately 150 mg of secukinumab subcutaneously at weeks 0, 1, 2, and 3. of AS, including administering it to patients by injection and then monthly starting at week 4. Objective signs of inflammation by elevated CRP and / or MRI, but without radiographic evidence have had a previous inadequate response to treatment with a TNF-alpha inhibitor, It is also a method of treating patients with severe axSpA.

[0105] Disclosed herein is a method for administering approximately 150 mg of secukinumab subcutaneously at weeks 0, 1, 2, and 3. Administered to patients by injection, followed by monthly dosing starting at week 4. No prior alpha antagonist treatment (no prior TNF medication) (not available), and is also a way to treat patients with severe axSpA.

[0106] Disclosed herein is a method for administering approximately 150 mg of secukinumab subcutaneously at weeks 0, 1, 2, and 3. of AS, including administering it to patients by injection and then monthly starting at week 4. Objective signs of inflammation by elevated CRP and / or MRI, but without radiographic evidence and had not previously received treatment with a TNF alpha antagonist (TNF medication It is also a way to treat patients with severe axSpA (those who have not received prior axSpA therapy).

[0107] Disclosed herein is a method for administering approximately 150 mg of secukinumab subcutaneously at weeks 0, 1, 2, and 3. of AS, including administering it to patients by injection and then monthly starting at week 4. Objective signs of inflammation by elevated CRP and / or MRI, but without radiographic evidence and had not previously received treatment with a TNF alpha antagonist (TNF medication It is also a way to treat patients with severe axSpA (those who have not received prior axSpA therapy).

[0108] kit The present disclosure provides a method for preventing structural damage (e.g., bone and joint) in patients with nr-axSpA. Such kits also include kits for administering IL-17 antagonists, e.g., IL-17 antagonists. IL-17 binding molecules (e.g., IL-17 antibodies or antigen-binding fragments thereof, e.g., sec- numab) or IL-17 receptor binding molecules (e.g., IL-17 antibodies or their antigen-binding a compound fragment) (e.g., in liquid or lyophilized form) or an IL-17 antagonist The pharmaceutical composition (described above) may further comprise an IL-17 antagonist. means for administering the agent (e.g., autoinjector, syringe and vial, pre-filled syringe, pre-filled pen) These kits may contain an encapsulated IL-17 antagonist. and an IL-17 binding molecule, e.g., an IL-17 antibody, e.g., secukinumab. For example, additional therapeutic agents for treating nr-axSpA for delivery in combination ( Such kits may include a kit for treating non-rx-SpA patients. and / or non-TNF-naive and / or non-TNF-naive axSpA patients (e.g., TNF-naive and / or TNF-IR in nr-axSpA patients, NSAID-failed nr-axSpA patients, etc. IL-17 antagonists (e.g., IL-17 antibodies) to inhibit the progression of structural damage caused by The patient information may also include instructions for administration of the compound (e.g., secukinumab). The present invention relates to an encapsulated IL-17 antagonist, e.g., an IL-17 binding molecule, e.g., Dosages (e.g., 10 mg / mL) for use with IL-17 antibodies, e.g., secukinumab kg, 75 mg, 150 mg, 300 mg), route of administration (e.g., IV, SC) and dose Regimen (e.g., approximately 10 mg / kg IV every other week at weeks 0, 2, and 4, then Starting at week 8, administer approximately 75 mg, 150 mg, or 300 mg SC once a month. SC administration of approximately 75 mg, 150 mg, or 300 mg once weekly in weeks 0, 1, 2, and 3 Then, starting in the fourth week, approximately 75 mg, 150 mg, or 300 mg is administered once a month. SC administration: approximately 75 mg, approximately 150 mg, or approximately 300 mg administered once a month ) may be provided.

[0109] The phrase "means for administering" includes pre-filled syringes, vials and syringes, syringe pens, including, but not limited to, auto-injectors, IV drips and bags, pumps, etc. It is used to refer to available devices for the systemic administration of drugs to the allowing patients to self-administer drugs (i.e., administer drugs without the assistance of a physician) or a doctor can administer the medication.

[0110] Disclosed herein are IL-17 antagonists (e.g., IL-17 binding molecules). , e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab), to treat patients with non-axial SpA and / or to reduce structural damage in patients with non-axial SpA In some embodiments, the kit comprises: In some embodiments, the method further comprises administering the IL-17 antagonist to the patient. In one embodiment, the kit comprises an IL-17 antagonist (e.g., an IL-17 binding molecule, e.g., IL-17 antibody or its antigen-binding fragment, e.g., secukinumab, administered alternately at weeks 0, 2, and 4. Approximately 10 mg / kg per week in patients (TNF-naive and / or TNF-experienced) should be administered intravenously (IV) at 8 weeks, then at approximately 75 mg to approximately 30 mg once a month starting at week 8. 00 mg (e.g., about 75 mg, about 150 mg, or about 300 mg) administered subcutaneously (SC) to the patient Further, instructions for administration of the IL-17 antagonist should be provided. In some embodiments, the kit further comprises an IL-17 antagonist (e.g., IL-17 binding molecules, e.g., IL-17 antibodies or antigen-binding fragments thereof, e.g., kinumab) with or without a loading regimen, e.g., once weekly at weeks 0, 1, 2, and 3 Approximately 75 mg to approximately 300 mg (e.g., approximately 75 mg, approximately 150 mg, or approximately 300 mg) SC, then about 75 mg to about 300 mg (e.g., about 75 mg) once a month starting in the fourth week. g, about 150 mg, or about 300 mg) SCat; or every 4 weeks (once a month) about 75 mg g to about 300 mg (e.g., about 75 mg, about 150 mg, or about 300 mg) Instructions for administering the IL-17 antagonist to the patient In some embodiments, the instructions further include instructions for dose escalation (as determined by a physician). For example, a dose of about 75 mg may be increased to about 150 mg or about 300 mg as needed. 00mg).

[0111] In some embodiments, the kit includes an IL-17 antagonist (e.g., an IL- 17-binding molecules, e.g., IL-17 antibodies or antigen-binding fragments thereof, e.g., secukinumab ) about 75 mg to about 300 mg (for example, about 75 mg, about Patients should be given SC doses of 150 mg or approximately 300 mg, followed by 2 doses starting at week 4. Once a month, about 75 mg to about 300 mg (for example, about 75 mg, about 150 mg, or about 300 mg) g); or every 4 weeks (once a month) about 75 mg to about 300 mg (e.g., about 75 mg, about IL-17 antibody should be administered SC to patients at doses of approximately 150 mg or approximately 300 mg. In some embodiments, the patient further comprises instructions for administration of the antagonist. The instructions should include dose titration (to be determined by a physician, e.g., from a dose of approximately 75 mg). to a higher dose of about 150 mg or about 300 mg as needed.

[0112] general In preferred embodiments of the disclosed methods, treatments, medicaments, regimens, uses and kits, The IL-17 antagonist is an IL-17 binding molecule. The IL-17 binding molecule is an IL-17 antibody or an antigen-binding fragment thereof. In some embodiments of the methods, treatments, regimens, uses and kits, an IL-17 antibody or The antigen-binding fragment thereof is an IL-17 antibody or an antigen-binding fragment thereof, which comprises: a) Leu74, Tyr 85, His86, Met87, Asn88, Val124, Thr125, Pro12 6. Binds to IL-17 epitopes including Ile127, Val128, and His129. a) an IL-17 antibody or an antigen-binding fragment thereof containing Tyr43, Tyr44, Arg46, and A; IL-17 antibody that binds to an epitope of IL-17 including Ia79 and Asp80, or antigen-binding fragment, c) an IL-17 homodimer having two mature IL-17 protein chains. It binds to an epitope that is located at Leu74, Tyr85, His8 on one chain. 6, Met87, Asn88, Val124, Thr125, Pro126, Ile12 7, Val128, His129 and Tyr43, Tyr44, Arg46 on the other chain; IL-17 antibody or antigen-binding fragment thereof containing Ala79 and Asp80, d) two mature IL-17 homodimer having an epitope of the IL-17 protein chain, Tope is Leu74, Tyr85, His86, Met87, Asn88 on one strand, Val124, Thr125, Pro126, Ile127, Val128, His12 9 and Tyr43, Tyr44, Arg46, Ala79, and Asp80 on the other chains , IL-17 binding molecules have a K of approximately 100-200 pM D and about 23 to about 35 days and e) an IL-17 antibody or antigen-binding fragment thereof having an in vivo half-life of i ) an immunoglobulin heavy chain variable domain (V) comprising the amino acid sequence set forth as SEQ ID NO: 8 H ii) an immunoglobulin light chain variable domain comprising the amino acid sequence set forth as SEQ ID NO: 10 In (V L ) iii) immunoglobulin V comprising the amino acid sequence shown as SEQ ID NO: 8 H Immunoglobulin V comprising the domain and the amino acid sequence shown as SEQ ID NO: 10 L Domestic iv) an immunogen comprising the hypervariable regions shown as SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3; Epidemic globulin V H domains, v) shown as SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 Immunoglobulin V containing hypervariable regions L domain, vi) SEQ ID NO: 11, SEQ ID NO: 12, and Immunoglobulin V comprising the hypervariable region set forth as SEQ ID NO: 13 H domain, vii) distribution Immunoglobulin V comprising the hypervariable regions shown as SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 H domain and hypervariable regions shown as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6. Immunoglobulin V L domains, viii) SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 1 Immunoglobulin V containing the hypervariable region designated as 3 H Domain and SEQ ID NO: 4, sequence Immunoglobulin V comprising the hypervariable region shown as SEQ ID NO: 5 and SEQ ID NO: 6 L domain, i x) an immunoglobulin light chain comprising the amino acid sequence set forth as SEQ ID NO: 14, 15, or xi) an immunoglobulin heavy chain comprising the amino acid sequence shown as SEQ ID NO: 14. and an immunoglobulin light chain comprising the amino acid sequence shown as SEQ ID NO: 15. an IL-17 antibody or an antigen-binding fragment thereof comprising an immunoglobulin heavy chain containing the amino acid sequence The compound is selected from the group consisting of:

