Methods of treating new-onset plaque type psoriasis using il-17 antagonists

Abstract

To provide a patient-centered therapeutic approach, undertaken early in the psoriasis treatment pathway (early intervention) with the goal of complete clearance, which may improve control of cutaneous symptoms and modify the course of the disease and the associated burden.SOLUTION: The present disclosure provides methods for treating new-onset plaque-type psoriasis patients and inhibiting the progression of structural damage in these patients using IL-17 antagonists, such as secukinumab.SELECTED DRAWING: None

Description

Technical Field

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 62 / 346,007, filed on July 19, 2016 (which is hereby incorporated by reference in its entirety).

[0002] The present disclosure relates to a method for treating patients with plaque psoriasis using an IL-17 antagonist, such as secukinumab, and inhibiting the progression of psoriasis disease in these patients .

Background Art

[0003] Psoriasis is an immune-mediated inflammatory disease that can have a significant impact on a patient's life, especially in moderate or severe cases. Treatment of psoriasis over the first few years is typically conservative and often based on topical agents that rarely completely eliminate the lesions. Treatment with systemic agents, including biologics, is often only initiated when topical agents, phototherapy, and conventional systemic treatments have been found to be inadequate in patients with moderate to severe disease. (M aza et al (2012) Br J Dermatol; 167(3): 643- 8.).

[0004] Psoriasis skin lesions are a "multifaceted" disorder characterized by dense inflammatory cell infiltration, hyperproliferation, epidermal differentiation defects, neovascularization, and lymphatic system structural changes. With effective treatment of chronic psoriasis, there is resolution of epidermal thickness, reduction in the number of inflammatory cells, and recovery from previously affected skin to a clinically normal state. However, when treatment is interrupted, psoriasis skin lesions tend to recur at the same sites as previously affected, but sometimes also appear at new sites.

Summary of the Invention

Problems to be Solved by the Invention

[0005] Therefore, there is a need for a patient-centered treatment (early intervention) at an early stage of the psoriasis treatment pathway aimed at complete elimination, which can improve the management of skin symptoms and modify the disease course and related burden. necessity exists.

Means for Solving the Problems

[0006] After effective treatment of chronic psoriasis, subclinical inflammation may persist in the psoriatic skin, and the clinical condition may occur, for example, during or after the "drug holiday" when treatment is discontinued. A possible explanation for this phenomenon can be found in the identification of a subset of T cells called tissue-resident memory T cells (Trm), which have been shown to contribute to tissue-localized immune memory against viral infections of the skin (e.g., herpes simplex virus infection). This T cell subtype may be a key player in causing the chronicity of immune-mediated inflammatory disorders or autoimmune disorders. (Clark , R. (2015) Sci Transl Med; 7(269):269rv1).

[0007] In newly published research, Trm cells remaining in the skin after lesion clearance during treatment with biological therapies have been identified in the lesional skin of psoriasis patients (Cheuk et al (2014 ) J Immunol; 192(7):3111-20). The presence of such cells in the skin can explain the chronicity of the disease and the recurrence at the same anatomical location. Cheuk et al (2014) also showed that Trm cells in psoriatic plaques produce interleukin (IL)-17A and IL-22 upon activation. From this, it follows that The view that Th17 cells, which have IL-17A as a major effector cytokine, are the Tr m cells in psoriasis is supported. In addition to the direct pathogenic effect of IL-17A from T cells on keratinocytes, IL-17A is also released by granulocytes and mast cells and plays an important role in early attracting more immune cells to the target organ. Therefore, early inhibition of IL-17A after disease onset is a novel and important therapy that interferes with the immune system before the establishment of extensive chronic inflammation. This would be achieved by early blocking the recruitment of inflammatory cells, including Th17, to the skin and further blocking the major effector function of Trm cells.

[0008] Secukinumab is the first IL-17A inhibitor approved for the treatment of psoriasis in patients who require systemic therapy. Early treatment of psoriasis patients with IL-17 antagonists such as secukinumab is expected to block the recruitment of inflammatory cells and antagonize the action of IL-17A produced by T cell subsets in patients with newly diagnosed moderate to severe psoriasis. The expected clinical outcome is to change the natural course of the disease to a milder state by interfering with the spread of psoriasis (Trm cells) to new anatomical locations or ultimately completely preventing the recurrence of new lesions, that is, by minimizing or completely suppressing the induction of disease activity.

[0009] Therefore, disclosed herein is a method of treating a patient having de novo plaque psoriasis, comprising administering a therapeutically effective amount of an IL-17 antagonist to a patient in need thereof. ​​​​​​​​​​​​​​

[0010] In addition, the present invention provides an IL-17 antibody or antigen-binding fragment thereof, The present invention relates to a method for treating psoriasis, comprising administering to a patient in need thereof ... Methods for reducing the number of memory T cells and IL-1 in the skin of patients with newly diagnosed plaque-type psoriasis Reduce the number of effector T cell subsets that produce IL-17 and / or IL-22 and a method for reducing the number of regulatory T cells in the skin of patients with incipient plaque-type psoriasis - Patents.com , and reduced the number of dermal dendritic cell-T cell aggregates in the skin of patients with early plaque-type psoriasis. and a method for reducing the immune system responsible for chronicity of psoriatic skin disease in patients with primary plaque-type psoriasis. Methods for modulating immune mechanisms and psoriasis disease progression in patients with primary plaque-type psoriasis Methods for delaying and reducing the severity of psoriasis flares in patients with primary plaque-type psoriasis and a method for reducing the frequency of psoriasis flares in patients with primary plaque-type psoriasis - Patents.com and / or methods of preventing psoriasis flares in patients with incipient plaque-type psoriasis and IL-17 antagonists for use in so doing.

[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. And in some embodiments of the kit, the IL-17 antibody or antigen-binding fragment thereof a) Leu74, Tyr85, His86, Met87, Asn88, Val12 4. His containing Thr125, Pro126, Ile127, Val128, and His129 an IL-17 antibody or an antigen-binding fragment thereof that binds to an epitope of IL-17; b) Human IL-1 containing Tyr43, Tyr44, Arg46, Ala79, and Asp80 7, or an antigen-binding fragment thereof; c) an IL-17 antibody or an antigen-binding fragment thereof that binds to an epitope of Binds to an epitope on the IL-17 homodimer that contains the mature human IL-17 protein chain. an IL-17 antibody or antigen-binding fragment thereof, wherein the epitope is The chain contains Leu74, Tyr85, His86, Met87, Asn88, Val124, and T hr125, Pro126, Ile127, Val128, His129, and the other strand containing Tyr43, Tyr44, Arg46, Ala79, and Asp80; d) two Binds to an epitope on the IL-17 homodimer that contains the mature human IL-17 protein chain. an IL-17 antibody or antigen-binding fragment thereof, wherein the epitope is The chain contains Leu74, Tyr85, His86, Met87, Asn88, Val124, and T hr125, Pro126, Ile127, Val128, His129, and the other strand Contains Tyr43, Tyr44, Arg46, Ala79, and Asp80, and is an IL-17 antibody. The antibody or antigen-binding fragment thereof has a K of about 100-200 pM. D With The IL-17 antibody or antigen-binding fragment thereof has an in vivo half-life of about 23 to about 35 days. and e) an immunoglobulin comprising the amino acid sequence shown as SEQ ID NO:8. Heavy chain variable domain (V H ii) an immunogen comprising the amino acid sequence shown as SEQ ID NO:10; Immunoglobulin light chain variable domain (V L iii) the amino acid sequence shown as SEQ ID NO:8 Immunoglobulin V containing columns H The domain and the amino acid sequence shown as SEQ ID NO: 10 Immunoglobulin V containing L domain, iv) Immunoglobulin V containing the hypervariable regions shown as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 domain, v) Immunoglobulin V containing the hypervariable regions shown as SEQ ID NO: 4, SEQ ID NO: 5 H and SEQ ID NO: 6 domain, vi) Immunoglobulin V containing the hypervariable regions shown as SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13 L domain, vii) Immunoglobulin V containing the hypervariable regions shown as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 domain, and Immunoglobulin V containing the hypervariable regions shown as SEQ ID NO: 4, SEQ ID NO: 5 H and SEQ ID NO: 6 domain, viii) H Immunoglobulin V containing the hypervariable regions shown as SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13 domain, and Immunoglobulin V containing the hypervariable regions shown as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 L domain, ix) Immunoglobulin light chain containing the amino acid sequence shown as SEQ ID NO: 14, x) Immunoglobulin heavy chain containing the amino acid sequence shown as SEQ ID NO: 15, or xi) Immunoglobulin light chain containing the amino acid sequence shown as SEQ ID NO: 14 and Immunoglobulin heavy chain containing the amino acid sequence shown as SEQ ID NO: 15, comprising an IL-17 antibody or an antigen-binding fragment thereof, selected from the group consisting of In some embodiments of the disclosed uses, methods, and kits, the IL-17 antibody or H its antigen-binding fragment is a human antibody or a humanized antibody. In some embodiments of the disclosed uses, methods, and kits, the IL-17 antibody or its antigen-binding fragment is selected from the group consisting of L domain, ix) Immunoglobulin light chain containing the amino acid sequence shown as SEQ ID NO: 14, x) Immunoglobulin heavy chain containing the amino acid sequence shown as SEQ ID NO: 15, or xi) Immunoglobulin light chain containing the amino acid sequence shown as SEQ ID NO: 14 and Immunoglobulin heavy chain containing the amino acid sequence shown as SEQ ID NO: 15, comprising an IL-17 antibody or an antigen-binding fragment thereof, selected from the group consisting of In some embodiments of the disclosed uses, methods, and kits, the IL-17 antibody or its antigen-binding fragment is selected from the group consisting of In some embodiments of the disclosed uses, methods, and kits, the IL-17 antibody or its antigen-binding fragment is selected from the group consisting of In some embodiments of the disclosed uses, methods, and kits, the IL-17 antibody or its antigen-binding fragment is selected from the group consisting of The agent is secukinumab.

Brief Description of the Drawings

[0012]

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Modes for Carrying Out the Invention

[0013] As used herein, IL-17 means interleukin 17A (IL-17A). means.

[0014] The term "comprising" includes "including" and "consisting of". For example, X A composition "comprising" X can consist exclusively of X or can include something additional (e.g., X + Y).

[0015] The term "about" associated with a numerical value x means, for example, ±10%. When used before a numerical range or a list of numerical values, the term "about" is applied sequentially to each numerical value. For example, the phrase "about 1 - 5" should be interpreted as "about 1 - 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." .

[0016] The word "substantially" does not necessarily exclude "completely". For example, a composition that is "substantially free" of Y can be completely free of Y. If desired, the word "substantially" can be omitted from the definitions of the present disclosure.

[0017] The term "antibody" as referred to herein includes all naturally occurring antibodies. Naturally occurring "antibodies" are glycoproteins comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain is composed of a heavy chain variable region (abbreviated as V H herein) and a heavy chain constant region. The heavy chain constant region is composed of three domains, namely CH1, CH2, and CH3. Each light chain is composed of a light chain variable region (abbreviated as V L herein) and a light chain constant region. The light chain constant region is composed of one domain, CL. The regions of V H and V L are referred to as framework regions (FR) is more conserved than the intervening hypervariable region or complementarity-determining region (CDR). The hypervariable region is further divisible. Each V H and V L consists of three CDRs and four FRs, namely FR1, CDR 1, FR2, CDR2, FR3, CDR3, FR4, arranged in the following order from the amino terminus to the carboxyl terminus. The variable regions of the heavy and light chains contain the binding domain that interacts with the antigen. The constant region of the antibody can mediate the binding of the immunoglobulin to various cells of the immune system (e.g., effector cells) and host tissues or factors including the first component (C1q) of the classical complement system and the like. Exemplary antibodies include secukinumab (Table 1), antibody XAB4 (U.S. Patent No. 9,193,788), and ixekizumab (U.S. Patent No. 7,838,638), the disclosures of which are incorporated herein by reference in their entirety ).

[0018] As used herein, the term "antigen-binding fragment" of an antibody means an antibody fragment that retains the ability to specifically bind to an antigen (e.g., , IL-17). It has been shown that the antigen-binding function of an antibody can be exerted by a fragment of the full-length antibody. Examples of binding fragments included within the term "antigen-binding portion" of an antibody include Fab fragments , monovalent fragments consisting of V , V , CL and CH1 domains, divalent fragments containing two Fab fragments linked by disulfide bridges in the hinge region L , V H , the F(ab)2 fragment, Fd fragments consisting of V domains and CH1 domains, and V of a single arm of the antibody , V H domains and CH1 domains, and V of a single arm of the antibody domains and CH1 domains, and V of a single arm of the antibody L ​Domain and V H Fv fragment consisting of the domain , V H dAb fragment consisting of the domain (Ward et al., 1989 Na ture 341:544 - 546) as well as isolated CDRs. Exemplary antigen - binding fragments include the CDRs of secukinumab shown in SEQ ID NOs: 1 - 6 and 11 - 13 (Table 1), preferably the heavy - chain CDR3. Furthermore, the two domains V of the Fv fragment are encoded by separate genes, but they can be linked by recombinant methods using a synthetic linker such that the V L and V H regions pair to form a single - chain protein molecule that forms a monovalent molecule (known as single - chain Fv (scFv L ). For example, see Bird et al., 1988 Science H 242:423 - 426 and Huston et al., 1988 Proc. Na tl. Acad. Sci. 85:5879 - 5883). Such single - chain anti bodies are also intended to be encompassed by the term "antibody". Single - chain antibodies and antigen - binding portions can be obtained using conventional techniques known to those skilled in the art. The term "isolated antibody" as used herein means an antibody that is substantially free of other antibodies having different antigen specificities (e.g., an isolated antibody that specifically binds to IL - 17 is substantially free of antibodies that specifically bind to antigens other than IL - 17). The term "monoclonal antibody" or "monoclonal antibody composition" as used herein is obtained using conventional techniques known to those skilled in the art.

[0019] ​​​​​The term refers to a preparation of antibody molecules of single-molecule composition. As used herein, "human antibody" is intended to include antibodies having a variable region in which both the framework region and the CDR region are derived from sequences of human origin . A "human antibody" need not be produced by a human, human tissue or human cells. The human antibodies of the disclosure may contain amino acid residues not encoded by human sequences (e.g., introduced by random or site-specific mutagenesis in vitro, by N-nucleotide addition at junctions in vivo during recombination of antibody genes, or by somatic mutation in vivo). In some embodiments of the disclosed processes and compositions, the IL-17 antibody is a human antibody, an isolated antibody and / or a monoclonal antibody.

[0020] The term "IL-17" refers to IL-17A, previously known as CTLA8, and includes wild-type IL-17 A from various species (e.g., human, mouse and monkey), polymorphic variants of IL-17A and functional equivalents of IL-17A. Functional equivalents of IL-17A according to the disclosure preferably have at least about 65%, 75%, 85%, 95%, 96%, 97%, 9 8%, and even 99% total sequence identity to wild-type IL-17A (e.g., human IL -17A) and substantially retain the ability to induce IL-6 production by human dermal fibroblasts.

[0021] The term "K D " is intended to mean the dissociation rate of a particular antibody-antigen interaction. As used herein, the term "K " is the ratio of Kd to Ka (i.e., Kd / K D ), ​​​​​​It is intended to mean the dissociation constant obtained from (a), and is expressed as molar concentration (M). The K D value of the antibody can be determined using methods well established in the art. The K D preferred method for determining is one using surface plasmon resonance or a biosensor system such as the Biacore( registered trademark) system. In some embodiments the IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab, binds to human IL-17 with a K of about 100-250 pM D .