[0113] In some embodiments of the disclosed methods, an IL-17 antibody or antigen-binding fragment thereof is a human antibody of the IgG1 isotype. In some embodiments of the disclosed methods wherein the antibody or antigen-binding fragment thereof is secukinumab.

[0114] The details of one or more embodiments of the present disclosure are set forth in the accompanying description above. Use of methods and materials similar to those described in or equivalent to those described in in the practice or testing of the present disclosure. While various methods and materials are possible, preferred methods and materials are now described. Other Features, Objects, and Advantages of the Present Disclosure The following will become apparent from the description and claims. In this context, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Unless otherwise noted, all technical and scientific terms used herein are of the art to which this disclosure belongs. All terms and phrases cited herein have the same meaning as commonly understood by practitioners. The patents and publications are incorporated by reference. The following examples illustrate preferred embodiments of the present disclosure. These examples are presented to more fully illustrate the embodiments defined by the appended claims. should not be construed to limit the scope of disclosed patient matter, as defined in do not have. [Example]

[0115] Proof-of-concept AS study CAIN457A2209 Example 1.1 - Study Design CAIN457A2209 This is a significant finding in patients with moderate to severe AS with or without prior TNF antagonist therapy. Repeated secukinumab 10 mg / kg, 1.0 mg / kg for the treatment of patients with a diagnosis and 0.1 mg / kg (two injections every three weeks) in a two-part, multicenter, proof-of-concept study. In Part 1, 30 patients received secukinumab 10 mg / kg or placebo. In part 2, an additional 30 patients received secukinumab 0.1 The mice received either 1.0 mg / kg, 1.0 mg / kg, or 10 mg / kg in a 2:2:1 ratio. The study consisted of a 28-day screening period, a 3-week treatment period, and a 25-week follow-up period. Subjects who met the inclusion / exclusion criteria at screening were included in the ASAS core Set domain (ASAS core set domain) (1-6) (Zochling et al (2006) Ann Rheu m Dis 65:442-452), including BASMI score, BASDAI score and physician global assessment. The primary endpoint of the study was the ASAS20 response rate at week 6. The proportion of patients achieving a response was

[0116] Patients who meet the modified New York criteria for the diagnosis of AS and whose disease is amenable to NSAID treatment (maximum 100 mg / kg / day) controlled with at least one NSAID at a well-tolerated dose for a period of at least 3 months Patients with moderate to severe AS who had not previously received AIN457 were randomly assigned to receive 2 × 10 mg / kg AIN457 or Patients were randomized to receive placebo. The minimum disease activity for patient inclusion was A SAS score set domains: total back pain or nighttime back pain despite concurrent NSAID use Based on a score of ≥40 (0–100 mm VAS) and a total BASDAI score of ≥4. Stable doses of methotrexate (MTX), sulfasalazine (SSZ), and low Concomitant use of dose-corticosteroids was permitted as specified in the inclusion / exclusion criteria. Immunosuppressants other than MTX, SSZ, and systemic low-dose corticosteroids were administered at baseline. A one-month washout period was required before administration.

[0117] Efficacy was assessed using the following assessment domains: (1) Patient Global Assessment (PGA); (2) Inflammatory Back pain (average of answers to questions #5 and #6 or Bath Ankylosing Sp ondylitis Disease Activity Index[BASDAI] )、(3)Bath Ankylosing Spondylitis Functio (4) Inflammatory Back Pain Index (0-100 mm on a VAS) The ASAS score was based on the ASAS score scale, which consisted of a total of 12 items (measured by back pain, back pain, or nighttime back pain). The objective of this study was to investigate whether these changes were affected by treatment with secukinumab. Magnetic resonance imaging of the spine using a scoring system for quantification of AS-associated lesions to The exploratory objective of the study was to evaluate the efficacy and safety of MRI scans in patients with moderate to severe AS. Genetic and mRNA expression profiling, flow cytometry, and serum protein analysis in patients with Protein quality assessment was used to identify biomarker profiles and to assess efficacy of secukinumab treatment. The objective of this study was to determine whether cerebrospinal fluid (CEF) affects these biomarkers.

[0118] Thirty patients received secukinumab (AIN457) 10 mg / kg IV or placebo IV The patients were asked to receive two intravenous injections given three weeks apart (on days 1 and 22). Patients were randomized in a 1:1 ratio. Patients were followed for safety through week 28. A Bayesian analysis of the ASAS20 response rates at week 6 for IN457 and placebo was performed. The prior distribution of the response rate is specified as a beta distribution, and the observed number of responders in each group is binomial. Eight randomized, placebo-controlled trials of anti-TNF-alpha treatment in AS were conducted. The predicted distribution of placebo response rates from the meta-analysis was used as the prior distribution of placebo response rates. This prior distribution predicts that we will observe 11 responders out of 43 (i.e., a 26% response rate). The weak prior distribution was calculated based on the active response rate (0.5 responders in 1.5 cases). The T1 and SH were measured at baseline, week 6, and week 28. Sagittal MR imaging of the spine was performed, including transient tau inversion recovery (STIR) sequences. Using the "Berlin modification" of the AS spine MRI (ASspiMRI-a) scoring system and analyzed by an independent reader who was blinded to treatment assignment and temporal sequence of the images. For assessment of changes between baseline and follow-up in each treatment arm, The Wilcoxon signed rank test was used.

[0119] ASAS (International Spondyloarthritis Assessment Society) criteria The ASAS (International Spondyloarthritis Assessment Society) assessment criteria (1-6) are based on the following assessment domains: 1) Patient global assessment of disease activity, assessed on a 100mm visual analogue scale (VAS) (2) pain, measured by VAS pain score (0-100 scale) or NRS (0-10); (3) physical function, assessed by the BASFI score (0–100 scale) (4) Inflammation, 2 BASDA scores on a 10-point scale related to morning stiffness (5)B: Assessed by the average of questions #5 and #6 or the 100mm VAS score. Ankylosing Spondylitis Measurement Index (ASM) BASMI); score (cervical rotation, chest expansion, lumbar lateral bending, (6) C-reactive protein (acute phase reactant) Or rather.

[0120] Definition of ASAS20 Responders Subjects are eligible to participate in the ASAS20 study if, and only if, both of the following conditions apply: It is defined as a responder. 1. Subjects demonstrate a ≥ 20% improvement in ≥ 3 of the following 4 core ASAS domains: ≥ 1 unit absolute improvement: Patient Global Assessment (measured on a 0-100 mm VAS) back pain (measured as total back pain or nighttime back pain on a 0-100 mm VAS); physical function (measured by BASFI, 0-10); inflammation (BASDAI, 2 morning stiffness) (measured by the average of questions #5 and #6 related to, 0-10); 2. Subject has no decline in the remaining possible domains (decline is from baseline (defined as a worsening of ≥ 20% and an absolute worsening of ≥ 1 unit).

[0121] Definition of ASAS40 Responders Subjects are eligible to participate in the ASAS40 study if, and only if, both of the following conditions apply: It is defined as a responder. 1. Subject achieves ≥ 40% improvement and ≥ 2 units absolute improvement in three of the following four domains: Improvement: Patient global assessment (measured on a VAS of 0 to 100 mm); back pain (measured on a VAS of 0 to 1 back pain (measured as total back pain or nighttime back pain on a 0.00 mm VAS); physical function (measured on the BASFI) Measured from 0 to 10; inflammation (BASDAI two morning stiffness-related questions) Measured by the average of #5 and #6, 0-10); 2. Subject achieves a >0.05 improvement from baseline in all remaining available domains. % or >0 units).

[0122] Definition of ASAS5 / 6 responders Subjects will have a ≥ 20% improvement in five of the following six ASAS domains: An ASAS 5 / 6 responder is defined if and only if: Patient Global Assessment (0–6) back pain (measured on a 0-100 mm VAS); back pain (measured on a 0-100 mm VAS as total back pain or night pain) physical function (measured by the BASFI, 0-10); inflammation (Measured by the average of two morning stiffness-related questions #5 and #6 of the BASDAI) (0-10); Bath Ankylosing Spondylitis Met BASMI score (cervical rotation, chest expansion, lumbar lateral bending, Positive Schober's index, interoccipital distance); (6) C-reactive protein (acute phase reactant).

[0123] Definition of ASAS partial response Subjects have a value of <2 units in each of the following four core ASAS domains: A partial response is defined as achieved if and only if: Patient Global Assessment (0 back pain (measured on a VAS ranging from 0 to 100 mm); back pain (measured on a VAS ranging from 0 to 100 mm); physical function (measured by the BASFI, 0-10); inflammation Symptoms (measured by the average of two morning stiffness-related questions #5 and #6 of the BASDAI) (0 to 10).

[0124] Bath Ankylosing Spondylitis Functional Index (BASFI) The BASFI was designed to assess the degree of functional limitation in patients with AS. The set of 10 questions was designed to answer key questions from patients with AS. The first eight questions were selected using a variety of inputs. The final two questions assess the patient's ability to cope with daily activities. Answer the questions using a 10cm visual analogue scale. The average of the 10 scales This gives a BASFI score, which is a value between 0 and 10.

[0125] Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) BASDAI is a scale of 0 to 10 (0 being no problem, 10 being the worst problem), It is used to answer six questions about S's five main symptoms: 1. Fatigue; 1. Spinal pain; 3. Joint pain / swelling; 4. Areas of localized tenderness (enthesitis or inflammation of tendons and ligaments) 5. Persistence of morning stiffness; 6. Severity of morning stiffness. Each symptom was given equal weight. To calculate the mean score for the two morning stiffness questions, we added the mean scores for the other four questions to the mean scores for the two morning stiffness questions. The resulting score of 0-50 is divided by 5 to get a final BASDAI score of 0-10. A BASDAI score of 4 or higher indicates suboptimal disease control, and a BASDAI score of 4 or higher indicates suboptimal disease control. Patients with scores above this level typically require a change in their medical therapy or treatment for AS. These patients are good candidates for enrollment in clinical trials evaluating novel drug therapies.

[0126] Patient Global Assessment of Disease Activity The patient global assessment of disease activity is "all the ways your arthritis affects you." Consider your condition and draw a line on the scale to indicate how well you are doing. In response to the question, "What is your risk?", a 100mm V scale ranging from no disease activity to maximum disease activity was used. The distance in mm from the left end of the scale is measured at the investigator's facility. Measurements were taken and values ​​entered into the eCRF.

[0127] Patient assessment of pain intensity Patient assessment of back pain is performed on a scale ranging from painless to intolerable, with separate assessments for total back pain or nocturnal back pain. The study will be conducted using a 100 mm VAS ranging from mild to severe pain. Measure the distance in mm from the left edge of the tube and enter the value into the eCRF.

[0128] Bath Ankylosing Spondylitis Measurement Index (BASMI) BASMI is an axial assessment aimed at defining clinically significant changes in spinal motion. Validated rating scales that use the minimum number of clinically relevant measures to accurately assess The parameters are: 1. cervical rotation; 2. tragus wall distance; 3. lumbar lateral flexion; 4. corrected show 5. Medial intermalleolar distance. Two additional parameters are also assessed: 6. Chest expansion and 7. occipital wall distance.

[0129] Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) The Mastricht Ankylosing Spondylitis Enthesitis Score (MASES) is a Mander index. The MASES index is constructed from 13 sites and includes evaluation of 13 sites. The sites of enthesitis included in the MASES index are the first rib Cartilage, 7th costal cartilage, posterior superior iliac spine, anterior superior iliac spine, iliac crest (all of the above evaluated bilaterally), 5th Lumbar spinous processes, proximal Achilles (both sides).

[0130] Leeds Enthesitis Index (LEI) LEI is an assessment of the attachments of the lateral epicondyle (L+R) of the humerus, the proximal Achilles tendon, and the lateral femoral condyle (L+R). The LEI is a validated enthesitis index that uses only six sites for evaluation. It showed substantial to excellent agreement with other scores in the indications of arthritis, but not in ankylosing spondylitis. showed a lower degree of agreement with MASES in this indication and therefore It can provide information.

[0131] MRI Magnetic resonance imaging (MRI) of the spine demonstrated that these changes were not due to treatment with secukinumab. A scoring system for quantification of AS-related lesions was developed to examine whether the disease was affected by the MRIs were acquired on-site at the clinical facility, and images were transmitted and quality-controlled. The data were collected, anonymized (if necessary), and analyzed centrally (blinded review). The study was conducted at baseline (preferably within 2 weeks before the first treatment) and at week 6 (± 1 week MRI scans were collected at 1 week (between 12 and 14 weeks) and at 28 weeks (± 1 week). Pre- and post-intravenous gadolinium contrast-enhanced MRI to monitor bone marrow edema The analysis methods included fat saturation techniques such as short tau inversion recovery (STIR). ASspiMRI-a Berlin Modification" (Lukas C et al (2007) J Rheumatol;34(4) :862-70 and Rudwaleit et al (2005) [abstract] Arthritis Rheum 50:S211), It scores inflammatory changes in almost the entire spine (C2-S1).

[0132] Example 1.2 - Secukinumab has a favorable safety and efficacy profile in the treatment of active ankylosing spondylitis Shows effectiveness Demographic and baseline characteristics were comparable between groups. The (SD)BASDAI was 7.1 (1.4) in patients receiving secukinumab and 1.4 (1.4) in patients receiving placebo. The RR was 7.2 (1.8) in 3 patients receiving placebo and 1 in 1 patient receiving secukinumab. Two patients discontinued the study before the primary endpoint, primarily due to unsatisfactory treatment response. Efficacy data for one patient were not available due to a protocol violation after randomization. At week 6, 14 of 23 secukinumab-treated patients included in the efficacy analysis Achieved an ASAS20 response compared with 1 of 6 placebo-treated patients (6 1% vs. 17%, probability of positive-treatment difference ) = 99.8%, 95% confidence interval 11.5%, 56.3%) (Table 3).

[0133] [Table 3]

[0134] The ASAS40 and ASAS5 / 6 responses in secukinumab-treated patients were 30% and 30%, respectively. The mean (range) BASDAI change was -1.8 (-5.6 to 0.8). In the majority of ASAS20 responders, secukinumab produced a response within one week of treatment. The ASAS response rate was highest for the primary endpoint at week 6, and This was followed by a decline in serotonin levels until the end of the study at week 28. This was the outcome of the study chosen for this proof-of-concept study. A preliminary dose of only two doses of 10 mg / kg IVIV was administered on days 1 and 22. In a post hoc analysis of subgroups, pre-exposure to a TNF-alpha antagonist was associated with Patients receiving TNF-alpha antagonists were more likely to be refractory to RA than non-RA patients (3 / 10; 30%). The results were excellent in patients who had never received TNF medication (11 / 13; 85%). The pharmacokinetic profile was comparable to that of secukinumab administered for other indications. were equal.

[0135] Secukinumab induced a significantly higher ASAS20 response than placebo at week 6 The primary endpoint of this study was met. Early safety signals were observed in this study population. was not recognized in

[0136] Example 1.3 - Secukinumab improves survival as early as 6 weeks as detected by magnetic resonance imaging Reduces spinal inflammation in patients with early-stage AS Magnetic resonance imaging (MRI) is considered the gold standard for assessing spinal inflammation in AS. Therefore, we observed the following after two injections of secukinumab (10 mg / kg IV). We determined whether the clinical benefit was consistent with the reduction in bone marrow edema seen on MRI. T1 and short tau inversion recovery (STI) were measured at baseline (BL), week 6, and week 28. Sagittal MRI of the spine was performed, including AS spine MRI (ASsp R) sequences. iMRI-a) The Berlin modification of the scoring system was used to determine treatment allocation and imaging time. The data were analyzed by an independent reader who was blinded to the sequence of the interventions. Changes between baseline and follow-up in the variances were evaluated by the Wilcoxon signed-rank test. More highly rated.