[0022] The term "affinity" means 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" interact with the antigen at multiple sites via weak non-covalent forces, and the more interactions there are, the stronger the affinity. Standard assays for evaluating the binding affinity of antibodies to various species of IL-17, such as EL ISA, Western blot, RIA, etc. are known in the art. The binding kinetics of the antibody e.g., binding affinity) can also be evaluated by standard assays known in the art, such as Biacor e analysis. For example, antibodies that "inhibit" one or more of these IL-1 7 functionalities (e.g., biochemical, immunochemical, cellular, physiological, biological activities, etc.) determined according to methods known in the art and described herein are understood to be related to a statistically significant decrease in a particular activity compared to what is seen in the absence of the antibody (or when a control antibody with irrelevant specificity is present). Antibodies that inhibit the activity of IL-17 are, for example

[0023] ​​​​​Statistically significant decreases in at least about 10%, at least 50%, 80% or 90% of the measurement parameters are affected, and in certain embodiments of the disclosed methods and compositions, the IL-17 antibodies used can inhibit more than 95%, more than 98% or more than 99% of the functional activity of IL-17.

[0024] As used herein, "IL-6 inhibition" means the ability of an IL-17 antibody or an antigen-binding fragment thereof (e.g., secukinumab) to reduce IL-6 production from primary human dermal fibroblasts. IL-6 production in primary human (dermal) fibroblasts is IL- 17-dependent (Hwang et al., (2004) Arthritis Res Ther; 6: R120-128). Briefly, human dermal fibroblasts are recombined with recombinant IL-17 in the presence of various concentrations of an IL-17-binding molecule having an Fc portion or human IL-17 receptor. For convenience, the chimeric anti-CD25 antibody Simulect (registered trademark) (basiliximab) can be used as a negative control. After 16 hours of stimulation, the supernatant is collected and IL-6 is assayed by ELISA. When tested as described above, i.e., when measuring the inhibitory activity with respect to IL-6 production induced by hu-IL-17 in human dermal fibroblasts, the IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab typically has an IC of about 50 nM or less (e.g., about 0.01 to about 50 nM) with respect to inhibition of IL-6 production (in the presence of 1 nM human IL-17). In some embodiments of the disclosed methods and compositions, the IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab and functional derivatives thereof, are as defined above 50 ​​​​​​​​​​​ It has an IC for inhibiting IL-6 production of about 20 nM or less, more preferably about 10 nM or less, more preferably about 5 nM or less, more preferably about 2 nM or less, more preferably about 1 nM or less. C 50 It has.

[0025] Unless otherwise specified, the term "derivative" is used, for example, for an IL-17 antibody or antigen-binding fragment thereof according to the disclosure of a specific sequence (e.g., a variable domain), such as amino acid sequence variants and covalent modifications (e.g., pegylated forms, de amidated forms, hydroxylated forms, phosphorylated forms, methylated forms, etc.) of secukinumab. It is used to define. "Functional derivative" includes molecules having the same qualitative biological activity as the disclosed IL-17 antibody. Functional derivatives include fragments and peptide analogs of the IL-17 antibodies disclosed herein. Fragments include, for example, regions within the sequence of a polypeptide according to the disclosure of a specific sequence. Functional derivatives of the IL-17 antibodies disclosed herein (e.g., functional derivatives of secukinumab) preferably have at least about 65%, 75%, 8 5%, 95%, 96%, 97%, 98%, and even 99% overall sequence identity to the V and / or V sequences (e.g., the V and / or V sequences of Table 1) of the IL-17 antibodies and antigen-binding fragments thereof disclosed herein, and substantially retain the ability to bind to human IL-17 or, for example, inhibit the IL-6 production of human dermal fibroblasts induced by IL-17. It binds to human IL-17 and / or inhibits the production of IL-6 by human dermal fibroblasts induced by IL-17. H and / or V L sequences (e.g., the V H and / or V L sequences), and substantially retain the ability to bind to human IL-17 or inhibit the IL-6 production of human dermal fibroblasts induced by IL-17. It has an overall sequence identity of at least about 65%, 75%, 8 H 5%, 95%, 96%, 97%, 98%, and even 99% to the V and / or V L domains, and substantially retain the ability to bind to human IL-17 or inhibit the IL-6 production of human dermal fibroblasts induced by IL-17. It binds to human IL-17 and / or inhibits the production of IL-6 by human dermal fibroblasts induced by IL-17. It inhibits.

[0026] The phrase "substantially identical" means that the relevant amino acid or nucleotide sequence (e.g., V H or V L domain) is identical to a particular reference sequence or has non-substantive differences (e.g., due to conservative amino acid substitutions) compared to it. Non-substantive differences include minor amino acid changes, such as one or two substitutions in a 5-amino acid sequence of a specified region (e.g., V or V H domain). In the case of an antibody, the second antibody has the same specificity and at least 50% of its affinity. L Sequences that are substantially identical (e.g., at least about 85% sequence identity) to the sequences disclosed herein are also part of this application. In some embodiments, the sequence identity of a derivative IL-17 antibody ( e.g., a derivative of secukinumab, e.g., a biosimilar antibody of secukinumab) is about 90% or more compared to the disclosed sequence, e.g., 90%, 91%, 92%, 9 3%, 94%, 95%, 96%, 97%, 98%, 99% or may exceed it. "Identity" as compared to a native polypeptide and its functional derivatives is defined herein as the percent of amino acid residues in a candidate sequence that are identical to the residues of the corresponding native polypeptide without considering any conservative substitutions as part of sequence identity, after aligning the sequences and introducing gaps as necessary to achieve the maximum percent identity. Neither N-terminal nor C-terminal extensions or insertions are considered to reduce identity. Methods of alignment and computer programs are well known.

[0027] The percent identity can be determined by standard alignment algorithms, such as the Basic Local Alignment Search Tool (BLAST) described by Altshul et al. ((1990) J. Mol. Biol., 215:403-410), the algorithm of Needleman et al. ((19 70) J. Mol. Biol, 48:444-453) or the algorithm of Meyers et al. ((1988) Comput. Appl. Biosci., 4:11-17). The parameter set can be a Blosum6 2 scoring matrix using a gap penalty of 12, a gap extension penalty of 4 and a frameshift gap penalty of 5. The percent identity between two amino acid sequences or nucleotide sequences can also be determined by the algorithm of E. Meyers and W. Miller incorporated into the ALIGN program (version 2.0) ((1989) CABIO S, 4:11-17) using a PAM120 weighted residue table, a gap length penalty of 12 and a gap penalty of 4.

[0028] "Amino acid" means, for example, all naturally occurring L-α-amino acids and includes D-amino acids as well. The phrase "amino acid sequence variant" means a molecule having some difference in its amino acid sequence as compared to the sequences according to the present disclosure. For example, an amino acid sequence variant of an antibody according to the present disclosure of a specified sequence still has the ability to bind to human IL-17 or inhibits the production of IL- 6 by human dermal fibroblasts induced by IL-17. Amino acid sequence variants include substitution variants (polypeptides according to the present disclosure ​​​​​​​​​​At least one amino acid residue in the polypeptide has been removed and replaced with a different amino acid at the same position ), insertion mutants (where one or more amino acids have been inserted directly adjacent to a particular position amino acid in the polypeptide according to the present disclosure ), and deletion mutants (where one or more amino acids in the polypeptide according to the present disclosure have been removed).

[0029] The term "pharmaceutically acceptable" means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredient.

[0030] The term "administering" in relation to a compound, such as an IL-17 binding molecule or other agent, is used to mean delivery of that compound to a patient by any route.

[0031] As used herein, a "therapeutically effective amount" is an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof), that is effective, upon single-dose administration or multiple-dose administration to a patient (e.g., a human), in treating, preventing, prophylaxis of onset, curing, delaying, reducing the severity, remission of at least one symptom, or prolonging the survival period of the patient beyond what would be expected in the absence of such treatment. When applied to an individual active ingredient administered alone (e.g., an IL-17 antagonist such as secukinumab), this term means that ingredient alone. When applied in combination, this term means the combined amount of the active ingredients that provides a therapeutic effect, whether administered sequentially or simultaneously in combination.

[0032] As used herein, the term "treatment" or "treating" refers to applying or administering to a subject, or to tissue or cell lines isolated from a subject, an IL-17 antibody according to the present disclosure, such as secukinumab, ixekizumab, or a pharmaceutical composition comprising said anti-IL-17 antibody. However, the subject has a particular disease (e.g., psoriasis), a symptom associated with the disease (e.g., psoriasis), or a predisposition to the development of the disease (e.g., psoriasis), and the purpose is to effect a cure (where applicable) of the disease, delay its onset, reduce its severity, relieve it, remission of one or more symptoms, improvement of the disease, reduction or amelioration of any symptom associated with the disease or the predisposition to the development of the disease. The term "treatment" or "treating" includes treating patients suspected of having the disease and patients with the disease or patients diagnosed with having the disease or medical condition, and includes suppression of clinical recurrence. As used herein, the phrase "de novo plaque psoriasis" means plaque psoriasis in which the first psoriasis plaque appeared (de novo) within 12 months (≤ 12 months) before the start of treatment with an IL-17 agonist (e.g., secukinumab). As used herein, the phrases "not previously treated with systemic therapy for psoriasis" and "naïve" mean psoriasis patients who have not previously been treated with systemic agents for psoriasis, such as methotrexate, cyclosporine, biological agents (e.g., ustekinumab, infliximab, TNFα inhibitors, etc.). Systemic agents (i.e., agents administered by oral, injection, etc.) have a systemic effect when delivered to the patient, as opposed to topical agents which have a local effect.

[0033] As used herein, the phrase "de novo plaque psoriasis" means plaque psoriasis in which the first psoriasis plaque appeared (de novo) within 12 months (≤ 12 months) before the start of treatment with an IL-17 agonist (e.g., secukinumab).

[0034] As used herein, the phrases "not previously treated with systemic therapy for psoriasis" and "naïve" mean psoriasis patients who have not previously been treated with systemic agents for psoriasis, such as methotrexate, cyclosporine, biological agents (e.g., ustekinumab, infliximab, TNFα inhibitors, etc.). Systemic agents (i.e., agents administered by oral, injection, etc.) have a systemic effect when delivered to the patient, as opposed to topical agents which have a local effect. ​ (e.g., topical agents and phototherapeutic agents). As used herein, the phrase "not previously treated with phototherapy" means a psoriasis patient who has not previously been treated with narrowband UVB (nb-UV B) for psoriasis. In some embodiments of the disclosed methods, regimens, uses, kits and pharmaceutical compositions, the patient has not previously been treated with systemic therapy for psoriasis. In some embodiments of the disclosed methods, regimens, uses, kits and pharmaceutical compositions, the patient has not previously been treated with phototherapy for psoriasis.

[0035] As used herein, the phrase "previously treated with a systemic agent for psoriasis" means a patient who has previously received treatment for psoriasis with a systemic agent. Such patients include those who have previously been treated with biologic agents such as ustekinumab and those who have previously been treated with non-biologic agents such as cyclosporine. In some embodiments of the present disclosure, the patient has previously been treated with a systemic agent for psoriasis.

[0036] In some embodiments, the patient has previously been treated with a systemic agent for psoriasis (e.g., methotrexate, cyclosporine), but the patient has not previously been treated with a systemic biologic agent (i.e., an agent produced by a living organism, e.g., an antibody, a receptor decoy, etc.) for psoriasis (e.g., ustekinumab, ixekizumab, brodalumab, a TNFα inhibitor (etanercept, adalimumab, remicade, etc.), secukinumab, etc.). In this case, the patient is said to be "biologic-naïve". In preferred embodiments, the patient is biologic-naïve.

[0037] As used herein, the term "TNF-deficient patient" means a patient who has had an inadequate response or was intolerant to previous treatment with a TNFα antagonist (e.g., etanercept, adalimumab, etc.). A patient who had an adequate response to previous treatment with a TNFα antagonist but was discontinued due to side effects is said to be "intolerant". TNF-deficient patients are sometimes also referred to as "TNF-IR" patients. In some embodiments, prior to administration of an IL-17 antagonist, the patient is a TNF-deficient patient. (e.g., etanercept, adalimumab, etc.). As used herein, "selecting" and "selected" in relation to a patient are used to mean that a particular patient is specifically selected from a larger group of patients based on (and arising from) certain pre-determined criteria. Similarly, "selectively treating" means providing treatment to a patient having a particular disease, and that patient is specifically selected from a larger group of patients based on certain pre-determined criteria. Similarly, "selectively administering" means administering a drug to a patient specifically selected from a larger group of patients based on (and arising from) certain pre-determined criteria. Selecting, selectively treating, and selectively administering do not provide a standard treatment regimen based on membership of patients in a larger group, but rather are based on a patient's personal history (e.g., previous treatment interventions, e.g., previous treatment with biologics), biological factors (e.g., certain genetic markers) and / or symptoms (e.g., those that do not meet certain diagnostic criteria). (e.g., etanercept, adalimumab, etc.). A patient who had an adequate response to previous treatment with a TNFα antagonist but was discontinued due to side effects is said to be "intolerant". TNF-deficient patients are sometimes also referred to as "TNF-IR" patients. In some embodiments, prior to administration of an IL-17 antagonist, the patient is a TNF-deficient patient.