[0137] Twenty-seven patients (22 secukinumab; 5 placebo) had a baseline A small number of patients (week 6: 2 secukinumab, 3 plamotherapy) had evaluable MRI images. Week 28: 6 secukinumab, 1 placebo) was primarily due to early discontinuation. Follow-up MRI was missing. MRI scores at baseline and at 6 and 7 weeks were The changes at 6 and 28 weeks are shown in Table 4. Improvement in MRI scores was observed as early as 6 weeks. The early improvement at week 6 was associated with a higher baseline score. Only small changes were observed in placebo-treated patients. There wasn't.

[0138] [Table 4]

[0139] Results from this exploratory study in patients with active AS support the efficacy of two injections of secukinumab. Substantial reduction in spinal inflammation detected by MRI occurred after treatment with IV injection alone. MRI changes were observed as early as 6 weeks after the start of treatment and at 28 weeks The results were consistent with MRI findings from previous AS trials using TNF-blockers. These results demonstrate the potential of secukinumab for patients with active AS. This supports the idea that it could be a treatment. [Example]

[0140] Phase III clinical trial CAIN457F2305 (MEASURE1) MEASURE1 (NCT01358175) is a study of subjects with ankylosing spondylitis (AS). Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients This was a randomized, double-blind, placebo-controlled trial that demonstrated efficacy and safety.

[0141] Example 2.1 - CAIN457F2305 Results Here, our objective is to evaluate the efficacy and safety of intravenous secukinumab loading and administration based on multiple endpoints. The objective of this study was to evaluate the efficacy of subcutaneous administration and subcutaneous maintenance administration.

[0142] 371 adults with active AS received intravenous (IV) secukinumab 10 mg / kg (0 , 2, and 4 weeks) followed by subcutaneous (SC) secukinumab 75 mg every 4 weeks (IV → 75 SC), IV secukinumab 10 mg / kg (weeks 0, 2, and 4) followed by SC every 4 weeks CSecukinumab 150 mg (IV → 150 SC) or on the same IV and SC schedule PBO subjects were randomized to receive placebo (PBO) at week 16. Secukinumab 75% CI, based on the International Spondyloarthritis Assessment Society (ASAS) 20 response assessment Responders were re-randomized to 150 mg SC or 150 mg SC at week 16 for non-responders and week 24 for responders. The disease activity (signs and symptoms) was measured using the Ankylosing Spondylitis Disease Activity Score (ANSS). (ASDAS)-C-reactive protein (ASDAS-CRP), ASDAS-erythrocyte sedimentation Speed ​​(ASDAS-ESR) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) The individual components of the ASAS reaction criteria (ASAS20, ASAS40, ASAS The effect of secukinumab on the 5 / 6 and ASAS partial response rates was assessed. Also reported in the following formats: Visual Analogue Scale (VAS), Bath Ankylosing Spondylitis The patient's global assessment of disease activity and inflammatory back pain, based on both the Basis for Severe Acute Myocardial Infarction and Functional Index (BASFI), and spinal inflammation based on BASDAI questions 5 and 6.

[0143] The primary endpoint was met by both secukinumab arms in MEASURE 1. In MEASURE 1, the ASAS20 response rate at week 16 was 60.8% with IV → 150 mg, 59.7% with IV secukinumab → 75 mg, and 59.7% with placebo The rate was 28.7% (P<0.001 for both comparisons vs. placebo) (Table 5). All pre-specified secondary endpoints were achieved in both MEASURE1 and MEASURE2. The ASAS40 response rate at week 16 was met by secukinumab (Table 5). 4 in the secukinumab IV → 150 mg, secukinumab IV → 75 mg, and placebo groups, respectively 1.6%, 33.1%, and 13.1% (P<0.05 for both comparisons vs. placebo). .001) (Table 5). Improvement in patients treated with secukinumab was sustained through week 52. Ta.

[0144] [Table 5]

[0145] Example 2.2 - CAIN457F2305 Imaging at Weeks 16 and 52 Here, our objective is to use magnetic resonance imaging (MRI) in the MEASURE1 study. The study was conducted to evaluate objective signs of inflammation in the sacroiliac (SI) joints and spine at 16 and 52 weeks. The purpose of this study was to examine the effects of secukinumab on gliomas with ...cerebrospinal fluid smear.

[0146] Active AS despite maximally tolerated therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) 371 adults with IV secukinumab or placebo: IV secukinumab 10 mg / kg (weeks 0, 2, and 4) followed by SC secukinumab 75 mg IV every 4 weeks (75 SC Secukinumab 150 mg SC every 4 weeks (IV → 150 SC); or the same schedule Patients were randomized to PBO in a SI joint and spine. MRI of the SI joint and spine demonstrated tumor necrosis factor-targeted 105 subjects with no prior exposure to anti-TNF therapy (anti-TNF medication naive) Assessments were performed at baseline, 16, 52, and 104 weeks. MRI variables included Berlin SI total joint edema score, MRI scan of spinal activity, and Core (ASspi-MRI-a) and Berlin Spine Score (ASspi-MRI-a The results were evaluated by two experienced All MRIs were evaluated by trained readers, and their mean scores were used for the final analysis. .

[0147] Mean baseline ASspi-MRI-a and Berlin spine scores were 5.0 and 5.2%. The IV → 150 SC group had lower seroconvertible steroids than the IV → 75 SC and placebo groups (Table 6). At week 6, secukinumab significantly reduced Berlin SI total joint edema scores compared with placebo. Improvement in the core was observed (mean change from baseline: secukinumab IV → 150 SC and -1.30 and -1.05 vs. -0.17 in the IV→75SC vs. placebo groups, respectively ; P < 0.01) (Table 6, Figure 2A). Both secukinumab doses significantly improved ASs compared with placebo. Greater percentage improvement from baseline in pi-MRI-a and Berlin spine score Secukinumab also resulted in improvements in all MRI measures (Table 6, Figure 2B). This persisted into the second week (Table 7).

[0148] [Table 6]

[0149] [Table 7]

[0150] Secukinumab significantly reduced early spinal inflammation in subjects with active AS as measured by MRI It has been shown that this treatment resulted in a reduction in schizophrenia, and improvement was sustained through 52 weeks of treatment. 16 and 52 subjects who switched from placebo to monthly SC secukinumab at week 24. Berlin SI total joint edema score (Fig. 3A) and Berlin spine score (Fig. 3B) were measured at 1 week. The results showed improvement from the 16-week scores for each group (Figure 3B).

[0151] Example 2.3-104 Week CAIN457F2305 Imaging Analysis X-rays of the neck, chest, and lumbar spine were performed at baseline and at week 104. mSAS of patients receiving secukinumab and those receiving placebo who switched to secukinumab treatment A summary of the SS and RASSS scores and changes from baseline is shown in Table 8. Increasing SSS and RASSS scores indicate worsening structural progression. Only patients with paired radiographic data at week 4 were analyzed. The placebo-secukinumab group consisted of placebo non-responders and responders who were re-randomized to secukinumab. The results were a pool of both participants.

[0152] At week 104, the overall cohort of patients randomized to secukinumab at study entry The mean change from baseline in mSASSS score was 0.30 in the IV→150 mg group and 0.30 in the IV→200 mg group. → 0.31 in the 75 mg group. Similar changes from baseline were observed with anti-TNF-α medication. The incidence was higher in patients who had never received IV steroids (0.37 with IV 150 mg and 0.37 with IV 75 mg). 0.36), but was lower in TNF-IR patients (0.14 and 0.13, respectively). The change from baseline in RASSS at week 104 was The results were consistent with the data.

[0153] Patients were switched to SC secukinumab at week 16 (non-responders) or week 24 (responders). , therefore, had 4-6 months less exposure to secukinumab and received an i.v. loading regimen. The placebo patients who did not receive secukinumab treatment were compared with those who received secukinumab treatment from the start of the study. There was a slightly greater increase from baseline in mSASSS compared with placebo ( 0.44 at 150 mg, 0.64 at 75 mg (placebo). This was observed in both α-naive and TNF-IR patients. Similar results were observed for the change in RASSS from baseline at 2 years. It was recognized as such.

[0154] [Table 8]

[0155] Probability plots of radiographic progression were generated (data not shown). Approximately 80% of patients in the IV 75 mg and IV 75 mg groups achieved 2 years of secukinumab treatment. Radiographic progression (change from baseline) by mSASSS and RASSS scores These high rates were observed with IV → 150 mg and IV → 75 mg doses. In both TNF-IR patients and anti-TNF-α medication-naive patients in the Similar high rates of non-progression were observed with placebo without the IV loading regimen → 15 This was also observed in patients receiving 0 mg SC or placebo → 75 mg SC. [Example]

[0156] Phase III clinical trial CAIN457F2310 (MEASURE2) MEASURE2 (NCT01649375) is a human anti-IL-17A monoclonal antibody Subcutaneous (SC) administration of the antibody secukinumab improves symptoms of ankylosing spondylitis (AS) after 16 weeks of therapy. A randomized, double-blind, placebo-controlled study previously shown to rapidly reduce signs and symptoms This is a controlled phase 3 trial.

[0157] Example 3.1 - CAIN457F2310 Results Here, our objective is to evaluate the SC secukinumab incidence in subjects enrolled in MEASURE2. The purpose of this study is to investigate the long-term efficacy and safety of nonsteroidal anti-inflammatory drugs (NSAIDs). ) in 219 adults with active AS despite maximally tolerated therapy. SC secukinumab 150 mg at 75°C at weeks 1, 2, 3, and 4, then every 4 weeks At week 16, patients in the PBO group were randomized to receive either 1 mg or 1 mg PBO. Patients were re-randomized to receive secukinumab 150 mg or 75 mg every 4 weeks. The endpoint is the proportion of subjects achieving an International Spondyloarthritis Assessment Society (ASAS) 20 response at week 16. Secondary endpoints included ASAS40, high-sensitivity C-reactive protein (HSC), and (hsCRP), ASAS5 / 6, Bath Ankylosing Spondylitis Disease Activity (BASDAI), Short Form 36-item Physical Dimension Summary (SF-36 PCS), Ankylosing Spondylitis Quality of Life (A Statistical analysis at 16 weeks included SQoL and ASAS partial response. Non-responders were randomly selected according to a pre-specified hierarchical hypothesis testing strategy to adjust for sex. Imputation (dichotomous variables) and mixed-effects repeated measures models (continuous variables) were used. Week 52 data , shown as observed.

[0158] 181 patients (82.6%) completed 52 weeks of treatment. ASAS20 at Week 16 The response rate was 61.1% with secukinumab 150 mg versus 28.4% with PBO. (P=0.0001) (Table 9). Secukinumab 150 mg was significantly , hsCRP, ASAS40, ASAS5 / 6, BASDAI, SF- at 16 weeks 36 PCS and ASQoL also improved significantly. Clinical response with secukinumab 75 mg is statistically significant for any of the pre-specified endpoints based on hierarchical testing. The improvement with secukinumab 150 mg was sustained through week 52, and The ASAS20 / 40 response rate with cukinumab 150 mg was 73.8% / 57% at week 52. The overall treatment duration (mean secukinumab exposure: 425.8 days; Over the mean PBO exposure (107.6 days), the exposure-adjusted adverse event (AE) rate was The mean ages were 21 years per 100 patient-years in subjects receiving 150 mg, 75 mg, and PBO, respectively. 4.1, 211.7 and 443.2.

[0159] [Table 9]

[0160] Secukinumab 150 mg SC reduced the signs and symptoms of disease in subjects with AS The results showed rapid improvement, reduced inflammation, and improved physical function and health-related quality of life. Secukinumab was well tolerated and safety findings were sustained throughout the 2 weeks of treatment. This was consistent with previous reports.

[0161] Example 3.3 - Efficacy Data of CAIN457F2310 by Anti-TNF-alpha Status Data In Example 3.2, our objective is to evaluate the efficacy and safety of the 16- and 52-week MEASURE2 study. To evaluate the efficacy and safety of secukinumab according to anti-TNF response status in eyes .

[0162] 219 adults with active AS were randomly assigned to receive a randomized controlled trial at baseline, weeks 1, 2, 3, and 4, and then Secukinumab (150 or 75 mg) or PBO was administered subcutaneously (SCSC) every 4 weeks. Randomization was based on prior anti-TNF response status: receiving anti-TNF medication have never received or have had an inadequate response or intolerance to more than one anti-TNF biologic agent ( At week 16, subjects receiving PBO were stratified according to their secukinumab 1 The patients were re-randomized to 50 or 75 mg. Subgroup analyses were performed on anti-TNF-naive and anti-TNF-IR subjects. The primary endpoint was the International Society for Spondyloarthritis Assessment (ASAS) 20 response rate. SAS40, high sensitivity C-reactive protein (hsCRP), ASAS5 / 6, Bath strong Orthotopic Spondylitis Disease Activity Index (BASDAI), Short 36-item Physical Dimension Summary (SF) -36 PCS), ankylosing spondylitis quality of life (ASQoL) and achieving ASAS partial remission The proportion of subjects with a non-responder attribution (dichotomous variable) and mixed effects were included in the analysis at week 16. Results: A repeated measures model (continuous variables) was used. Week 52 data are presented as observed.

[0163] 62% of enrolled subjects were anti-TNF medication naive, and 38% were anti-TNF- At week 16, secukinumab 150 mg (except 75 mg) was administered without anti-TNF therapy. Drug-naive (68.2% vs. 31.1%, respectively; P<0.001) and anti-T compared with PBO in both NF-IR (50.0% vs. 24.1%; P < 0.05). Secukinumab 150 mg improved the ASAS20 response rate. All secondary endpoints were achieved except for ASAS partial response in patients who had not received steroid therapy. For most secondary endpoints in anti-TNF-IR subjects, The results of secukinumab 75 mg were generally higher than those of secukinumab 150 mg (Table 10). g and showed no difference from placebo in ASAS20 response rate at 16 weeks. Clinical response to secukinumab was observed in anti-TNF-naive and anti-TNF- IR was sustained or continued through week 52 in both subjects (Table 10).

[0164] [Table 10]

[0165] Secukinumab 150mg SCSC is for anti-TNF-naive and anti-TNFR Improved signs and symptoms of AS disease in both F-IR subjects, reducing inflammation and promoting the body's Improved function and health-related QoL. [Example]

[0166] Secukinumab versus TNF-alpha inhibitors in the treatment of nr-axSpA In patients with axial spondylitis (AS), secukinumab demonstrated efficacy comparable to that of TNF-alpha inhibitors. The effectiveness of the study was demonstrated by RTI health solutions. Comparison of AS between cukinumab 150mg SC and all approved TNF-alpha inhibitors Pairwise comparisons were used in network meta-analyses comparing data from clinical trials. If the efficacy endpoint (ASAS20, ASAS40, BASDAI50, A Significant differences in SAS PR, ASAS5 / 6, and BASFI (change from baseline) was not observed (data not shown).

[0167] In trials with TNF-alpha inhibitors, the response to treatment was The results were very similar in patients with and without active non-r-axSpA. Specifically, RAPID-axSp of certolizumab pegol (Cimzia®) In Study A, patients with both AS and non-r-axSpA were enrolled (Landewe R et al. (2014) Ann Rheum Dis 2014;73:39-47). Selection of patients with nr-axSpA The selection criteria were as outlined in Example 5 for nr-axSpA CAIN457H2315. The inclusion criteria were very similar to those of the secukinumab trial, including BASDAI ≥ 4 and spinal pain ≥ 4. and active disease as defined by CRP>ULN and / or SJI MRI In addition, patients had to have an inadequate response or intolerance to NSAIDs. There wasn't.

[0168] In the RAPID-axSpA trial, the primary endpoint ASAS20 was 56.9% (CZP 200 mg Q2W) to 64.3% (CZP 400 mg Q4W) of patients ) in 58.7% of non-rx-SpA patients (CZP 200mg Q2W) to 62.7% % (CZP 400 mg Q4W) achieved the secondary endpoint ASAS40 Response rates were 40.0% (CZP 200 mg Q2W) to 50.0% (CZP 40 mg Q2W) of AS patients. 0 mg Q4W) resulted in 47.1% of nr-axSpA patients (CZP 400 mg Q4 W) ~ 47.8% (CZP 200 mg Q2W). Other outcomes include AS PR, ASAS5 / 6, and BASDAI mean change from baseline The endpoints of certolizumab in both AS and nr-axSpA patients were Very similar effectiveness of the goals was observed.

[0169] In addition to the direct comparison of non-r-axSpA and AS patients in the RAPID-axSpA trial, Additionally, an indirect comparison of the efficacy of adalimumab in patients with non-rxSpA and AS was performed. This shows very similar response rates in both patient groups. Responses were observed in 58.2% of AS patients (van der Heijde et al (2006) Arthritis Rheum 2006;54(7):2136-46), and by 51.6% of nr-axSpA patients (Sieper et al ( 2013) Ann Rheum Dis 2013;72:815-822) was achieved. Consistently, ASAS40 39.9% of AS patients (van der Heijde et al (2006) Arthritis Rheum 2006;54( 7):2136-46), and by 36.3% of patients with nr-axSpA (Sieper et al (2013) An n Rheum Dis 2013;72:815-822) was achieved.