[0038] (e.g., etanercept, adalimumab, etc.). As used herein, "selecting" and "selected" in relation to a patient are used to mean that a particular patient is specifically selected from a larger group of patients based on (and arising from) certain pre-determined criteria. Similarly, "selectively treating" means providing treatment to a patient having a particular disease, and that patient is specifically selected from a larger group of patients based on certain pre-determined criteria. Similarly, "selectively administering" means administering a drug to a patient specifically selected from a larger group of patients based on (and arising from) certain pre-determined criteria. Selecting, selectively treating, and selectively administering do not provide a standard treatment regimen based on membership of patients in a larger group, but rather are based on a patient's personal history (e.g., previous treatment interventions, e.g., previous treatment with biologics), biological factors (e.g., certain genetic markers) and / or symptoms (e.g., those that do not meet certain diagnostic criteria). (e.g., etanercept, adalimumab, etc.). A patient who had an adequate response to previous treatment with a TNFα antagonist but was discontinued due to side effects is said to be "intolerant". TNF-deficient patients are sometimes also referred to as "TNF-IR" patients. In some embodiments, prior to administration of an IL-17 antagonist, the patient is a TNF-deficient patient. (e.g., etanercept, adalimumab, etc.). As used herein, "selecting" and "selected" in relation to a patient are used to mean that a particular patient is specifically selected from a larger group of patients based on (and arising from) certain pre-determined criteria. Similarly, "selectively treating" means providing treatment to a patient having a particular disease, and that patient is specifically selected from a larger group of patients based on certain pre-determined criteria. Similarly, "selectively administering" means administering a drug to a patient specifically selected from a larger group of patients based on (and arising from) certain pre-determined criteria. Selecting, selectively treating, and selectively administering do not provide a standard treatment regimen based on membership of patients in a larger group, but rather are based on a patient's personal history (e.g., previous treatment interventions, e.g., previous treatment with biologics), biological factors (e.g., certain genetic (e.g., etanercept, adalimumab, etc.). As used herein, "selecting" and "selected" in relation to a patient are used to mean that a particular patient is specifically selected from a larger group of patients based on (and arising from) certain pre-determined criteria. Similarly, "selectively treating" means providing treatment to a patient having a particular disease, and that patient is specifically selected from a larger group of patients based on certain pre-determined criteria. Similarly, "selectively administering" means administering a drug to a patient specifically selected from a larger group of patients based on (and arising from) certain pre-determined criteria. Selecting, selectively treating, and selectively administering do not provide a standard treatment regimen based on membership of patients in a larger group, but rather are based on a patient's personal history (e.g., previous treatment interventions, e.g., previous treatment with biologics), biological factors (e.g., certain genetic (e.g., etanercept, adalimumab, etc.). As used herein, "selecting" and "selected" in relation to a patient are used to mean that a particular patient is specifically selected from a larger group of patients based on (and arising from) certain pre-determined criteria. Similarly, "selectively treating" means providing treatment to a patient having a particular disease, and that patient is specifically selected from a larger group of patients based on certain pre-determined criteria. Similarly, "selectively administering" means administering a drug to a patient specifically selected from a larger group of patients based on (and arising from) certain pre-determined criteria. Selecting, selectively treating, and selectively administering do not provide a standard treatment regimen based on membership of patients in a larger group, but rather are based on a patient's personal history (e.g., previous treatment interventions, e.g., previous treatment with biologics), biological factors (e.g., certain genetic (e.g., etanercept, adalimumab, etc.). As used herein, "selecting" and "selected" in relation to a patient are used to mean that a particular patient is specifically selected from a larger group of patients based on (and arising from) certain pre-determined criteria. Similarly, "selectively treating" means providing treatment to a patient having a particular disease, and that patient is specifically selected from a larger group of patients based on certain pre-determined criteria. Similarly, "selectively administering" means administering a drug to a patient specifically selected from a larger group of patients based on (and arising from) certain pre-determined criteria. Selecting, selectively treating, and selectively administering do not provide a standard treatment regimen based on membership of patients in a larger group, but rather are based on a patient's personal history (e.g., previous treatment interventions, e.g., previous treatment with biologics), biological factors (e.g., certain genetic (e.g., etanercept, adalimumab, etc.). As used herein, "selecting" and "selected" in relation to a patient are used to mean that a particular patient is specifically selected from a larger group of patients based on (and arising from) certain pre-determined criteria. Similarly, "selectively treating" means providing treatment to a patient having a particular disease, and that patient is specifically selected from a larger group of patients based on certain pre-determined criteria. Similarly, "selectively administering" means administering a drug to a patient specifically selected from a larger group of patients based on (and arising from) certain pre-determined criteria. Selecting, selectively treating, and selectively administering do not provide a standard treatment regimen based on membership of patients in a larger group, but rather are based on a patient's personal history (e.g., previous treatment interventions, e.g., previous treatment with biologics), biological factors (e.g., certain genetic (e.g., etanercept, adalimumab, etc.). As used herein, "selecting" and "selected" in relation to a patient are used to mean that a particular patient is specifically selected from a larger group of patients based on (and arising from) certain pre-determined criteria. Similarly, "selectively treating" means providing treatment to a patient having a particular disease, and that patient is specifically selected from a larger group of patients based on certain pre-determined criteria. Similarly, "selectively administering" means administering a drug to a patient specifically selected from a larger group of patients based on (and arising from) certain pre-determined criteria. Selecting, selectively treating, and selectively administering do not provide a standard treatment regimen based on membership of patients in a larger group, but rather are based on a patient's personal history (e.g., previous treatment interventions, e.g., previous treatment with biologics), biological factors (e.g., certain genetic (e.g., etanercept, adalimumab, etc.). As used herein, "selecting" and "selected" in relation to a patient are used to mean that a particular patient is specifically selected from a larger group of patients based on (and arising from) certain pre-determined criteria. Similarly, "selectively treating" means providing treatment to a patient having a particular disease, and that patient is specifically selected from a larger group of patients based on certain pre-determined criteria. Similarly, "selectively administering" means administering a drug to a patient specifically selected from a larger group of patients based on (and arising from) certain pre-determined criteria. Selecting, selectively treating, and selectively administering do not provide a standard treatment regimen based on membership of patients in a larger group, but rather are based on a patient's personal history (e.g., previous treatment interventions, e.g., previous treatment with biologics), biological factors (e.g., certain genetic markers) and / or symptoms (e.g., those that do not meet certain diagnostic criteria). means providing individualized treatment to a patient. In connection with the treatment methods used herein Selecting, in the context of, does not mean an accidental treatment of a patient with certain criteria, but rather an intentional selection to treat a patient based on patients with certain criteria. Therefore, selective treatment / administration is different from standard treatment / administration that delivers a specific drug to all patients with a specific disease, regardless of personal history, disease symptoms, and / or biological factors. In some embodiments treatment is selected based on the patient having psoriasis vulgaris plaque type at onset.

[0039] As used herein, the phrase "cutaneous tissue-resident memory T cells" means non-recirculating memory T cells that persist in the epidermis. (See, e.g., Clark (2015), supra). In some embodiments of the present disclosure, treatment with an IL-17 antagonist (e.g., secukinumab) reduces cutaneous tissue-resident memory T cells.

[0040] As used herein, the phrase "subset effector T cells that produce interleukin-17 (IL-17) and / or interleukin-22 (IL-22) in the skin" means epidermal CD4 and CD8 T cells that produce IL-17 and IL-22. (See, e.g., Clark (2015), supra). In some embodiments of the present disclosure, treatment with an IL-17 antagonist (e.g., secukinumab) reduces subset effector T cells that produce interleukin-17 (IL-17) and / or interleukin-22 (IL-22) in the skin.

[0041] As used herein, the phrase "skin regulatory T cells" refers to a population of T cells found in the skin characterized by the expression of the transcription factor Foxp3. (See, e.g., S anchez Rodriguez et al. (2014) J. Clin. Inve st. 124(3):1027-1036). In some embodiments of the present disclosure, treatment with an IL-17 antagonist (e.g., secukinumab) reduces and normalizes the number of skin regulatory T cells.

[0042] As used herein, the phrase "skin dermal dendritic cell-T cell aggregate" refers to a dermal cluster comprising dendritic cells and infiltrating T cells. (See, e.g., Kim e t al. (2014) J. Invest. Derm. 134(5):1462-65 ). In some embodiments of the present disclosure, treatment with an IL-17 antagonist (e.g., secukinumab) reduces skin dermal dendritic cell-T cell aggregates.

[0043] Overall, the act of reducing tissue-resident memory T cells in the skin, the act of reducing subsets of effector T cells that produce interleukin-17 (IL-17) and / or interleukin-22 (IL-22) in the skin, the act of reducing skin regulatory T cells, and the act of reducing skin dermal dendritic cell-T cell aggregates (e.g., the act of reducing cell-mediated immunity in the skin, the act of reducing T cell-mediated immune responses in the skin ) are herein referred to as "modulating the immune mechanisms that cause psoriasis disease chronicity." In some embodiments of the present disclosure, an IL-17 antagonist (e.g., secukinumab) ) Treatment with a mab) modulates the immune mechanisms that cause the chronicity of psoriasis disease.

[0044] The plaque psoriasis disease course typically begins with small skin plaques about 1 / 8 inch wide in the same area on both sides of the body. It gradually grows into thick, dry plaques. Scratching or rubbing the plaque causes pinpoint-sized bleeding spots to appear below, which is known as Auspitz sign. Some patches become annular with a clear center and a scaly raised border. Eventually, the individual patches join together to form a larger area. In some cases, the patches cover a large area of the back or chest and are called map-like plaques. As used herein, the phrase "retarding the progression of psoriasis disease" means reducing the rate of progression of the plaque-type psoriasis disease course. In some embodiments of the present disclosure, treatment with an IL-17 antagonist (e.g., secukinumab) retards the progression of psoriasis disease.

[0045] As used herein, the phrase "psoriasis flare" includes symptoms of plaque-type psoriasis, including plaques, skin irritation patches, erythema (e.g., especially on the elbows, knees, trunk, and scalp), nail changes and / or appearance damage, pityriasis capitis, and any combination thereof. Typically, a psoriasis flare includes the formation of psoriasis plaques. In some embodiments of the present disclosure, treatment with an IL-17 antagonist (e.g., secukinumab) prevents psoriasis flares, reduces the severity of psoriasis flares, and / or reduces the frequency of psoriasis flares.

[0046] As used herein, phrases such as "reducing the severity of a psoriasis flare" refer to psoriasis Reducing the degree of flare, for example, reducing the percentage of skin affected by psoriasis , reducing the degree of certain flare components (e.g., reducing the number, size, thickness, etc. of plaques , reducing the range of skin irritation, reducing scaling, reducing erythema , reducing nail changes and / or cosmetic damage, reducing pityriasis capitis whatever), and / or reducing the duration for which the flare (or its components) persists . The severity of the flare can be measured using various tools, such as the body surface area (BSA) test, the Investigator's Global Assessment (IGA, IGA revised 2011), the Physician's Global Assessment (PGA), the Psoriasis Area and Severity Index (PASI), and patient-reported outcomes, such as the Dermatology Life Quality Index (DLQI) as well as the Work Productivity and Activity Impairment Questionnaire: Psoriasis (WPAI:PSO). In some embodiments of the disclosed methods, kits, and uses, a patient achieves at least a 50% reduction (PASI50) in the Psoriasis Area and Severity Index score at 12 weeks of treatment. In some embodiments of the disclosed methods, kits, and uses, a patient achieves at least a 75% reduction (PASI75) in the Psoriasis Area and Severity Index score at 12 weeks of treatment. In some embodiments of the disclosed methods, kits, and uses, a patient achieves at least a 90% reduction (PASI90) in the Psoriasis Area and Severity Index score at 12 weeks of treatment. In some embodiments of the disclosed methods, kits, and uses, a patient achieves at least a 100% reduction (PASI100) in the Psoriasis Area and Severity Index score at 12 weeks of treatment. In some embodiments of the disclosed methods, kits, and uses, a patient achieves at least a 100% reduction (PASI100) in the Psoriasis Area and Severity Index score at 12 weeks of treatment.

[0047] As used herein, phrases such as "reducing the frequency of psoriasis flares" refer to reducing the incidence of psoriasis flares, e.g., reducing the incidence of plaques and / or other psoriasis flare components (such as, for example, plaques, skin irritation, scaling, erythema, nail changes, scalp pityriasis, etc.). By reducing the frequency of psoriasis flares, patients will encounter fewer psoriasis recurrences. The incidence of flares can be evaluated by monitoring patients over time to determine if the incidence of flares decreases.

[0048] As used herein, the phrase "preventing psoriasis flares" means precluding future psoriasis flares and / or flare components.

[0049] Many psoriasis patients will ultimately progress to psoriatic arthritis (PsA). Treatment of patients with psoriasis de novo with an IL-17 antagonist (e.g., an IL-17 antibody such as secukinumab) is expected to reduce the likelihood that such patients will ultimately develop PsA, cardiovascular disease, metabolic syndrome (diabetes, obesity), and other pathologies. As used herein, the phrase "reducing the likelihood that a psoriasis patient will develop psoriatic arthritis" means reducing the likelihood that a psoriasis patient will develop psoriatic arthritis. As used herein, the phrase "delaying the onset of psoriatic arthritis in a psoriasis patient" means delaying the occurrence of signs and symptoms and / or structural damage associated with PsA in a psoriasis patient. As used herein, the phrase "preventing the progression from psoriasis to psoriatic arthritis in a psoriasis patient" means inhibiting the development of PsA in a psoriasis patient.

[0050] As used herein, "mild psoriasis" is defined as a psoriasis disease where body surface area (BSA) ≤ 10 and psoriasis area and severity index (PASI) < 10 and dermatology life quality index (DLQI) ≤ 10. As used herein, "moderate to severe psoriasis" is defined as a psoriasis disease where (BSA > 10 or PASI > 10) and DLQI > 10. See Mrowietz et al. (2011) Arch Dermatol Res .303(1):1-10. In some embodiments of the disclosed methods, uses, and kits, the patient has mild psoriasis. In some embodiments of the disclosed methods, uses, and kits, the patient has moderate to severe psoriasis. In some embodiments of the disclosed methods, uses, and kits, patients undergoing long-term treatment with an IL-17 antagonist (e.g., an IL-17 antibody such as secukinumab) change from having moderate to severe psoriasis to having mild psoriasis based on modification of the psoriasis disease course. See Mrowietz et al. (2011) Arch Dermatol Res .303(1):1-10. In some embodiments of the disclosed methods, uses, and kits, the patient has mild psoriasis. In some embodiments of the disclosed methods, uses, and kits, the patient has moderate to severe psoriasis. In some embodiments of the disclosed methods, uses, and kits, patients undergoing long-term treatment with an IL-17 antagonist (e.g., an IL-17 antibody such as secukinumab) change from having moderate to severe psoriasis to having mild psoriasis based on modification of the psoriasis disease course. In some embodiments of the disclosed methods, uses, and kits, the patient has mild psoriasis. In some embodiments of the disclosed methods, uses, and kits, the patient has moderate to severe psoriasis. In some embodiments of the disclosed methods, uses, and kits, patients undergoing long-term treatment with an IL-17 antagonist (e.g., an IL-17 antibody such as secukinumab) change from having moderate to severe psoriasis to having mild psoriasis based on modification of the psoriasis disease course. In some embodiments of the disclosed methods, uses, and kits, the patient has mild psoriasis. In some embodiments of the disclosed methods, uses, and kits, the patient has moderate to severe psoriasis. In some embodiments of the disclosed methods, uses, and kits, patients undergoing long-term treatment with an IL-17 antagonist (e.g., an IL-17 antibody such as secukinumab) change from having moderate to severe psoriasis to having mild psoriasis based on modification of the psoriasis disease course. In some embodiments of the disclosed methods, uses, and kits, patients undergoing long-term treatment with an IL-17 antagonist (e.g., an IL-17 antibody such as secukinumab) change from having moderate to severe psoriasis to having mild psoriasis based on modification of the psoriasis disease course. In some embodiments of the disclosed methods, uses, and kits, patients undergoing long-term treatment with an IL-17 antagonist (e.g., an IL-17 antibody such as secukinumab) change from having moderate to severe psoriasis to having mild psoriasis based on modification of the psoriasis disease course. In some embodiments of the disclosed methods, uses, and kits, patients undergoing long-term treatment with an IL-17 antagonist (e.g., an IL-17 antibody such as secukinumab) change from having moderate to severe psoriasis to having mild psoriasis based on modification of the psoriasis disease course.

[0051] In preferred embodiments, the methods and uses disclosed herein provide treatment of moderate to severe chronic plaque psoriasis in adult patients who are candidates for systemic therapy (or phototherapy). In some embodiments, adult patients who are candidates for systemic therapy (or phototherapy) have a BSA ≥ 5%. In some embodiments, adult patients who are candidates for systemic therapy (or phototherapy) have a BSA ≥ 3%. In preferred embodiments, the methods and uses disclosed herein provide treatment of moderate to severe chronic plaque psoriasis in adult patients who are candidates for systemic therapy (or phototherapy). In some embodiments, adult patients who are candidates for systemic therapy (or phototherapy) have a BSA ≥ 5%. In some embodiments, adult patients who are candidates for systemic therapy (or phototherapy) have a BSA ≥ 3%. In preferred embodiments, the methods and uses disclosed herein provide treatment of moderate to severe chronic plaque psoriasis in adult patients who are candidates for systemic therapy (or phototherapy). In some embodiments, adult patients who are candidates for systemic therapy (or phototherapy) have a BSA ≥ 5%. In some embodiments, adult patients who are candidates for systemic therapy (or phototherapy) have a BSA ≥ 3%. In some embodiments, adult patients who are candidates for systemic therapy (or phototherapy) have a BSA ≥ 5%. In some embodiments, adult patients who are candidates for systemic therapy (or phototherapy) have a BSA ≥ 3%. In some embodiments, adult patients who are candidates for systemic therapy (or phototherapy) have a BSA ≥ 5%. In some embodiments, adult patients who are candidates for systemic therapy (or phototherapy) have a BSA ≥ 3%.