[0170] Very similar responses to TNF-alpha inhibitors in patients with nr-axSpA and AS Response rates and non-response of secukinumab and TNF-alpha inhibitors in patients with AS Based on the above evidence of consistently similar efficacy, it is possible that secukinumab may be beneficial in treating nr-axSpA. It is expected that the compound will be effective in treating patients with [Example]

[0171] Clinical trial CAIN457H2315 Example 5.1: Objectives and Study Objectives The purpose of this study was to evaluate the efficacy and safety of steroids in patients with non-r-axSpA at 16 and 52 weeks. To demonstrate the clinical efficacy, safety, and tolerability of secukinumab compared to placebo in Additionally, the 1-year progression of MRI-proven structural changes will be assessed at 52 weeks. The study will assess the long-term efficacy of secukinumab based on MRI and X-ray results up to 104 weeks. Safety, tolerability, and the occurrence of radiographic correlates of inflammation and structural progression will also be monitored. The primary objective is to identify subjects who achieve an ASAS40 response (International Society for Spondyloarthritis Assessment criteria). Proportion of placebo-related benefit at week 16 (for EMA) or week 52 (for FDA) The objective of this study is to demonstrate the superiority of cukinumab 150 mg SC. Secondary objectives are to demonstrate the superiority of cukinumab 150 mg SC at 16 weeks and 5 weeks. The efficacy of secukinumab 150 mg SC at week 2 was greater than placebo based on: Demonstration of excellence includes: proportion of patients meeting ASAS5 / 6 response criteria, total Ba Change from baseline in the Ankylosing Spondylitis Disease Activity Index (BASDAI), BASD The proportion of subjects achieving AI50, the Short Form 36 Physical Profile Summary (SF-36 P Change from baseline in CS), proportion of subjects achieving ASAS20 response, total Bat h Change from baseline in Ankylosing Spondylitis Functional Index (BASFI), SI joint on MRI Change from screening edema, proportion of patients achieving ASAS partial remission, ankylosing spine Inflammatory Disease Activity Score (ASDAS) - C-reactive protein defined as ASDAS < 1.3 The proportion of patients achieving protein (CRP) inactive disease and ASAS40 response at 16 weeks Percentage of subjects achieving

[0172] Example 5.2: Study Design Study H2315 is a randomized, double-blind, placebo-controlled trial. Approximately 555 patients will be enrolled. One of the three treatment arms (secukinumab 150 mg using a 1:1:1 ratio SC loading; Patients will be randomized to receive secukinumab 150 mg without SC loading or placebo. Group 1 (secukinumab 150 mg loading): BSL, weeks 1, 2, and 3, then week 4 Secukinumab 150 mg (1 mL, 150 mg / mL) SC every 4 weeks starting Prefilled syringes (PFS); Group 2 (secukinumab 150 mg unloaded): secukinumab 150 mg (1 mL, 150 mg / mL) SC PFS, placebo at weeks 1, 2, and 3, then Secukinumab 150 mg PFS every 4 weeks starting at week 4; Group 3 (placebo): BSL at weeks 1, 2, and 3, followed by 4 doses starting at week 4 Weekly administration, placebo (1 mL) SC PFS

[0173] NSAIDs and DM based on clinical judgment of disease activity by the investigator and patient Basic medications such as ARDs are not effective in treating the signs and symptoms of non-rxSpA after 16 weeks. In addition, investigator and patient assessment of disease activity may be performed. Repeatedly (e.g., on two or more consecutive visits) inappropriate treatment based on the clinical judgment of the Patients deemed to be adequate responders will receive secukinumab as standard of care from week 20 onwards. Patients can receive 150 mg sc or other biologics. The objective signs of inflammation to which the patient belongs (based on the patient's CRP and MRI status at the time of screening) Stratification at randomization according to subgroups. The only condition enrolled is 15% of patients. These are the three subgroups of objective signs of inflammation: CRP+ and MRI+, CRP+ and and should belong to one of the following categories: MRI-, CRP-, and MRI+.

[0174] Additionally, it is planned to enroll approximately 30% or less of patients with TNF-IR in the study. Patients receiving blinded study treatment (secukinumab 150mg / mL) during the first 52 weeks of the study were randomly assigned to receive the treatment starting with the first 52 weeks of the study. All patients were randomly assigned to the study in an open-label setting, except for those who discontinued the study (i.e., placebo or steroid). Patients will be assigned to receive numab 150 mg sc.

[0175] The initial randomized treatment assignment (secukinumab 150 mg or placebo) was All patients will remain blinded until they have completed the 52-week visit. After completing treatment period 2 (week 52) and database lock at week 52, The investigator and patient may be unblinded to the original randomized treatment assignment at baseline. All patients will remain on open-label treatment until week 100 unless they discontinue study treatment. Patients will continue to receive secukinumab as treatment.

[0176] Follow-up visits will determine whether patients complete the entire study as planned or discontinue early. For all patients, regardless of age, the study will be conducted 12 weeks after the last dose of study treatment. .

[0177] Subjects who complete the 2-year study may be eligible to participate in a planned extension study. The dosing regimen in this study was the same as that in two Phase III studies in AS (CAIN457F 2305, CAIN457F2310). CAIN457F2305 and CAIN457F2310 are available in 75mg and 150mg doses. g Both SC maintenance doses and intravenous doses (CAIN457F2305: BSL, weeks 2 and 4) administered every 2 weeks for three doses of 10 mg / kg IV) or subcutaneously (CAIN457 F2310: BSL, 75 mg or 150 mg SC administered at weeks 1, 2, and 3 To evaluate the efficacy of a loading regimen consisting of four weekly SC doses coincident with maintenance doses of cefotaxime. The primary endpoint of the 16-week 150 mg dose in each of these studies was Considering the similarity of the ASAS20 and ASAS40 response rates, respectively, it is recommended that the loading dose be administered IV ( CAIN457F2305: 60.8% vs. 60.8% for ASAS20 IV at 150 mg 28.7% with sebo and 41.6% with IV-150 mg ASAS40 vs. placebo 13.1%) or SC (CAIN457F2310:ASAS20 150 mg 61.1% with SC vs. 27.0% with placebo and 150 mg with ASAS40 36.1% vs. 10.8% with placebo) for 150 mg SC. , a dose sufficient to produce clinically and statistically significant efficacy, but at a higher dose Numab exposure does not appear to result in greater efficacy in AS.

[0178] Evaluate a 150mg SC loading and maintenance regimen for efficacy compared with placebo In addition, this study also demonstrated the therapeutic approach of 150 mg maintenance dose without SC loading regimen. By including this regimen, we will also evaluate the impact of the SC loading regimen itself on efficacy. Therefore, the loading regimen (150 mg loading) was administered over 4 weeks (BSL, weeks 1, 2, and 3). 150 mg once weekly initially, followed by every 4 weeks at the same dose starting in week 4 The unloading regimen was evaluated every 4 weeks from the previous BSL. The 150 mg dose was evaluated during the loading phase to mask the two active treatment regimens. To conceal the placebo treatment compared to both active treatment arms, Both secukinumab regimens were compared with a placebo arm in which administration mimicked the loading regimen. do.

[0179] Example 5.3: Inclusion and Exclusion Criteria Patients eligible for inclusion into the study must meet all of the following criteria: 1. The patient understands and is able to communicate with the investigator and comply with the requirements of this study. written, signed and dated information must be provided before the test evaluation is conducted. Informed consent must be provided. 2. Male or non-pregnant, non-lactating female patient at least 18 years of age 3. Diagnosis of axSpA according to the following ASAS axSpA criteria: Inflammatory back pain for at least 6 months; b. Onset before age 45; and c. Sacroiliitis on MRI with ≥ 1 SpA feature or ≥ 2 SpA features HLA-B-27 positive with symptoms 4. Objective signs of inflammation at screening, evidenced by: MRI of sacroiliac joint inflammation; and / or ·hsCRP>ULN (defined by central laboratory); 5. Total BASDAI ≥ 4cm (0-10cm) at baseline , active axSpA 6. BASDAI Question #2 ≥ 4 cm (0-10 cm) at baseline Spinal pain 7. Total back pain measured by VAS ≥ 40mm (0-100mm) at baseline pain 8. Inadequate or no response, or worse, intolerance, toxicity or if therapy had to be discontinued due to contraindications, patients were At least two different NSAIDs at the highest recommended doses for a total of at least 4 weeks should be receiving 9. Patient is taking an NSAID (COX-1 or COX-2 inhibitor) as part of their axSpA therapy. Patients taking a regular dose of any of the following drugs (including steroids) must have been on a stable dose for at least 2 weeks prior to randomization. are required to receive 10. Patients who have received TNFα inhibitors (≥1) must have received at least one TNFα inhibitor for at least 2 weeks prior to randomization. Patients with an inadequate response to previous or current therapy administered at approved doses for 3 months must have experienced or been intolerant to at least one dose of an anti-TNFα drug. Ta 11. Patients who have previously received a TNFα inhibitor must have received the appropriate washout period prior to randomization. Allowed to participate in the study after the out-of-period 12. Taking MTX (≤25 mg / week) or sulfasalazine (≤3 g / day) Patients were allowed to continue their medications and had to take them for at least 3 months. Patients must be on a stable dose for at least 4 weeks prior to randomization. 13. Patients receiving MTX must be on stable folic acid supplementation prior to randomization. must 14. Patients receiving DMARDs other than MTX or sulfasalazine should not take this medicine. Must be discontinued 8 weeks prior to randomization unless a tyramine washout is performed DMARDs must be discontinued for 4 weeks prior to randomization, with the exception of leflunomide. Not 15. Patients taking systemic corticosteroids for at least 2 weeks prior to randomization Must be receiving a stable dose of prednisone or equivalent at ≤10 mg / day for

[0180] Patients who meet any of the following exclusion criteria are not eligible to participate in this study: To ensure that the panel represents all eligible patients, further exclusions were not made by the investigator. Therefore, it cannot be applied. 1. Bilateral grade ≥ 2 or unilateral grade ≥ 3 (corrected AS) assessed by a central reader Radiographic evidence of sacroiliitis (radiological criteria according to the New York criteria) Patients 2. Unable or unwilling to undergo MRI (e.g., pacemaker, aneurysm clip) (patients with MRI-incompatible skin or body) 3. Ongoing inflammatory bowel disease, assessed by a qualified physician within 3 months of screening Chest x-ray or MRI with evidence of infection or malignant process 4. Taking high-potency opioid analgesics (e.g., methadone, hydromorphone, morphine) Patients using 5. Secukinumab or other drugs that directly target IL-17 or the IL-17 receptor Prior exposure to biologic agents 6. Treatment within 4 weeks of randomization or 5 half-lives of the investigational drug, whichever is longer. Use of investigational drug and / or device 7. History of hypersensitivity to the study drug or its excipients or drugs of a similar chemical class 8. Therapy with intra-articular injections (e.g., corticosteroids) within 4 weeks prior to randomization 9. Intramuscular corticosteroid injections within 2 weeks prior to randomization 10. Previous treatment with a biological immunomodulator, except those targeting TNFα Patients 11.Patients who have taken multiple anti-TNFα drugs 12. Anti-CD20 or investigational drugs (e.g., CAMPATH, anti-CD4, anti-CD5, anti-CD 3. Prior treatment with cell-depleting therapy, including but not limited to anti-CD19 13. Pregnant or lactating (breast-feeding) women, where pregnancy is defined as a positive human chorionic gonadotropin (HCG) test. (hCG) Defined as the state of a woman after conception and until the end of pregnancy, confirmed by a laboratory test can 14. Women should be monitored for the entire study period or more if required by locally approved prescribing information. unless you have been using an effective method of contraception for a longer period (e.g., 20 weeks in the EU) Women of childbearing potential, defined as any woman who is physiologically capable of becoming pregnant 15. Any condition that may confound the assessment of the benefit of secukinumab therapy, including inflammatory bowel disease or uveitis. Active, progressive inflammatory diseases other than axSpA 16. Any condition that, in the opinion of the investigator, renders the patient immunocompromised and / or predisposes the patient to immunomodulatory therapy puts the patient at unacceptable risk of metabolic, hematological, renal, hepatic, pulmonary, neurological, or endocrine disorders Urinary, cardiac, infectious or gastrointestinal conditions 17. Any serious medical problem or illness, including but not limited to: Unknown hypertension (≥160 / 95 mmHg), congestive heart failure (Class III or IV) New York Heart Association status, uncontrolled diabetes or inability to care for oneself Possible very poor functioning state 18.SGOT (AST), SGPT (ALT), alkaline phosphatase or serum vitamin D History of clinically significant liver disease or liver injury as evidenced by abnormal liver function tests such as lirubin Investigators should be guided by the following criteria: No single parameter should exceed 2 × upper limit of normal (ULN). Up to 2 × ULN Any increase in a single parameter, including If necessary, rule out laboratory errors at least prior to enrollment / randomization. If the total bilirubin concentration rises above 2×ULN, direct and indirect reactions of total bilirubin It should be differentiated from responsive bilirubin. 19. Patients with a history of renal trauma, glomerulonephritis, or only one kidney, or a blood glucose level of 1.5 mg / dL Serum creatinine levels above (132.6 μmol / L) 20. Screening total WBC count <3,000 / μL or platelets <100,000 / μL L or neutrophils 1,500 / μL or hemoglobin <8.5g / dL (85g / L) 21. Active systemic infection in the last 2 weeks before randomization (exclusion: common cold) 22. Progressive, chronic or recurrent infections or positive purified protein derivative (PPD) skin Skin examination (induration size was measured 48-72 hours later; a positive result was defined as an induration of ≥ 5 mm or (or as defined according to local practice / guidelines) or positive QuantiFERON Evidence of tuberculosis infection as defined by the TB-Gold test. Patients with a positive test should also Further workup (according to local practice / guidelines) confirms that the patient has no evidence of active TB. If the presence of latent tuberculosis is conclusively established, the patient may participate in the study. If so, treatment had to be initiated according to local national guidelines. 23. Human immunodeficiency virus (HIV), hepatitis B, or is a known infection with hepatitis C 24. History of lymphoproliferative disorders or known malignant tumors or malignancies of any organ system within the past 5 years History of cancer (treated basal cell carcinoma or actinic keratosis without evidence of recurrence in the past 3 months) , excluding removed cervical intraepithelial neoplasia or non-invasive malignant colon polyps) 25. Current severe progressive or uncontrolled disease that, in the judgment of the clinical investigator, makes the patient unsuitable for the study. Unrecognized diseases 26. Inability or unwillingness to undergo repeated venipuncture (e.g., lack of venous access) (due to lack of adequate tolerance) 27. Unable or unwilling to receive PFS injections 28. In the opinion of the investigator, the participant's compliance with the protocol or Any medical or psychiatric condition that would preclude completing the study according to the rules. 29. Donation or loss of 400 mL or more of blood within 8 weeks prior to administration 30. History of ongoing alcohol or drug abuse within the last 6 months prior to randomization or evidence 31. Planned administration of live vaccines during the study period or in the 6 weeks prior to randomization

[0181] Example 5.4: Treatment Arms Patients will be divided into two treatment arms, with approximately 185 subjects in each arm: are assigned to one of the following in a 1:1:1 ratio. Group 1: Secukinumab 150 mg loading Group 2: Secukinumab 150 mg unloaded Group 3: Placebo

[0182] Subjects received study treatment at BSL, weeks 1, 2, 3, and 4, and then four-week intervals until week 100. Treatment may be repeated after 20 weeks based on clinical judgment of disease activity (e.g., Patients who are considered poor responders (e.g., on two or more consecutive visits) should be considered for sex. Patients can receive numab 150 mg SC or standard of care treatment. If it is a TNFα inhibitor, a 12-week washout period must be observed. .

[0183] After database lock at week 52, patients will be switched from placebo unless they discontinue study treatment. All patients received secukinumab 150 mg without a loading regimen. Patients will receive SC in an open-label fashion. Blinding of the initial treatment assignment will be completed in treatment period 2. The study will be maintained until the evaluation is completed by all patients (week 52). All secukinumab and placebo administrations at study site or at home according to schedule shall be self-managed.

[0184] Example 5.5: Efficacy Measurement · International Society for Spondyloarthritis Assessment (ASAS) criteria Patient Global Assessment of Disease Activity (VAS) Patient assessment of back pain intensity (total back pain and nighttime back pain) (VAS) ·Bath Ankylosing Spondylitis Functional Index (BASFI) ·Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Spinal mobility assessed by the Bath Ankylosing Spondylitis Measurement Index (BASMI) Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) and Extended Enthesitis hsCRP and ESR ASDAS-ESR, ASDAS-CRP and ASDAS Response Categories 44-Tender and swollen joint count EQ-5D ASQoL ·WPAI-GH SF-36 (PCS and MCS) FACIT - Fatigue MRI of the spine and sacroiliac joints - Cervical, thoracic and lumbar spinal pain assessed by the modified Stoke's Ankylosing Spondylitis Spine Score (mSASSS) X-ray of the lumbar spine Sacroiliac joint x-ray

[0185] Each subject underwent an MRI of the sagittal spine (cervical, thoracic, and lumbar) and oblique coronal view of the pelvis, including both sacroiliac joints. X-ray requirements include T1 and STIR sequences for mSASSS scoring. Lateral view of the cervical and thoracic-lumbar spine (from the lower 1 / 3 of C2 to the upper 1 / 3 of T1, both ends included) An anteroposterior view of the pelvis including visibility of both sacroiliac joints for the modified New York criteria for determining AS was performed. include.