[0052] IL-17 antagonist The various disclosed processes, kits, uses, and methods involve an IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., a soluble IL-17 receptor, an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab), or an IL-17 receptor -binding molecule (e.g., an IL-17 receptor antibody or an antigen-binding fragment thereof) is utilized. In some embodiments, the IL-17 antagonist is an IL-17 binding molecule, preferably an IL-17 antibody or an antigen-binding fragment thereof.

[0053] In one embodiment, the IL-17 antibody or an antigen-binding fragment thereof comprises at least one immunoglobulin heavy chain variable domain containing CDR1, CDR2, and CDR3, the hypervariable regions (V H ), wherein CDR1 has the amino acid sequence of SEQ ID NO: 1, CD R2 has the amino acid sequence of SEQ ID NO: 2, and CDR3 has the amino acid sequence of SEQ ID NO: 3. In one embodiment, the IL-17 antibody or an antigen-binding fragment thereof comprises at least one immunoglobulin light chain variable domain (V ) containing CDR1', CDR2', and CDR3', the hypervariable regions L’ ), wherein CDR1' has the amino acid sequence of SEQ ID NO: 4, CDR2' has the amino acid sequence of SEQ ID NO: 5, and CDR3 ' has the amino acid sequence of SEQ ID NO: 6. In one embodiment, the IL-17 antibody or an antigen-binding fragment thereof comprises at least one immunoglobulin heavy chain variable domain containing CDR1-x, CDR2-x, and CDR3-x, the hypervariable regions (V ), wherein CDR1-x has the amino acid sequence of SEQ ID NO: 11, CDR2-x has the amino acid sequence of SEQ ID NO: 12 H ), and CDR3-x has the amino acid sequence of SEQ ID NO: 13 . . .

[0054] 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 domain, provided that a) the immunoglobulin V domain comprises (e.g., sequentially) i) hypervariable regions H CDR1, CDR2 and CDR3, wherein said CDR1 has the amino acid sequence of SEQ ID NO: 1, said CDR2 has the amino acid sequence of SEQ ID NO: 2, and said CDR3 has the amino acid sequence of SEQ ID NO: 3, or ii) hypervariable regions CDR1-x, CDR2 -x and CDR3-x, wherein said CDR1-x has the amino acid sequence of SEQ ID NO: 11, said CDR2-x has the amino acid sequence of SEQ ID NO: 12, and said CDR 3-x has the amino acid sequence of SEQ ID NO: 13, and b) the immunoglobulin V domain comprises (e.g., sequentially) hypervariable regions CDR1', CDR2' and CDR3', and wherein said CDR1' has the amino acid sequence of SEQ ID NO: 4, said CDR2' has the amino acid sequence of SEQ ID NO: 5, and said CDR3' has the amino acid sequence of SEQ ID NO: 6. L The immunoglobulin V domain comprises (e.g., sequentially) hypervariable regions CDR1', CDR2' and CDR3', and wherein said CDR1' has the amino acid sequence of SEQ ID NO: 4, said CDR2' has the amino acid sequence of SEQ ID NO: 5, and said CDR3' has the amino acid sequence of SEQ ID NO: 6.

[0055] 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 shown as SEQ ID NO: 8, b) an immunoglobulin light chain variable domain (V H ) comprising the amino acid sequence shown as SEQ ID NO: 10, c) an immunoglobulin V L domain comprising the amino acid sequence shown as SEQ ID NO: 8 and the light chain c) an immunoglobulin V H domain comprising the amino acid sequence shown as SEQ ID NO: 8 and the light chain ​An immunoglobulin V domain comprising the amino acid sequence shown as column number 10 L domain, d) SEQ ID Nos: 1, SEQ ID No: 2, and an immunoglobulin V domain comprising the hypervariable regions shown as SEQ ID No: 3 H domain, e) SEQ ID No: 4, SEQ ID No: 5, and an immunoglobulin V domain comprising the hypervariable regions shown as SEQ ID No: 6 domain, f) SEQ ID No: 11, SEQ ID No: 12, and an immunoglobulin V domain comprising the hypervariable regions shown as SEQ ID No: 13 L domain, g) SEQ ID No: 1, SEQ ID Nos: 2, and an immunoglobulin V domain comprising the hypervariable regions shown as SEQ ID No: 3 H domain, and also an immunoglobulin V domain comprising the hypervariable regions shown as SEQ ID No: 4, SEQ ID No: 5, and SEQ ID No: 6 H domain, or h) SEQ ID No: 11, SEQ ID No: 12, and an immunoglobulin V domain comprising the hypervariable regions shown as SEQ ID No: 13 domain, and also an immunoglobulin V domain comprising the hypervariable regions shown as SEQ ID No: 4, SEQ ID No: 5, and SEQ ID No: 6 domain L domain, or i) SEQ ID No: 11, SEQ ID No: 12, and an immunoglobulin V domain comprising the hypervariable regions shown as SEQ ID No: 13 domain, and also an immunoglobulin V domain comprising the hypervariable regions shown as SEQ ID No: 4, SEQ ID No: 5, and SEQ ID No: 6 H domain, and an immunoglobulin V domain comprising the hypervariable regions shown as SEQ ID No: 4, SEQ ID Nos: 5, and SEQ ID No: 6 L domain .

[0056] For ease of reference, the amino acid sequences of the hypervariable regions of the secukinumab monoclonal antibody based on the Kabat definition determined by X-ray analysis using the method of Chothia et al. are provided in Table 1 below. Based on the Kabat definition, the amino acid sequences of the hypervariable regions of the secukinumab monoclonal antibody determined by X-ray analysis using the method of Chothia et al. are provided in Table 1 below. provided in Table 1 below.

[0057]

Table 1

[0058] In a preferred embodiment, the constant region domain is also a suitable human constant region domain, such as For example, "Sequences of Proteins of Immunologica l Interest", Kabat E.A. et al, US Departmen t of Health and Human Services, Public He alth Service, National Institute of Healt h includes those described therein. The DNA encoding the V L of secukinumab is shown in SEQ ID NO: 9 . The DNA encoding the V H of secukinumab is shown in SEQ ID NO: 7.

[0059] In some embodiments, the IL-17 antibody or an antigen-binding fragment thereof (e.g., , secukinumab) includes the three CDRs of SEQ ID NO: 10. In other embodiments, the IL-1 7 antibody or an antigen-binding fragment thereof includes the three CDRs of SEQ ID NO: 8. In other embodiments , the IL-17 antibody or an antigen-binding fragment thereof includes the three C DRs of SEQ ID NO: 10 and the three CDRs 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 (CysL97) in the light chain can be found in SEQ ID NO: 6 .

[0060] In some embodiments, the IL-17 antibody or an antigen-binding fragment thereof includes the light chain of SEQ ID NO: 14. In other embodiments, the IL-17 antibody or an antigen-binding fragment thereof includes the heavy chain of SEQ ID NO: 15. In other embodiments, the IL-17 antibody or an antigen-binding fragment thereof includes the light chain of SEQ ID NO: 14 and the heavy domain of SEQ ID NO: 15. In some embodiments, the IL-17 antibody or an antigen-binding fragment thereof includes SEQ ID NO: 14 comprises three CDRs. In other embodiments, the IL-17 antibody or its antigen-binding fragment comprises three CDRs of SEQ ID NO: 15. In other embodiments, the IL-17 antibody or its antigen-binding fragment comprises three CDRs of SEQ ID NO: 14 and three CDRs of SEQ ID NO: 15. The CDRs of SEQ ID NO: 14 and SEQ ID NO: 15 can be found in Table 1.

[0061] The hypervariable regions can be associated with any type of framework region, but are preferably of human origin. Suitable framework regions are those described in Kabat E.A.et al,ib id. A preferred heavy-chain framework is a human heavy-chain framework, such as that of the secukinumab antibody. It consists, sequentially, of regions such as FR1 (amino acids 1-30 of SEQ ID NO: 8), FR2 (amino acids 36-49 of SEQ ID NO: 8), FR3 (amino acids 67-98 of SEQ ID NO: 8) and FR4 (amino acids 117-127 of SEQ ID NO: 8). Considering the hypervariable regions of secukinumab determined by X-ray analysis, another preferred heavy-chain framework consists, sequentially, of regions of FR1-x (amino acids 1-25 of SEQ ID NO: 8), FR2-x (amino acids 36-49 of SEQ ID NO: 8), FR3-x (amino acids 61-95 of SEQ ID NO: 8) and FR4 (amino acids 119-127 of SEQ ID NO: 8). Similarly, the light-chain framework consists, sequentially, of regions of FR1’ (amino acids 1-23 of SEQ ID NO: 10), FR2’ (amino acids 36-50 of SEQ ID NO: 10), FR3’ (amino acids 58-89 of SEQ ID NO: 10) and FR4’ (amino acids 99-109 of SEQ ID NO: 10).

[0062] In one embodiment, the IL-17 antibody or its antigen-binding fragment (e.g., secuki The Numab) comprises a variable domain that sequentially includes a) hypervariable regions CDR1, CDR2, and CDR3 and a constant region of a human heavy chain or a fragment thereof, wherein the CDR1 has the amino acid sequence of SEQ ID NO: 1, the CDR2 has the amino acid sequence of SEQ ID NO: 2, and the CDR3 has the amino acid sequence of SEQ ID NO: 3, an immunoglobulin heavy chain or a fragment thereof, and b) a variable domain that sequentially includes hypervariable regions CDR1', CDR2', and CDR3 and a constant region of a human light chain or a fragment thereof, wherein the CDR1' has the amino acid sequence of SEQ ID NO: 4, the CDR2' has the amino acid sequence of SEQ ID NO: 5, and the CDR3' has the amino acid sequence of SEQ ID NO: 6, and is selected from human IL-17 antibodies that at least include an immunoglobulin light chain or a fragment thereof. In one embodiment, the IL-17 antibody or an antigen-binding fragment thereof comprises a) a first domain that sequentially includes hypervariable regions CDR1, CDR2, and CDR3, wherein the CDR1 has the amino acid sequence of SEQ ID NO: 1, the CDR2 has the amino acid sequence of SEQ ID NO: 2, and the CDR3 has the amino acid sequence of SEQ ID NO: 3, b) a second domain that sequentially includes hypervariable regions CDR1', CDR2', and CDR3', wherein the CDR1' has the amino acid sequence of SEQ ID NO: 4, the CDR2' has the amino acid sequence of SEQ ID NO: 5, and the CDR3' has the amino acid sequence of SEQ ID NO: 6, and c) an antigen-binding site that includes a peptide linker bound to either the N-terminus of the first domain and the C-terminus of the second domain, or the C-terminus of the first domain and the N-terminus of the second domain.

[0063] ​​​​​​​​​​​​​​​​It is selected from a single-chain antibody containing the same or its antigen-binding fragment.

[0064] Alternatively, the IL-17 antibody or its antigen-binding fragment used in the disclosed method may include derivatives of the IL-17 antibody shown by the sequence herein (e.g., the pegylated form of secukinumab ). Alternatively, the IL-17 antibody or its antigen-binding fragment's V H or V L domain may have a V H or V L domain that is substantially identical to the V H or V L domain shown herein (e.g., those shown in SEQ ID NOs: 8 and 10). The human IL-17 antibody disclosed herein may have a heavy chain substantially identical to that shown as SEQ ID NO: 15 and / or a light chain substantially identical to that shown as SEQ ID NO: 14 . The human IL-17 antibody disclosed herein may include a heavy chain containing SEQ ID NO: 15 and a light chain containing SEQ ID NO: 14. The human IL-17 antibody disclosed herein may include a) one heavy chain containing a variable domain having an amino acid sequence substantially identical to that shown in SEQ ID NO: 8 and a constant region of a human heavy chain, and b) one light chain containing a variable domain having an amino acid sequence substantially identical to that shown in SEQ ID NO: 10 and a constant region of a human light chain.

[0065] Alternatively, the IL-17 antibody or its antigen-binding fragment used in the disclosed method may be an amino acid sequence variant of the reference IL-17 antibody shown herein as long as it contains CysL97. The present disclosure also relates to the V H or V L domain of secukinumab's amino one or more of the acid residues (but not CysL97), typically a very small number (e.g., 1 to 10) are changed, for example, by mutagenesis such as site-directed mutagenesis of the corresponding DNA sequence to obtain an IL-17 antibody or an antigen-binding fragment thereof (e.g., secukinumab ). In any of such cases of derivatives and mutants, the IL-17 antibody or its antigen-binding fragment can inhibit the activity of about 1 nM (=30 ng / ml) of human IL-17 by 50% at a concentration of the molecule 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 1 nM or less. However, the inhibition activity is measured by IL-6 production induced by hu-IL-17 in human dermal fibroblasts as described in Example 1 of WO 2006 / 013107 pamphlet as follows.

[0066] In some embodiments, the IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab, binds to an epitope of mature human IL-17 comprising Leu74, Tyr85, His86, Met87, Asn88, Va l124, Thr125, Pro126, Ile127, Val128, His129. In some embodiments, the IL-17 antibody, e.g., secukinumab, binds to an epitope of mature human IL-17 comprising Tyr43, Tyr44, Arg46, Ala79, A sp80. In some embodiments, the IL-17 antibody, e.g., secukinumab, binds to an epitope of the IL- 17 homodimer having two mature human IL-17 chains. However, the epitope has Leu u74, Tyr85, His86, Met87, Asn88, Val124, Thr12 on one chain​ 5, Pro126, Ile127, Val128, His129, and Tyr on the other chain 43, Tyr44, Arg46, Ala79, Asp80. The residue numbering scheme used to define such epitopes is based on designating the first amino acid of the mature protein as residue 1 (i.e., IL-17A starting from glycine with a 23-amino acid N-terminal signal peptide lacking). The sequence of immature IL-17A is shown in Swiss-Prot entry Q16552. In some embodiments, the IL-17 antibody has a K of about 1 00 - 200 pM (e.g., as determined by Biacore® assay). In some embodiments, the IL-17 antibody has an IC D of about 0.4 nM with respect to the in vitro neutralization of the biological activity of about 0.67 nM human IL -17A. In some embodiments, the absolute bioavailability of the subcutaneously (SC) administered IL-17 antibody is 50 in the range of about 60 - about 80%, e.g., about 76%. In some embodiments, an IL-17 antibody such as secukinumab has an elimination half-life of about 4 weeks (e.g., about 23 - about 35 days, about 23 - about 30 days, e.g., about 30 days). In some embodiments, the I L-17 antibody (e.g., secukinumab) has a T of about 7 - 8 days. In some embodiments, a particularly preferred IL-17 antibody or its antigen-binding fragment used in the disclosed methods max is a human antibody, particularly secukinumab as described in Examples 1 and

[0067] 2 of WO 2006 / 013107 pamphlet. Secukinumab is for the treatment of immune-mediated inflammatory diseases ​​​The IgG1 / κ isotype recombinant high-affinity fully human monoclonal antibody against human interleukin 17A (IL-17A, IL-17) is currently in clinical trials. Secukinumab (see, e.g., WO 2006 / 013107 and WO 2 007 / 117749) has very high similarity to IL-17, i.e., a K of about 100-200 pM and an IC of about 0.4 nM for in vitro neutralization of the biological D activity of about 0.67 nM human IL-17A. Therefore, secukinumab inhibits the antigen in a molar ratio of about 1:1. Due to this high 50 binding affinity, the secukinumab antibody is particularly suitable for therapeutic use. Furthermore, secukinumab has a very long, i.e., about 4-week half-life, and it has been confirmed that the dosing interval can be extended, which is a particularly advantageous property when treating chronic disorders such as psoriasis over a lifetime.