Claims

1. administering an IL-17 antibody or antigen-binding fragment thereof to a patient in need thereof. A method of treating a patient with x-ray negative axial spondyloarthritis (nr-axSpA), the IL-17 antibody or antigen-binding fragment thereof has two mature IL-17 protein chains. and the epitope of the IL-17 homodimer is located at Leu7 on one chain. 4, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 and Tyr43 on the other chain, Tyr44, Arg46, Ala79, Asp80, The antigen-binding fragment has a K of about 100-200 pM Ｄ the IL-17 antibody or its antigen binding agent, The method wherein the combined fragment has an in vivo half-life of about 4 weeks.

2. administering an IL-17 antibody or antigen-binding fragment thereof to a patient in need thereof.

2. A method for inhibiting the progression of structural damage in a patient with nr-axSpA, comprising administering to said patient a The IL-17 antibody or antigen-binding fragment thereof has two mature IL-17 protein chains. binds to an epitope on the L-17 homodimer, said epitope being Leu74 on one chain, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pr o126, Ile127, Val128, His129 and Tyr43, Ty on the other chain r44, Arg46, Ala79, Asp80, Binding fragment K of approximately 100-200 pM Ｄ the IL-17 antibody or antigen-binding fragment thereof, The method wherein the strips have an in vivo half-life of about 4 weeks.

3. 3. The method of claim 1 or 2, wherein the patient has moderate to severe nr-axSpA. 。

4. The method of any one of claims 1 to 3, wherein the patient has severe nr-axSpA. 。

5. The method of any one of claims 1 to 4, wherein the patient has active nr-axSpA. 。

6. The patient was assessed by a baseline total BASDAI of ≥ 4 cm (0-10 cm). Active nr-axSpA, BASDAI Question 2 ≥ 4 cm at baseline Spinal pain measured by a scintigraphy (0-10 cm) and a VAS ≥ 40 m at baseline 6. The method of claim 5, wherein the patient has total back pain measured by sciatica (sciatica) or sciatica (sciatica) in mm (0-100 mm).

7. 1 to 3, wherein the patient has nr-axSpA according to the ASAS axSpA criteria.

7. The method according to any one of claims 6 to 6.

8. a) prior to treatment with the IL-17 antibody or antigen-binding fragment thereof, the patient receives at least have had inflammatory back pain for at least 3 months, preferably at least 6 months, b) the onset of the inflammatory back pain in a) occurred before the patient was 45 years of age, and c) the patient has MRI evidence of sacroiliac joint (SIJ) inflammation and at least one SpA or the patient is HLA-B27 positive and has at least two SpA characteristics. have the characteristics The method of claim 7.

9. The patient has elevated C-reactive protein (CRP) and / or SIJ inflammation on magnetic resonance imaging.

9. Any of claims 1 to 8, having objective signs of inflammation as shown by MRI evidence. The method described below.

10. The patient had MRI evidence of SIJ inflammation as determined according to the Berlin SIJ scoring system.

10. The method of claim 1, wherein the patient has objective signs of inflammation as indicated by:

11. 10. The method of claim 1, wherein the patient has objective signs of inflammation as indicated by MRI evidence of inflammation of the spine.

11. The method according to any one of 1 to 10.

12. The patient has active nonr-axSpA as assessed by a total BASDAI of ≥ 4 cm. The method according to claim 5 .

13. The patient met the radiological criteria according to the modified New York diagnostic criteria for ankylosing spondylitis.

13. The method of claim 1, wherein the method does not

14. The patient has previously failed to respond to treatment with nonsteroidal anti-inflammatory drugs (NSAIDs).

14. The method of any one of claims 1 to 13, wherein the patient had an inadequate or insufficient response.

15. the patient has previously failed to respond or has responded inadequately to treatment with a TNF alpha inhibitor; The method of any one of claims 1 to 14, wherein the patient had a TNF-IR response.

16. The patient had not previously been treated with a TNF alpha inhibitor (i.e., had not received TNF medication).

16. The method of claim 1, wherein the method has not been performed.

17. Cyclosporine, hydroxychloroquine, methotrexate, NSAIDs, sulfasalazine Patients receiving fluprednisolone, leflunomide, prednisolone, prodnisone, or methylprednisolone 17. The method of any of claims 1 to 16, further comprising administering to:

18. About 75 mg to about 300 mg of an IL-17 antibody or antigen-binding fragment thereof is administered in 0, 1, 2, and 3 doses. The drug is administered to patients by subcutaneous injection on week 1 of each month, followed by monthly administration starting on week 4.

18. The method of any one of claims 1 to 17.

19. 150 mg of IL-17 antibody or its antigen-binding fragment was administered subcutaneously at weeks 0, 1, 2, and 3. and then monthly thereafter starting at week 4. The method described below.

20. Approximately 75 mg to approximately 300 mg of an IL-17 antibody or an antigen-binding fragment thereof is administered to the patient by subcutaneous injection.

18. The method of any of claims 1 to 17, comprising administering the method to a subject once a month.

21. Approximately 150 mg of the IL-17 antibody or its antigen-binding fragment is administered to the patient by subcutaneous injection once a month.

22. The method of claim 21, comprising administering

22. The IL-17 antibody or antigen-binding fragment thereof is i) an immunoglobulin heavy chain variable domain comprising the amino acid sequence shown as SEQ ID NO: 8 (V) Ｈ ) ii) an immunoglobulin light chain variable domain comprising the amino acid sequence shown as SEQ ID NO: 10; In (V Ｌ ), iii) Immunoglobulin V comprising the amino acid sequence shown as SEQ ID NO: 8 Ｈ domain and immunoglobulin V comprising the amino acid sequence shown as SEQ ID NO: 10 Ｌ domain, iv) an immunoglobulin comprising the hypervariable regions shown as SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3; Globulin V Ｈ domain, v) an immunoglobulin comprising the hypervariable regions shown as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6; Roblin V Ｌ domain, vi) comprising the hypervariable regions set forth as SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:13; Immunoglobulin V Ｈ domain, vii) an immunogen comprising the hypervariable regions shown as SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3; Epidemic globulin V Ｈ The domains are shown as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:

6. Immunoglobulin V containing hypervariable regions Ｌ domain, viii) hypervariable regions shown as SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 Immunoglobulin V containing Ｈ domain and SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 Immunoglobulin V containing the hypervariable region shown Ｌ domain, ix) an immunoglobulin light chain comprising the amino acid sequence set forth as SEQ ID NO: 14; x) an immunoglobulin heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 15; or xi) an immunoglobulin light chain comprising the amino acid sequence shown as SEQ ID NO: 14 and the sequence An immunoglobulin heavy chain comprising the amino acid sequence shown as number 15.

22. The method of any preceding claim, comprising:

23. 23. The method of claim 22, wherein the IL-17 antibody or antigen-binding fragment thereof is secukinumab. 。

24. Approximately 150 mg of secukinumab is administered to the patient by subcutaneous injection at weeks 0, 1, 2, and 3; Thereafter, radiographic evidence of ankylosing spondylitis, including monthly dosing starting at week 4. severe, without inflammatory bowel disease but with objective signs of inflammation as shown by CRP and / or MRI A method of treating a patient with active axial spondyloarthritis (axSpA).

25. Approximately 150 mg of secukinumab is administered to the patient by subcutaneous injection at weeks 0, 1, 2, and 3; Thereafter, starting at week 4, monthly dosing will be administered. Patients with objective signs of inflammation as indicated by steroid therapy and who have had an inadequate response to NSAID treatment. Also, a method of treating patients with severe axSpA.

26. Approximately 150 mg of secukinumab is administered to the patient by subcutaneous injection at weeks 0, 1, 2, and 3; Thereafter, patients without radiographic evidence of AS should receive monthly starting at week 4. However, patients with elevated CRP and / or objective signs of inflammation by MRI who are not on NSAID treatment Patients with severe axSpA who have had an inadequate response to or are intolerant to How to treat.

27. Approximately 150 mg of secukinumab is administered to the patient by subcutaneous injection at weeks 0, 1, 2, and 3; Thereafter, patients without radiographic evidence of AS should receive monthly starting at week 4. However, patients with elevated CRP and / or objective signs of inflammation by MRI and who are not TNF-alpha inhibitors severe pulmonary embolism that has previously failed to respond or had an inadequate response to treatment with harmful drugs A method of treating a patient with axSpA.

28. Approximately 150 mg of secukinumab is administered to the patient by subcutaneous injection at weeks 0, 1, 2, and 3; Thereafter, patients without radiographic evidence of AS should receive monthly starting at week 4. However, patients with objective signs of inflammation by elevated CRP and / or MRI and who are not receiving TNF-alpha To treat patients with severe axSpA who have not previously received treatment with an antagonist. How to do it.

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