[0068] Other preferred IL-17 antibodies used in the disclosed methods, kits, and regimens are those shown in U.S. Patent Nos. 8,057,794, 8,003,099, 8,1 10,191, and 7,838,638, and U.S. Patent Application Publication Nos. 2 0120034656 and 20110027290 (the entireties of which are incorporated herein by reference).

[0069] Methods for treating plaque psoriasis vulgaris and use of IL-17 antagonists for the same. The disclosed IL-17 antagonists, e.g., IL-17 binding molecules -17 antibody or an antigen-binding fragment thereof, such as secukinumab) or an IL-1 7 receptor-binding molecule (e.g., an IL-17 receptor antibody or an antigen-binding fra gment) can be used in vitro, ex vivo, or incorporated into a pharmaceutical composition for treating a patient with plaque psoriasis (e.g., a human patient) and administered in vivo. .

[0070] The disclosed IL-17 antagonists, such as IL-17 binding molecules (e.g., an IL -17 antibody or an antigen-binding fragment thereof, such as secukinumab) or an IL-1 7 receptor-binding molecule (e.g., an IL-17 receptor antibody or an antigen-binding fra gment) can be used in vitro, ex vivo, or incorporated into a pharmaceutical composition for treating pyoderma gangrenosum, ichthyosis, pityriasis rubra pilaris, rosacea (e.g., papulopustular rosacea), lichen planopilaris, atopic der matitis, allergic contact dermatitis, alopecia areata, and human papillomavirus (HPV) and administered in vivo. Preferred dosing and treatment regimens (including both induction and maintenance regimens) for treating such diseases are provided in PCT International Application No. PCT / US Patent Application Publication No. 2011 / 064307 and PCT / IB2014 / 063902 (which are incorporated herein by reference in their entirety). In some embodiments, an IL-17 antibody or an antigen -binding fragment thereof (e.g., preferably secukinumab) at about 150 mg to about 300 mg (e g., preferably about 150 mg or about 300 mg) is administered subcutaneously (SC) to a patient at 0, 1, 2, 3, and 4 weeks, followed by monthly administration. In some embodiments, about 150 mg to about 300 mg (e.g., preferably about 150 mg or about 300 mg) of an IL-17 antibody or an antigen -binding fragment thereof (e.g., preferably secukinumab) is administered subcutaneously (SC) to a patient at 0, 150 mg to approximately 300 mg (e.g., preferably approximately 150 mg or approximately 300 mg) of an IL-17 antibody or an antigen-binding fragment thereof (e.g., preferably secukinumab) is administered to a patient once a month (i.e., at 0, 4, 8, 12, 16 weeks) by subcutaneous (SC) injection .

[0071] An IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor -binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof) can be used as a pharmaceutical composition in combination with a pharmaceutically acceptable carrier. Such a composition can contain, in addition to the IL -17 antagonist, a carrier, various diluents, fillers, salts, buffers, stabilizers, solubilizers and other substances well known in the art. The properties of the carrier will depend on the route of administration. The pharmaceutical composition used in the disclosed method can also contain an additional therapeutic agent for the treatment of a specific target disease . For example, the pharmaceutical composition can also contain an anti-inflammatory agent . Such additional factors and / or agents can provide a synergistic effect with the IL-17 binding molecule or can be included in the pharmaceutical composition to minimize side effects caused by an IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) or an IL -17 receptor-binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof). In a preferred embodiment, the pharmaceutical composition used in the disclosed method contains 150 mg / ml of secukinumab .

[0072] ​The pharmaceutical composition used in the disclosed method can be manufactured by conventional methods. In one embodiment , the pharmaceutical composition is provided in lyophilized form. When intended for immediate administration, it is dissolved in a suitable aqueous carrier, such as sterile water for injection, sterile buffered saline. When it is considered desirable to prepare a larger volume of solution for administration by infusion rather than by bolus injection, it may be advantageous to introduce human serum albumin or the patient's own heparinized blood into the solvent at the formulation stage. The presence of an excess of such physiologically inert protein prevents loss of antibody due to adsorption on the walls of the containers and tubes used in the infusion solution. When using albumin, a suitable concentration is 0.5 - 4.5% by weight based on the aqueous saline solution. Other formulations include liquid formulations or lyophilized formulations. Antibodies, such as anti - IL - 17 antibodies, are typically formulated in an aqueous form suitable for parenteral administration or as a lyophilized product that is reconstituted with a suitable diluent before administration. In some embodiments of the disclosed methods and uses, IL - 17 antagonists, such as anti - IL - 17 antibodies like secukinumab,

[0073] are formulated as lyophilized products. Suitable lyophilized formulations are reconstitutable in a small volume (e.g., 2 ml or less) for subcutaneous administration and can provide a solution with a low level of antibody aggregation. The use of antibodies as active pharmaceutical ingredients is widespread currently, such as in products like HERCEPTIN™ (trastuzumab), RITUXAN™ (rituximab), SY NAGIS™ (pembrolizumab), etc. Techniques for purifying antibodies to pharmaceutical grade are well - known in the art. A therapeutically effective amount of an IL - 17 antagonist, such as an IL - 17 binding molecule (e.g., an anti - IL - 17 antibody or its antigen binding fragment)​​​​​​ a binding fragment, such as secukinumab), or an IL-17 receptor binding molecule (such as, an IL-17 antibody or an antigen-binding fragment thereof) is administered by intravenous, cutaneous or subcutaneous injection, the IL-17 antagonist will be in the form of a pyrogen-free parenterally acceptable solution. The pharmaceutical composition to be administered by intravenous, cutaneous or subcutaneous injection will, in addition to the IL-17 antagonist, contain an isotonic medium such as sodium chloride solution, Ringer's solution, dextrose solution, dextrose and sodium chloride solution, lactated Ringer's solution or other media known in the art.

[0074] An appropriate dosage will vary, for example, depending on the particular IL-17 antagonist utilized, such as an IL-17 binding molecule (such as, an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab), or an IL-17 receptor binding molecule (such as, an IL-17 antibody or an antigen-binding fragment thereof), the host, the mode of administration, and the nature and severity of the condition being treated, as well as the nature of any previous treatments the patient has received. Ultimately, the amount of IL-17 antagonist to be used in the treatment of each individual patient will be determined by the attending healthcare provider. In some embodiments, the attending healthcare provider may administer a low dose of the IL-17 antagonist and observe the patient's response. In other embodiments, the initial dose of the IL-17 antagonist administered to the patient is high and then reduced until signs of recurrence appear. More doses of the IL-17 antagonist may be administered until an optimal therapeutic effect is achieved in the patient, and generally the dosage will not be further increased.

[0075] When practicing some of the treatment methods or uses of the present disclosure, a therapeutically effective amount of an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen binding fragment thereof, such as secukinumab) or an IL-17 receptor binding molecule (such as, for example, an IL-17 antibody or an antigen binding fragment thereof), is administered to a patient, such as a mammal (e.g., a human). The disclosed methods are understood to provide treatment of patients with plaque psoriasis vulgaris using an IL-17 antagonist (such as, for example, secukinumab), but if a patient is to be treated to the extreme with an IL-17 antagonist, such IL- 17 antagonist therapy need not necessarily be monotherapy. In fact, even if a patient is selected to be treated with an IL-17 antagonist, the IL-17 antagonist ( e.g., secukinumab) can be administered either alone or in combination with other agents and therapies for treating patients with plaque psoriasis vulgaris, such as in combination with at least one additional psoriasis agent and can be administered according to the methods of the present disclosure. When co-administered with one or more additional psoriasis agents, the IL- 17 antagonist can be administered simultaneously with or sequentially to the other agent. When administered sequentially, the attending physician will determine the appropriate order of administration and the appropriate dosages for co-delivery of the IL-17 antagonist in combination with the other agent.

[0076] When treating plaque psoriasis vulgaris and other disorders disclosed herein, the various therapies can be advantageously combined with the disclosed IL-17 antibodies, such as secukinumab. Such therapies include topical agents (commercially available non-steroidal and steroidal compounds), phototherapy, and systemic ​​Treatment (eg, with a biological agent or chemical entity) is included.

[0077] Examples of topical psoriasis agents that may be used with the disclosed IL-17 antibodies, such as secukinumab, include Examples include, but are not limited to, salicylic acid, coal tar, Dovonex (registered trademark). (calcipotriene), Taclonex® (calcipotriene and dimethicone) Betamethasone dipropionate), Tazorec® (tazarotene), pimeclovir Mus, Tacrolimus, Vectical® (Calcitriol), Zithr anol-RR® (anthralin) and topical steroids (e.g., corticosteroids) corticosteroids).

[0078] As an example of phototherapy that may be used in conjunction with the disclosed IL-17 antibodies, such as secukinumab, Treatment with psoralen plus UVA (PUVA) or UVB (with or without tar) Treatment options include:

[0079] It is used in systemic therapy with the disclosed IL-17 antibodies, such as secukinumab. Examples of suitable psoriatic agents include retinoids, such as acitretin (e.g., Soriat ne®), cyclosporine, methotrexate, hydroxyurea (e.g. , Hydrea®), isotretinoin, mycophenolate mofetil, myco Phenolic acids, sulfasalazine, 6-thioguanine, fumarates (e.g., dimethyl Fumarates and fumarate esters), azathioprine, corticosteroids, leflunomide amide, tacrolimus, T-cell blockers (e.g., Amevive® (Arex Facetcept) and Raptiva® (efalizumab), tumor necrosis factor- α (TNF-α) blockers (e.g., Enbrel® (etanercept) , Humira® (adalimumab), Remicade® (infli ximab) and Simponi® (golimumab)), and interleukin 12 / 23 blockers (e.g., Stelara® (ustekinumab ), tasocitinib, and briakinumab).

[0080] When used in combination with an IL-17 antibody such as secukinumab during the treatment of psoriasis Additional psoriasis agents include apremilast, mometasone, tacrolimus, ketoconazole, Neutrosqin forte, recombinant human interleukin-10, tacrolimus, M K-3222, tofacitinib, VX-765, MED-I545, flufenamic acid decanoate, acetaminophen, bimosiamose cream, doxycycline, vancomycin, AbGn168, vitamin D3, RO5310074, fludarabine calcipotri ol, and hydrocortisone (LEO80190), LE80185 (Taclonex ® scalp suspension / Xamiol® gel), Focetria (1 valent MF59 adjuvanted vaccine, tgAAC94 gene therapy vector, apremilast , capsaicin, Psirelax, ABT-874 (anti-IL-12), IDEC-1 14, MEDI-522, INCB018424 phosphate cream, LE29102, B MS587101, CD2027, CRx-191, 8-methoxypsoralen or 5-meth oxypsoralen. Toxisolaren, Bicillin L-A, LY2525623, INCB01842 4, LY2439821, CEP-701, CC-10004, Certolizumab (CZP )), GW786034 (Pazopanib), Doxycycline Curcuminoid C3 Complex, N YC0462, RG3421, hOKT3γ1(Ala-Ala), BT061, Tepri zumab, Chondroitin Sulfate, CNTO1275, IL-12p40 and IL-23p 40 subunit monoclonal antibody, BMS-582949, MK0873, MEDI-507, M518101, ABT-874, AMG827, AN2728, A MG714, AMG139, PTH(1-34), U0267 Form, CNTO127 5, QRX-101, CNTO1959, LEO22811, Imiquimod, CTLA4I g, Dunaliella Bardawil, AS 101 Cream, Pioglitazone, Pimecrolimus, Ranibizumab, Zidovudine CDP8 70 (Certolizumab Pegol), Onercept (r-hTBP-1), ACT-128 800, 4,4-Dimethyl-Benzoiso-2H-Selenazine, CRx-191, CRx- 197, Doxercalciferol, LEO19123 Cream (Calcipotriol + LEO80122), LAS41004, WBI-1001, Tacrolimus, RAD00 1, Rapamycin, Rosiglitazone, Pioglitazone, ABT-874, Aminopterin , AN2728, CD2027, ACT-128800, Fluticasone Mometasone, CT327 , Clobetasol + LCD, BTT1023, E6201, Topical Vitamin B12, INC B018424 Phosphate Cream, Xamiol Gel, IP10.C8, BFH772, LEO22811, fluphenazine, MM-093, clobetasol, SCH527123 , CF101, SRT2104, BIRT2584, CC10004, tetrathiomolyb date, CP-690,550, U0267, ASP015K, VB-201, asitretin (also called U0279), RWJ-445380, Psoralait, propi onic acid clobetasol, botulinum toxin type A, alefacept, erlotinib, BCT1 94, ultravate ointment, roflumilast, CNTO1275, halobetasol, I LV-094, CTA018 cream, COL-121, MEDI-507, AEB07 1. Additional agents used in combination with secukinumab during the treatment of psoriasis and include IL-6 antagonists, CD20 antagonists, CTLA4 antagonists , IL-17 antagonists, IL-8 antagonists, IL-21 antagonists, I L-22 antagonists, VGEF antagonists, CXCL antagonists, MMP a ntagonists, defensin antagonists, IL-1β antagonists and IL-2 3 antagonists (e.g., receptor decoys, antagonist antibodies, etc.) are included . Appropriate dosages of additional agents co-delivered with the disclosed IL-17 antibodies such as secukinumab will be known to those skilled in the art.

[0081] IL-17 antagonists, e.g., IL-17 binding molecules (e.g., IL-17 antibodies or antigen-binding fragments thereof, e.g., secukinumab) or IL-17 recep tor-binding molecules (e.g., IL-17 receptor antibodies or antigen-binding fragments thereof) For convenience, it is administered parenterally, for example, intravenously (e.g., into the antecubital or other peripheral vein), intramuscularly or subcutaneously. The duration of intravenous (IV) therapy using the pharmaceutical composition according to the present disclosure will vary depending on the severity of the disease being treated and the condition and individual response of each individual patient and is also contemplated. Subcutaneous (SC) therapy using the pharmaceutical composition according to the present disclosure is also contemplated. Healthcare providers will determine the appropriate duration of IV or SC therapy using the pharmaceutical composition according to the present disclosure and the timing of therapy application.

[0082] Preferred dosages and treatment regimens (including both induction and maintenance regimens) for treating plaque psoriasis vulgaris and other disorders found herein are provided in PCT International Application No. PCT / US2011 / 064307 and PCT / IB2014 / 063902, which are incorporated herein by reference in their entireties.

[0083] An IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) or an IL-17 receptor -binding molecule (e.g., an IL-17 receptor antibody or an antigen-binding fragment thereof) can be administered intravenously (IV) to a patient, for example, at about 10 mg / kg at weeks 0, 2, and 4, once a week and then subcutaneously (SC) to the patient, for example, starting at week 8 at about 75 mg to about 300 mg (e.g., about 150 mg, about 300 mg) once a month Thereby, it can be administered IV to a patient at about 10 mg / kg at weeks 0, 2, and 4 and then at about 150 mg to about 300 mg (e.g.,​​​​ , an IL-17 antagonist (e.g., secukinumab) at about 150 mg, about 300 mg is administered SC to the patient.

[0084] An IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor - binding molecule (e.g., an IL-17 receptor antibody or an antigen-binding fragment thereof) can be administered SC to the patient once a week at about 150 mg to about 300 mg (e.g., about 1 50 mg, about 300 mg) at weeks 0, 1, 2, and 3, and then, for example, starting at week 4, once a month at about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) is administered SC to the patient. In this way, at weeks 0, 1, 2, 3, 4, 8, 12 , 16, 20, etc., an IL-17 antagonist (e.g., secukinumab) at about 150 mg to about 300 mg (e.g., about 150 mg, about 30 0 mg) is administered SC to the patient.

[0085] Alternatively, an IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., an IL - 17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-1 7 receptor binding molecule (e.g., an IL-17 receptor antibody or an antigen-binding fragment thereof) can be administered to the patient without using a loading regimen. For example, every 4 weeks (once a month) an antagonist at about 150 mg to about 300 mg (e.g., about 150 mg, about 30 0 mg) can be administered SC to the patient. In this way, at weeks 0, 4, 8, 12 , 16, 20, etc., an antagonist at about 150 mg to about 300 mg (e.g., about 75 mg, about 150 mg, about 300 mg) of an IL-17 antagonist (e.g., secukinumab) to a patient can be administered subcutaneously.

[0086] Certain patients, e.g., those who may show an inappropriate response to treatment with an IL-17 antagonist, e.g., an IL-17 binding molecule, e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody or an antigen-binding fragment thereof) may require dose escalation. It will be understood that. Therefore, the subcutaneous dose of secukinumab can be from about 15 0 mg to more than about 300 mg SC, e.g., about 80 mg, about 100 mg, about 125 mg, about 1 75 mg, about 200 mg, about 250 mg, about 350 mg, about 400 mg, about 450 mg, etc., and similarly, the intravenous dose can be more than about 10 mg / kg, e.g., about 11 m g / kg, 12 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 m g / kg, 35 mg / kg, etc. Also, certain patients, e.g., those who show an adverse event or an adverse reaction to treatment with an IL-17 antagonist, e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) may require dose reduction. It will be understood that. Therefore, the dose of an IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) can be from less than about 150 mg to about 300 mg SC, e.g., about 80 mg, about 100 mg, about 12 5 mg, about 175 mg, about 200 mg, 250 mg, etc., and similarly, the intravenous dose can be less than about 10 mg / kg, e.g., about 9 mg / kg, 8 mg / kg, 5 mg / kg, etc. The dose of an IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) is from less than about 150 mg to about 300 mg SC, e.g., about 80 mg, about 100 mg, about 12 5 mg, about 175 mg, about 200 mg, 250 mg, etc., and similarly, the intravenous dose can be less than about 10 mg / kg, e.g., about 9 mg / kg, 8 mg / kg, 5 mg / kg, etc. It can be, for example, kg, 4 mg / kg, 3 mg / kg, 2 mg / kg, 1 mg / kg, etc. Several In some embodiments, an IL-17 antagonist, such as an IL-17 binding molecule (such as, for example, an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) or an IL-17 receptor binding molecule (such as, for example, an IL-17 receptor antibody or an antigen binding fragment thereof) can be administered to a patient at an initial SC dose of 150 mg or 300 mg and then the dose can be titrated to about 450 mg as determined by a physician as needed.

[0087] In certain embodiments of the disclosed methods, uses, and kits, during the induction period (typically the first 16 weeks of treatment, but can be extended up to 24 weeks depending on the type and dosing regimen of the agent used) and during maintenance therapy, if the reduction in PASI is ≧75%, the treatment can be continued without modification. If the improvement in PASI is <50%, the treatment regimen can be modified (e.g., dose increase [from 150 mg to 300 mg or from 300 mg to 400 mg or 450 mg] or frequency increase [e.g., from every 4 weeks to every 3 weeks or every 2 weeks]). In situations where the improvement in treatment response as assessed by PASI is ≧50%, but < 75%, the therapy can be modified if DLQI is >5, but can be continued if DLQI is ≦5. See Mrowietz et al. (2011) Arch Dermatol Res. 303(1):1-10.

[0088] The timing of administration is the day of the first administration of secukinumab (also known as the "baseline") ) are generally measured from. However, healthcare providers often specify the dosing schedule using different naming conventions, as shown in Table 2. In particular, week 0 can be referred to as week 1 by some healthcare providers, and day 0

[0089] **Table 2**

[0090] can be referred to as day 1 by some healthcare providers. Therefore, different physicians may specify administrations occurring, for example, at 3 weeks / 21 days, 3 weeks / 22 days, 4 weeks / 21 days, 4 weeks / 22 days, but these represent the same dosing schedule. To maintain consistency, the first week of dosing is referred to herein as week 0, while the first day of dosing is referred to as day 1. However, it will be understood by those skilled in the art that this naming convention is used solely to maintain consistency and should not be construed as limiting. That is, once-weekly dosing means providing a weekly dose of the IL-17 antibody, regardless of whether the physician designates a particular week as "week 1" or "week 2". Furthermore, in a preferred dosing regimen, the antibody is administered at weeks 0, 1, 2, 3, 4, 8, 12, 16, 20, etc. Some providers may describe this regimen as once weekly for 5 weeks, then starting at week 8 once monthly (or every 4 weeks), while others may describe this regimen as once weekly for 4 weeks, then starting at week 4 once monthly (or every 4 weeks). Therefore, administering injections to a patient at weeks 0, 1, 2, and 3, followed by monthly administrations starting at week 4 is equivalent to 1) administering injections to a patient at weeks 0, 1, 2, 3, and 4, and then starting monthly administrations starting at week 4. and then starting monthly administrations starting at week 4 (or every 4 weeks). So, giving a patient injections at weeks 0, 1, 2, and 3, followed by monthly administrations starting at week 4 is the same as 1) giving a patient injections at weeks 0, 1, 2, 3, and 4, Subsequently, administration is started from 8 weeks and carried out once a month, 2) patients are injected at 0, 1, 2, 3, and 4 weeks, and subsequently administered every 4 weeks, and 3) patients are injected at 0, 1, 2, 3, and 4 weeks, and subsequently administered monthly, which will be understood by those skilled in the art.

[0091] Disclosed herein is a method for treating a patient having psoriasis vulgaris plaque type, which comprises administering an IL-17 antibody or an antigen-binding fragment thereof to a patient in need thereof, and an IL-17 antagonist used therefor. However, the IL-17 antibody or an antigen-binding fragment thereof binds to an epitope of an IL-17 homodimer having two mature human IL-17 protein chains, and the epitope comprises Leu 74, Tyr85, His86, Met87, Asn88, Val124, Thr125 on one chain, Pro126, Ile127, Val128, His129, and Tyr4 3, Tyr44, Arg46, Ala79, Asp80 on the other chain, and the IL-17 antibody or an antigen-binding fragment thereof has a K of about 100 - 200 pM, and the IL-17 antibody or an antigen-binding fragment thereof has an in vivo half-life of about 4 weeks. D

[0092] In addition, disclosed herein are a method for modulating an immune mechanism that causes psoriasis disease chronicity in psoriasis vulgaris plaque type and an IL-17 antagonist used therefor, provided that the IL-17 antagonist (for example, an IL-17 antibody or an antigen binding fragment thereof, for example, secukinumab) has two mature human IL-17 protein chains ​​​​​binds to an epitope of an IL-17 homodimer, said epitope comprising on one chain Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr 125, Pro126, Ile127, Val128, His129, and on the other chain T yr43, Tyr44, Arg46, Ala79, Asp80, and the IL-17 antibody or an antigen-binding fragment thereof has a K of about 100 - 200 pM D and the IL-17 antibody or an antigen-binding fragment thereof has an in vivo half-life of about 4 weeks.

[0093] In addition, provided herein is a method of reducing the number of tissue resident memory T cells in the skin of a patient having plaque psoriasis vulgaris, the method comprising administering an IL-17 antibody or an antigen-binding fragment thereof to a patient in need thereof, a method of reducing the number of interleukin-17 (IL-17) and / or interleukin-22 (IL-22 )-producing subset effector T cells in the skin of a patient having plaque psoriasis vulgaris, a method of reducing the number of regulatory T cells in the skin of a patient having plaque psoriasis vulgaris, and / or a method of reducing the number of dermal dendritic cell-T cell aggregates in the skin of a patient having plaque psoriasis vulgaris a method of slowing the progression of psoriasis disease in a patient having plaque psoriasis vulgaris, a method of reducing the severity of a psoriasis flare in a patient having plaque psoriasis vulgaris, a method of reducing the frequency of a psoriasis flare in a patient having plaque psoriasis vulgaris, and / or a method of preventing a psoriasis flare in a patient having plaque psoriasis vulgaris, and further provided is an IL-17 antagonist for use in such )-producing subset effector T cells in the skin of a patient having plaque psoriasis vulgaris, a method of reducing the number of regulatory T cells in the skin of a patient having plaque psoriasis vulgaris, and / or a method of reducing the number of dermal dendritic cell-T cell aggregates in the skin of a patient having plaque psoriasis vulgaris a method of slowing the progression of psoriasis disease in a patient having plaque psoriasis vulgaris, a method of reducing the severity of a psoriasis flare in a patient having plaque psoriasis vulgaris, a method of reducing the frequency of a psoriasis flare in a patient having plaque psoriasis vulgaris, and / or a method of preventing a psoriasis flare in a patient having plaque psoriasis vulgaris, and further provided is an IL-17 antagonist for use in such a method of reducing the number of dermal dendritic cell-T cell aggregates in the skin of a patient having plaque psoriasis vulgaris, a method of slowing the progression of psoriasis disease in a patient having plaque psoriasis vulgaris, a method of reducing the severity of a psoriasis flare in a patient having plaque psoriasis vulgaris, a method of reducing the frequency of a psoriasis flare in a patient having plaque psoriasis vulgaris, and / or a method of preventing a psoriasis flare in a patient having plaque psoriasis vulgaris, and further provided is an IL-17 antagonist for use in such a method of slowing the progression of psoriasis disease in a patient having plaque psoriasis vulgaris, a method of reducing the severity of a psoriasis flare in a patient having plaque psoriasis vulgaris, a method of reducing the frequency of a psoriasis flare in a patient having plaque psoriasis vulgaris, and / or a method of preventing a psoriasis flare in a patient having plaque psoriasis vulgaris, and further provided is an IL-17 antagonist for use in such a method of reducing the severity of a psoriasis flare in a patient having plaque psoriasis vulgaris, a method of reducing the frequency of a psoriasis flare in a patient having plaque psoriasis vulgaris, and / or a method of preventing a psoriasis flare in a patient having plaque psoriasis vulgaris, and further provided is an IL-17 antagonist for use in such a method of reducing the frequency of a psoriasis flare in a patient having plaque psoriasis vulgaris, and / or a method of preventing a psoriasis flare in a patient having plaque psoriasis vulgaris, and further provided is an IL-17 antagonist for use in such a method of preventing a psoriasis flare in a patient having plaque psoriasis vulgaris, and further provided is an IL-17 antagonist for use in such However, the IL-17 antibody or its antigen The binding fragment is an IL-17 homodimer that contains the two mature human IL-17 protein chains. and the epitope of the chromatin is located at Leu74, Tyr85, and His86, Met87, Asn88, Val124, Thr125, Pro126, I Le127, Val128, His129, and Tyr43, Tyr44, and A on the other strand. rg46, Ala79, and Asp80, The cation has a K of about 100 to 200 pM. D an IL-17 antibody or its antigen-binding flag The ment has an in vivo half-life of approximately 4 weeks.

[0094] Additionally, the present invention relates to a method for the manufacture of a medicament for treating a patient with incipient plaque-type psoriasis. IL-17 antagonists (e.g., IL-17 antibodies or antigen-binding Fragments of secukinumab are disclosed, however, that are not IL-17 antagonists. (e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g., Seckinumab (B) is an epitope of the IL-17 homodimer that contains two mature human IL-17 protein chains. and the epitope is comprised of Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129, and Tyr43, Tyr44, Arg46, and A on the other chain. and the IL-17 antibody or antigen-binding fragment thereof comprises about 1 K from 00 to 200 pM D and the IL-17 antibody or antigen-binding fragment thereof has a It has an in vivo half-life of 4 weeks.

[0095] In addition, the present specification discloses an IL-17 antagonist ( e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) for use in the manufacture of a medicament for modulating an immune mechanism that causes psoriasis disease chronicity in patients with plaque psoriasis vulgaris. However, the IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) binds to an epitope of an IL-17 homodimer having two mature human IL-17 protein chains, and the epitope contains Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 in one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 in the other chain. The IL-17 antibody or an antigen-binding fragment thereof has a K of about 100-200 pM and the IL-1 7 antibody or an antigen-binding fragment thereof has an in vivo half-life of about 4 weeks. In addition, the present specification discloses an IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) for use in the manufacture of a medicament for treating a patient having plaque psoriasis vulgaris. However, the medicament is formulated to include a container, and each container contains an amount of the IL-17 antagonist (e.g., an IL D -17 antibody or an antigen-binding fragment thereof, such as secukinumab) sufficient to enable subcutaneous delivery of at least about 150 mg to about 300 mg ( e.g., about 150 mg, about 300 mg) of the IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) per unit dose.

[0096] per unit dose. In addition, the present specification discloses an IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) for use in the manufacture of a medicament for treating a patient having plaque psoriasis vulgaris. However, the medicament is formulated to include a container, and each container contains an amount of the IL-17 antagonist (e.g., an IL -17 antibody or an antigen-binding fragment thereof, such as secukinumab) sufficient to enable subcutaneous delivery of at least about 150 mg to about 300 mg ( e.g., about 150 mg, about 300 mg) of the IL-17 antagonist (e.g., an IL -17 antibody or an antigen-binding fragment thereof, such as secukinumab) per unit dose. In addition, the present specification discloses an IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding has an antigen-binding fragment, such as secukinumab), and further, an IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukin umab) binds to the epitope of an IL-17 homodimer having two mature human IL-17 protein chains, and the epitope contains Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127 on one chain and Val128, His129, and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain, and the IL-17 antibody or an antigen-binding fragment thereof has a K of about 100-200 pM and the IL-17 antibody or an antigen-binding fragment thereof has an in vivo half-life of about 4 weeks 100-200 pM of K D and the IL-17 antibody or an antigen-binding fragment thereof has an in vivo half-life of about 4 weeks

[0097] In addition, disclosed herein is an IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) for use in the manufacture of a medicament for modulating the immune mechanism that causes psoriasis disease chronicity in patients with plaque psoriasis However, the medicament is formulated to contain a container, and each container contains an amount of IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) sufficient to enable subcutaneous delivery of at least about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) of IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) per unit dose for each unit dose for each unit dose of at least about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) of an IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab), and further, an IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) sufficient to enable subcutaneous delivery of an IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) for each unit dose for each unit dose Its antigen-binding fragments, such as secukinumab, bind to two mature human IL-17 proteins. The epitope of the IL-17 homodimer having a protein chain is Leu74, Tyr85, His86, Met87, Asn88, Val124 on one strand , Thr125, Pro126, Ile127, Val128, His129, and other The IL-1 7. The antibody or antigen-binding fragment thereof has a K of about 100-200 pM. D IL- The 17 antibody or antigen-binding fragment thereof has an in vivo half-life of approximately 4 weeks.

[0098] As used herein, "a dosage that allows for the delivery of [specified dose] through [route of administration]" means The phrase "formulated" refers to a pharmaceutical composition that is used to deliver a drug via a designated route of administration (e.g., SC). or IV) to administer a desired dose of an IL-17 antagonist, such as an IL-17 antibody. For example, the term "secukinumab" is used to refer to the provision of If the desired subcutaneous dose is 300 mg, the clinician should administer 2 ml of 150 mg / ml l of IL-17 antibody preparation, 1 ml of IL-17 antibody preparation having a concentration of 300 mg / ml , 0.5 ml of an IL-17 antibody formulation having a concentration of 600 mg / ml, etc. may be used. In each such case, these IL-17 antibody formulations allow for subcutaneous delivery of the IL-17 antibody. Subcutaneous delivery is typically achieved in a volume of about 2 ml or less. , preferably requiring delivery of a volume of about 1 ml or less. A preferred formulation is about 25 mg / m L to about 150 mg / mL secukinumab, about 10 mM to about 30 mM histidine pH 5.8, A liquid pharmaceutical composition containing about 200 mM to about 225 mM trehalose, about 0.02% polysorbate 80, and about 2 .5 mM to about 20 mM methionine.

[0099] As used herein, the phrase "a container having an amount of an IL- 17 antagonist sufficient to enable delivery of [designated dose]" means that a volume of an IL-17 antagonist (e.g., as part of a pharmaceutical composition) that can be used to provide the desired dose is disposed in a given container (e.g., a vial, pen, syringe). For example, if the desired dose is 150 mg, a clinician can use 2 ml from a container containing an IL-17 antibody formulation having a concentration of 75 mg / ml, 1 ml from a container containing an IL-17 antibody formulation having a concentration of 150 mg / ml, or 0.5 ml from a container containing an IL- 17 antibody formulation having a concentration of 300 mg / ml. In each such case, these containers have an amount of an IL-17 antagonist sufficient to enable delivery of the desired 150 mg dose. In addition, disclosed herein are methods for reducing the likelihood that a patient with psoriasis vulgaris will develop psoriatic arthritis, delaying the onset of psoriatic arthritis in a patient with psoriasis vulgaris, and preventing progression from psoriasis to psoriatic arthritis in a patient with psoriasis vulgaris, including administering to the patient an IL-17 antibody or an antigen-binding fragment thereof at a dose of about 150 mg to about 300 mg (e.g., 150 mg or 300 mg) by subcutaneous injection at 0, 1, 2, 3, and 4 weeks, followed by monthly administration, and the IL-17 antagonists used therefor.

[0100] mg).

[0101] ​​​​​​​​​​ In some embodiments of the disclosed uses, methods and kits, the patient has mild plaque psoriasis. In some embodiments of the disclosed uses, methods and kits, the patient has moderate to severe plaque psoriasis. In some embodiments of the disclosed uses, methods and kits, the patient has not been previously treated with systemic therapy for psoriasis. In some embodiments of the disclosed uses, methods and kits, the patient is naïve to biologic agents. In some embodiments of the disclosed uses, methods and kits, the patient is naïve to topical agents. In some embodiments of the disclosed uses, methods and kits, the patient has not been previously treated with phototherapy for psoriasis.

[0102] In some embodiments of the disclosed uses, methods and kits, from 0, 1, 2, and 3 weeks by subcutaneous (SC) injection, followed by monthly administration starting at 4 weeks, from about 150 mg to about 300 mg of an IL-17 antibody or an antigen-binding fragment thereof is administered to the patient. In some embodiments of the disclosed uses, methods and kits, at 0, 1, 2, and 3 weeks by SC injection, followed by monthly administration starting at 4 weeks, about 150 mg of an IL-1 7 antibody or an antigen-binding fragment thereof is administered to the patient. In some embodiments of the disclosed uses, methods and kits, at 0, 1, 2, and 3 weeks by SC injection, followed by monthly administration starting at 4 weeks, about 300 mg of an IL-17 antibody or an antigen-binding fragment thereof is administered to the patient.

[0103] In some embodiments, in the step of administering the IL-17 antibody every 4 weeks, about 5 μg / ml ~ about 70 μg / ml, about 5 μg / ml to about 33 μg / ml, or about 11 μg / ml to An IL-17 antibody is provided at an average steady state trough level of about 70 μg / ml.

[0104] In some embodiments of the disclosed uses, methods, and kits, the IL-17 antibody or its antigen-binding fragment comprises: i) an immunoglobulin heavy chain variable domain (V H) having the amino acid sequence shown as SEQ ID NO: 8, ii) an immunoglobulin light chain variable domain (V H L) having the amino acid sequence shown as SEQ ID NO: 10, iii) an immunoglobulin V H domain having the amino acid sequence shown as SEQ ID NO: 8 and an immunoglobulin V L L domain having the amino acid sequence shown as SEQ ID NO: 10, iv) an immunoglobulin V H domain comprising the hypervariable regions shown as SEQ ID NOs: 1, 2, and H 3, v) an immunoglobulin V H domain comprising the hypervariable regions shown as SEQ ID NOs: 4, L 5, and 6, vi) an immunoglobulin V H H domain comprising the hypervariable regions shown as SEQ ID NOs: 11, 12, and 13, vii) an immunoglobulin V L H domain comprising the hypervariable regions shown as SEQ ID NOs: 1, 2, and 3, and an immunoglobulin V H domain comprising the hypervariable regions shown as SEQ ID NOs: 4, H 5, and 6, vi ii) an immunoglobulin V H H domain comprising the hypervariable regions shown as SEQ ID NOs: 11, 12, and 13, and an immunoglobulin V L H domain comprising the hypervariable regions shown as SEQ ID NOs: 4, 5, and 6, viii) an immunoglobulin V H H domain, and Immunoglobulin V containing the variable region shown L domain, ix) an immunoglobulin light chain containing the amino acid sequence shown as SEQ ID NO: 14, x) an immunoglobulin heavy chain containing the amino acid sequence shown as SEQ ID NO: 15, or xi) an immunoglobulin light chain containing the amino acid sequence shown as SEQ ID NO: 14 and an immunoglobulin heavy chain containing the amino acid sequence shown as SEQ ID NO: 15 is included.

[0105] In some embodiments of the present disclosure, the IL-17 antibody or its antigen-binding fragment is a monoclonal antibody. In some embodiments of the present disclosure, the IL-17 antibody or its antigen-binding fragment is a human antibody or a humanized antibody. In some embodiments of the present disclosure the IL-17 antibody or its antigen-binding fragment is a human antibody. In some embodiments of the present disclosure the IL-17 antibody or its antigen-binding fragment is a human antibody of the IgG1 subtype. In some embodiments, the IL-17 antibody or its antigen-binding fragment has a κ light chain. In some embodiments of the present disclosure, the IL-1 7 antibody or its antigen-binding fragment is a human antibody of the IgG1κ type. In some embodiments of the present disclosure the IL-17 antibody or its antigen-binding fragment is a secukinumab.

[0106] In some embodiments, the dose of the IL-17 antibody or its antigen-binding fragment is about 300 mg when the patient's weight is > or ≧ 90 kg. In some embodiments about 300 mg when the patient's weight is > or ≧ 100 kg. In some embodiments, the IL-17 antibody When the weight of the patient is < or ≤ 90 kg, the dosage of the whole body or its antigen-binding fragment is about 150 mg. In some embodiments, when the weight of the patient is < or ≤ 100 kg, the dosage of the IL-17 antibody or its antigen-binding fragment is about 150 mg. There is.

[0107] In some embodiments, the dosage of the IL-17 antibody (e.g., secukinumab) is about 1 50 mg, and the IL-17 antibody (e.g., secukinumab) is contained in a liquid pharmaceutical preparation. 1 ml of the pharmaceutical preparation is disposed in a pre-filled syringe, an injection pen or an auto injector disposed in the kit, and the kit further includes instructions for use. In some embodiments the dosage of the IL-17 antibody (e.g., secukinumab) is about 150 mg, and the IL -17 antibody (e.g., secukinumab) is contained in a liquid pharmaceutical preparation at a concentration of 150 mg / ml. 1 ml of the pharmaceutical preparation is disposed in an autoinjector disposed in the kit, and the kit further includes instructions for use.

[0108] In some embodiments, the dosage of the IL-17 antibody (e.g., secukinumab) is about 3 00 mg, and the IL-17 antibody (e.g., secukinumab) is contained in a liquid pharmaceutical preparation at a concentration of 150 mg / ml. The pharmaceutical preparation is disposed in a pre-filled syringe, an injection pen or an autoinjector disposed in the kit, and the kit further includes instructions for use. In some embodiments the dosage of the IL-17 antibody (e.g., secukinumab) is about 300 m g, and the IL-17 antibody (e.g., secukinumab) is contained in a liquid pharmaceutical preparation at a concentration of 150 mg / ml. 2 ml of the pharmaceutical preparation is disposed in an autoinjector disposed in the kit. is disposed, and the kit further includes an instruction manual.

[0109] In some embodiments, the patient has a baseline IGA score of ≧3. Some embodiments, the patient has a baseline PASI score of ≧12. Some embodiments, the patient has a baseline BSA of ≧10%. The PASI and IGA scores of patients who respond to treatment with secukinumab can be found in Langley et al. (2 014) N Engl J Med 371:326-38 (which is incorporated herein by reference in its entirety).

[0110] In some embodiments of the disclosed uses, methods, and kits, at least 60%, at least 67%, at least 70%, at least 71%, at least 77%, or at least 81% of the patients (e.g., adult patients) treated according to the disclosed method achieve PASI75 at 12 weeks.

[0111] In some embodiments, at least 50%, at least 51%, at least 62%, or at least 65% of the patients (e.g., adult patients) treated according to the disclosed method have a response of 0 or 1 in the modified global assessment (IGA) by the treating physician at 12 weeks.

[0112] In some embodiments of the disclosed uses, methods, and kits, at least 35%, at least 39%, at least 41%, at least 54%, or at least 59% of the patients (e.g., adult patients) treated according to the disclosed method achieve PASI90 at 12 weeks.

[0113] In some embodiments, at least 10%, at least 12%, at least 14%, at least 24%, or at least 28% of patients (e.g., adult patients) treated according to the disclosed method achieve PASI 100 at 12 weeks.

[0114] In some embodiments, the disclosed method is used to treat a population of patients having moderate to severe chronic plaque psoriasis, and at least 60%, at least 67%, at least 70%, at least 71%, at least 77%, or at least 81% of said patients achieve at least a PASI 75 response at 12 weeks of treatment.

[0115] In some embodiments, the disclosed method is used to treat a population of patients having moderate to severe chronic plaque psoriasis, and at least 50%, at least 51%, at least 62%, or at least 65% of said patients achieve a Physician's Global Assessment (IGA) response of 0 or 1 at 12 weeks of treatment.

[0116] In some embodiments, the disclosed method is used to treat a population of patients having moderate to severe chronic plaque psoriasis, and at least 35%, at least 39%, at least 41%, at least 54%, or at least 59% of said patients achieve at least a PASI 90 response at 12 weeks of treatment.

[0117] In some embodiments, the disclosed method is used to treat a population of patients having moderate to severe chronic plaque psoriasis, and at least 10%, at least 12%, at least 14%, at least 24%, or at least 28% of said patients achieve PAS at Achieve the I100 response. In addition, herein, a method for treating a patient having moderate to severe plaque psoriasis at onset, which comprises administering to the patient approximately 150 mg of secukinumab by subcutaneous injection at 0, 1, 2, and 3 weeks, followed by monthly administration starting from 4 weeks, is disclosed. However, the patient is naive to biologics. In addition, herein, a method for treating a patient having moderate to severe plaque psoriasis at onset, which comprises administering to the patient approximately 300 mg of secukinumab by subcutaneous injection at 0, 1, 2, and 3 weeks, followed by monthly administration starting from 4 weeks, is disclosed. However, the patient is naive to biologics. Herein, a method for treating a patient having moderate to severe plaque psoriasis at onset, which comprises administering to the patient approximately 150 mg of secukinumab by subcutaneous injection at 0, 1, 2, and 3 weeks, followed by monthly administration starting from 4 weeks, is disclosed. However, the patient is naive to biologics. Herein, a method for treating a patient having moderate to severe plaque psoriasis at onset, which comprises administering to the patient approximately 150 mg of secukinumab by subcutaneous injection at 0, 1, 2, and 3 weeks, followed by monthly administration starting from 4 weeks, is disclosed. However, the patient is naive to biologics. Herein, a method for treating a patient having moderate to severe plaque psoriasis at onset, which comprises administering to the patient approximately 150 mg of secukinumab by subcutaneous injection at 0, 1, 2, and 3 weeks, followed by monthly administration starting from 4 weeks, is disclosed. However, the patient is naive to biologics. Herein, a method for treating a patient having moderate to severe plaque psoriasis at onset, which comprises administering to the patient approximately 150 mg of secukinumab by subcutaneous injection at 0, 1, 2, and 3 weeks, followed by monthly administration starting from 4 weeks, is disclosed. However, the patient is naive to biologics. Herein, a method for treating a patient having moderate to severe plaque psoriasis at onset, which comprises administering to the patient approximately 150 mg of secukinumab by subcutaneous injection at 0, 1, 2, and 3 weeks, followed by monthly administration starting from 4 weeks, is disclosed. However, the patient is naive to biologics. Herein, a method for treating a patient having moderate to severe plaque psoriasis at onset, which comprises administering to the patient approximately 150 mg of secukinumab by subcutaneous injection at 0, 1, 2, and 3 weeks, followed by monthly administration starting from 4 weeks, is disclosed. However, the patient is naive to biologics. Herein, a method for treating a patient having moderate to severe plaque psoriasis at onset, which comprises administering to the patient approximately 150 mg of secukinumab by subcutaneous injection at 0, 1, 2, and 3 weeks, followed by monthly administration starting from 4 weeks, is disclosed. However, the patient is naive to biologics.

[0118] In addition, herein, a method for treating moderate to severe chronic plaque psoriasis, which comprises subcutaneously administering 150 mg or 300 mg of secukinumab to adult patients with early-onset moderate to severe chronic plaque psoriasis at 0, 1, 2, 3, and 4 weeks, and then monthly thereafter, is disclosed. However, when the method is used to treat a population of patients having moderate to severe chronic plaque psoriasis, at least 60%, at least 67%, at least 70%, at least 71%, at least 77%, or at least 81% of said patients achieve at least a PASI75 response at 12 weeks of treatment. Preferably, the patient is naive to biologics. In addition, herein, a method for treating moderate to severe chronic plaque psoriasis, which comprises subcutaneously administering 150 mg or 300 mg of secukinumab to adult patients with early-onset moderate to severe chronic plaque psoriasis at 0, 1, 2, 3, and 4 weeks, and then monthly thereafter, is disclosed. However, when the method is used to treat a population of patients having moderate to severe chronic plaque psoriasis, at least 60%, at least 67%, at least 70%, at least 71%, at least 77%, or at least 81% of said patients achieve at least a PASI75 response at 12 weeks of treatment. Preferably, the patient is naive to biologics. In addition, herein, a method for treating moderate to severe chronic plaque psoriasis, which comprises subcutaneously administering 150 mg or 300 mg of secukinumab to adult patients with early-onset moderate to severe chronic plaque psoriasis at 0, 1, 2, 3, and 4 weeks, and then monthly thereafter, is disclosed. However, when the method is used to treat a population of patients having moderate to severe chronic plaque psoriasis, at least 60%, at least 67%, at least 70%, at least 71%, at least 77%, or at least 81% of said patients achieve at least a PASI75 response at 12 weeks of treatment. Preferably, the patient is naive to biologics. In addition, herein, a method for treating moderate to severe chronic plaque psoriasis, which comprises subcutaneously administering 150 mg or 300 mg of secukinumab to adult patients with early-onset moderate to severe chronic plaque psoriasis at 0, 1, 2, 3, and 4 weeks, and then monthly thereafter, is disclosed. However, when the method is used to treat a population of patients having moderate to severe chronic plaque psoriasis, at least 60%, at least 67%, at least 70%, at least 71%, at least 77%, or at least 81% of said patients achieve at least a PASI75 response at 12 weeks of treatment. Preferably, the patient is naive to biologics. In addition, herein, a method for treating moderate to severe chronic plaque psoriasis, which comprises subcutaneously administering 150 mg or 300 mg of secukinumab to adult patients with early-onset moderate to severe chronic plaque psoriasis at 0, 1, 2, 3, and 4 weeks, and then monthly thereafter, is disclosed. However, when the method is used to treat a population of patients having moderate to severe chronic plaque psoriasis, at least 60%, at least 67%, at least 70%, at least 71%, at least 77%, or at least 81% of said patients achieve at least a PASI75 response at 12 weeks of treatment. Preferably, the patient is naive to biologics. In addition, herein, a method for treating moderate to severe chronic plaque psoriasis, which comprises subcutaneously administering 150 mg or 300 mg of secukinumab to adult patients with early-onset moderate to severe chronic plaque psoriasis at 0, 1, 2, 3, and 4 weeks, and then monthly thereafter, is disclosed. However, when the method is used to treat a population of patients having moderate to severe chronic plaque psoriasis, at least 60%, at least 67%, at least 70%, at least 71%, at least 77%, or at least 81% of said patients achieve at least a PASI75 response at 12 weeks of treatment. Preferably, the patient is naive to biologics. In addition, herein, a method for treating moderate to severe chronic plaque psoriasis, which comprises subcutaneously administering 150 mg or 300 mg of secukinumab to adult patients with early-onset moderate to severe chronic plaque psoriasis at 0, 1, 2, 3, and 4 weeks, and then monthly thereafter, is disclosed. However, when the method is used to treat a population of patients having moderate to severe chronic plaque psoriasis, at least 60%, at least 67%, at least 70%, at least 71%, at least 77%, or at least 81% of said patients achieve at least a PASI75 response at 12 weeks of treatment. Preferably, the patient is naive to biologics. In addition, herein, a method for treating moderate to severe chronic plaque psoriasis, which comprises subcutaneously administering 150 mg or 300 mg of secukinumab to adult patients with early-onset moderate to severe chronic plaque psoriasis at 0, 1, 2, 3, and 4 weeks, and then monthly thereafter, is disclosed. However, when the method is used to treat a population of patients having moderate to severe chronic plaque psoriasis, at least 60%, at least 67%, at least 70%, at least 71%, at least 77%, or at least 81% of said patients achieve at least a PASI75 response at 12 weeks of treatment. Preferably, the patient is naive to biologics.

[0119] In addition, herein, a method for treating moderate to severe chronic plaque psoriasis, which comprises subcutaneously administering 150 mg or 300 mg of secukinumab to adult patients with early-onset moderate to severe chronic plaque psoriasis at 0, 1, 2, 3, and 4 weeks, and then monthly thereafter, is disclosed. However, when the method is used to treat a population of patients having moderate to severe chronic plaque psoriasis, at least 60%, at least 67%, at least 70%, at least 71%, at least 77%, or at least 81% of said patients achieve at least a PASI75 response at 12 weeks of treatment. Preferably, the patient is naive to biologics. In addition, herein, a method for treating moderate to severe chronic plaque psoriasis, which comprises subcutaneously administering 150 mg or 300 mg of secukinumab to adult patients with early-onset moderate to severe chronic plaque psoriasis at 0, 1, 2, 3, and 4 weeks, and then monthly thereafter, is disclosed. However, when the method is used to treat a population of patients having moderate to severe chronic plaque psoriasis, at least 60%, at least 67%, at least 70%, at least 71%, at least 77%, or at least 81% of said patients achieve at least a PASI75 response at 12 weeks of treatment. Preferably, the patient is naive to biologics. In addition, herein, a method for treating moderate to severe chronic plaque psoriasis, which comprises subcutaneously administering 150 mg or 300 mg of secukinumab to adult patients with early-onset moderate to severe chronic plaque psoriasis at 0, 1, 2, 3, and 4 weeks, and then monthly thereafter, is disclosed. However, when the method is used to treat a population of patients having moderate to severe chronic plaque psoriasis, at least 60%, at least 67%, at least 70%, at least 71%, at least 77%, or at least 81% of said patients achieve at least a PASI75 response at 12 weeks of treatment. Preferably, the patient is naive to biologics. A method is disclosed that includes the following. However, when using the method to treat a patient population with moderate to severe chronic plaque psoriasis, at least 50%, at least 51 %, at least 62% or at least 65% of the patients achieve a modified Physician's Global Assessment (IGA) response of 0 or 1 at 12 weeks of treatment. Preferably, the patients are naive to biologic agents.

[0120] In addition, described herein is a method of treating moderate to severe chronic plaque psoriasis, comprising subcutaneously administering 150 mg or 300 mg of secukinumab to adult patients with early-onset moderate to severe chronic plaque psoriasis at 0, 1, 2, 3 and 4 weeks, and then monthly thereafter. However, when using the method to treat a patient population with moderate to severe chronic plaque psoriasis, at least 35%, at least 39 %, at least 41%, at least 54% or at least 59% of the patients achieve at least a PASI90 response at 12 weeks of treatment. Preferably, the patients are naive to biologic agents.

[0121] In addition, described herein is a method of treating moderate to severe chronic plaque psoriasis, comprising subcutaneously administering 150 mg or 300 mg of secukinumab to adult patients with early-onset moderate to severe chronic plaque psoriasis at 0, 1, 2, 3 and 4 weeks, and then monthly thereafter. However, when using the method to treat a patient population with moderate to severe chronic plaque psoriasis, at least 10%, at least 12 %, at least 14%, at least 24% or at least 28% of the patients achieve a P ​​​​​​​​​​Achieve the ASI100 response. Preferably, the patient is naive to biological agents.

[0122] In addition, provided herein is a method of modulating the immune mechanism causing psoriasis chronicity in patients with moderate to severe plaque psoriasis, comprising administering to the patient by subcutaneous injection at 0, 1, 2, and 3 weeks, followed by monthly administration starting at 4 weeks, about 150 mg or about 300 mg of secukinumab. However, the patient is naive to biological agents, and the patient is naive to biological agents. In addition, provided herein is a method of reducing the number of tissue resident memory cells in the lesional skin of patients with moderate to severe plaque psoriasis, comprising administering to the patient by subcutaneous injection at 0, 1, 2, and 3 weeks, followed by monthly administration starting at 4 weeks, about 150 mg or about 300 mg of secukinumab. However, the patient is naive to biological agents. 300 mg of secukinumab. However, the patient is naive to biological agents, and the patient is naive to biological agents. In addition, provided herein is a method of reducing the number of tissue resident memory cells in the lesional skin of patients with moderate to severe plaque psoriasis, comprising administering to the patient by subcutaneous injection at 0, 1, 2, and 3 weeks, followed by monthly administration starting at 4 weeks, about 150 mg or about 300 mg of secukinumab. However, the patient is naive to biological agents. Reduce the number of tissue resident memory cells in the lesional skin of patients with moderate to severe plaque psoriasis, comprising administering to the patient by subcutaneous injection at 0, 1, 2, and 3 weeks, followed by monthly administration starting at 4 weeks, about 150 mg or about 300 mg of secukinumab. However, the patient is naive to biological agents. 300 mg of secukinumab. However, the patient is naive to biological agents. A method is disclosed that includes administering to the patient by subcutaneous injection at 0, 1, 2, 3, and 4 weeks, followed by monthly administration, an IL-17 antibody or an antigen-binding

[0123] fragment in a dose of about 150 mg to about 300 mg, to reduce the likelihood of developing psoriatic arthritis in patients with psoriasis vulgaris, delay the onset of psoriatic arthritis in patients with psoriasis vulgaris, and prevent the progression from psoriasis to psoriatic arthritis in patients with psoriasis vulgaris, and further, an IL-17 antagonist for use in such

[0124]

[0124] In addition, provided herein are pyoderma gangrenosum, ichthyosis, rosacea (e.g., papulopustular rosacea), pityriasis rubra pilaris, lichen planopilaris, atopic dermatitis, allergic contact dermatitis, discoid A method for treating alopecia or human papillomavirus (HPV) disease, comprising administering to a patient by subcutaneous injection at 0, 1, 2 , 3 and 4 weeks, followed by monthly administration, about 150 mg or about 300 mg of secukinumab. In addition, the present specification discloses a method for treating pyoderma gangrenosum, ichthyosis, rosacea (e.g., papulopustular rosacea), lichen planopilaris , pityriasis rubra pilaris, atopic dermatitis, allergic contact dermatitis, alopecia areata or human papillomavirus (HPV) disease, comprising administering to a patient by subcutaneous injection about 150 mg or about 300 mg of secukinumab every 4 weeks (once a month).

[0125] Kit The present disclosure also encompasses a kit for treating plaque psoriasis. Such a kit comprises an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof) (e.g., in liquid form or lyophilized form) or a pharmaceutical composition comprising an IL-17 antagonist (as described above). In addition, such a kit may include means for administering the IL-17 antagonist (e.g., an autoinjector, syringe, pre-filled syringe, pre-filled pen, and vial) and instructions for use. These kits may be used to treat plaque psoriasis in combination with the included IL-17 antagonist, such as an IL-17 binding molecule, such as an IL-17 antibody, such as secukinumab, for delivery. ​​​​​​​may contain an additional therapeutic psoriasis agent (as described above). Such a kit may also include instructions regarding the administration of an IL-17 antagonist (e.g., an IL-1 7 antibody, e.g., secukinumab) for treating patients with plaque psoriasis at onset. Such instructions may provide, for use with the included IL-17 antagonist, e.g., an IL-17 binding molecule, e.g., an IL-17 antibody, e.g., secukinumab, the dosage (e.g., 10 mg / kg , 75 mg, 150 mg, 300 mg), the route of administration (e.g., IV, SC) and the administration regimen (e.g., at weeks 0, 2 and 4 then monthly starting at week 8, once weekly at weeks 0, 1, 2 and 3 then monthly starting at week 4 (every 4 weeks ) etc.).

[0126] The phrase "means for administration" is used to denote any appliance available for systemically administering a drug to a patient, e.g., but not limited to, pre-filled syringes, vials and syringes, injection pens, autoinjectors, IV drips and bags, pumps, etc. Using such items, a patient may self-administer (i.e., administer the drug without the assistance of a physician) or a physician may administer the drug.

[0127] As used herein, a kit used in modulating the immune mechanisms that cause psoriasis chronicity in patients with plaque psoriasis at onset and / or in treating patients having plaque psoriasis at onset, the kit comprising an IL-17 antagonist (e.g., an IL-17 binding molecule, e.g., an IL-17 antibody or an antigen-binding fragment ​A kit is disclosed. In some embodiments, the kit further comprises means for administering an IL-17 antagonist to a patient. In some embodiments, the kit further comprises instructions regarding administration of the IL-17 antagonist. The instructions indicate that the IL-17 antagonist (e.g., an IL-17 binding molecule, e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) is administered SC at weeks 0, 1, 2, and 3 once weekly at about 150 mg to about 300 mg (e.g., about 150 mg or about 300 mg), and then starting at week 4 at about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) once monthly (every 4 weeks) SC to the patient. In some embodiments, the instructions will provide for dose escalation (e.g., from a dose of about 150 mg or about 300 mg to a higher dose of about 450 mg as determined by a physician as needed). In some embodiments, the kit further comprises means for administering an IL-17 antagonist to a patient. In some embodiments, the kit further comprises instructions regarding administration of the IL-17 antagonist. The instructions indicate that the IL-17 antagonist (e.g., an IL-17 binding molecule, e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) is administered SC at weeks 0, 1, 2, and 3 once weekly at about 150 mg to about 300 mg (e.g., about 150 mg or about 300 mg), and then starting at week 4 at about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) once monthly (every 4 weeks) SC to the patient. In some embodiments, the instructions will provide for dose escalation (e.g., from a dose of about 150 mg or about 300 mg to a higher dose of about 450 mg as determined by a physician as needed). In some embodiments, the kit further comprises instructions regarding administration of the IL-17 antagonist. The instructions indicate that the IL-17 antagonist (e.g., an IL-17 binding molecule, e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) is administered SC at weeks 0, 1, 2, and 3 once weekly at about 150 mg to about 300 mg (e.g., about 150 mg or about 300 mg), and then starting at week 4 at about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) once monthly (every 4 weeks) SC to the patient. In some embodiments, the instructions will provide for dose escalation (e.g., from a dose of about 150 mg or about 300 mg to a higher dose of about 450 mg as determined by a physician as needed). In some embodiments, the kit further comprises instructions regarding administration of the IL-17 antagonist. The instructions indicate that the IL-17 antagonist (e.g., an IL-17 binding molecule, e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) is administered SC at weeks 0, 1, 2, and 3 once weekly at about 150 mg to about 300 mg (e.g., about 150 mg or about 300 mg), and then starting at week 4 at about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) once monthly (every 4 weeks) SC to the patient. In some embodiments, the instructions will provide for dose escalation (e.g., from a dose of about 150 mg or about 300 mg to a higher dose of about 450 mg as determined by a physician as needed). In some embodiments, the kit further comprises instructions regarding administration of the IL-17 antagonist. The instructions indicate that the IL-17 antagonist (e.g., an IL-17 binding molecule, e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) is administered SC at weeks 0, 1, 2, and 3 once weekly at about 150 mg to about 300 mg (e.g., about 150 mg or about 300 mg), and then starting at week 4 at about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) once monthly (every 4 weeks) SC to the patient. In some embodiments, the instructions will provide for dose escalation (e.g., from a dose of about 150 mg or about 300 mg to a higher dose of about 450 mg as determined by a physician as needed). In some embodiments, the kit further comprises instructions regarding administration of the IL-17 antagonist. The instructions indicate that the IL-17 antagonist (e.g., an IL-17 binding molecule, e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) is administered SC at weeks 0, 1, 2, and 3 once weekly at about 150 mg to about 300 mg (e.g., about 150 mg or about 300 mg), and then starting at week 4 at about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) once monthly (every 4 weeks) SC to the patient. In some embodiments, the instructions will provide for dose escalation (e.g., from a dose of about 150 mg or about 300 mg to a higher dose of about 450 mg as determined by a physician as needed). In some embodiments, the kit further comprises instructions regarding administration of the IL-17 antagonist. The instructions indicate that the IL-17 antagonist (e.g., an IL-17 binding molecule, e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) is administered SC at weeks 0, 1, 2, and 3 once weekly at about 150 mg to about 300 mg (e.g., about 150 mg or about 300 mg), and then starting at week 4 at about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) once monthly (every 4 weeks) SC to the patient. In some embodiments, the instructions will provide for dose escalation (e.g., from a dose of about 150 mg or about 300 mg to a higher dose of about 450 mg as determined by a physician as needed). In some embodiments, the kit further comprises instructions regarding administration of the IL-17 antagonist. The instructions indicate that the IL-17 antagonist (e.g., an IL-17 binding molecule, e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) is administered SC at weeks 0, 1, 2, and 3 once weekly at about 150 mg to about 300 mg (e.g., about 150 mg or about 300 mg), and then starting at week 4 at about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) once monthly (every 4 weeks) SC to the patient. In some embodiments, the instructions will provide for dose escalation (e.g., from a dose of about 150 mg or about 300 mg to a higher dose of about 450 mg as determined by a physician as needed). In some embodiments, the kit further comprises instructions regarding administration of the IL-17 antagonist. The instructions indicate that the IL-17 antagonist (e.g., an IL-17 binding molecule, e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) is administered SC at weeks 0, 1, 2, and 3 once weekly at about 150 mg to about 300 mg (e.g., about 150 mg or about 300 mg), and then starting at week 4 at about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) once monthly (every 4 weeks) SC to the patient. In some embodiments, the instructions will provide for dose escalation (e.g., from a dose of about 150 mg or about 300 mg to a higher dose of about 450 mg as determined by a physician as needed). In some embodiments, the kit further comprises instructions regarding administration of the IL-17 antagonist. The instructions indicate that the IL-17 antagonist (e.g., an IL-17 binding molecule, e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) is administered SC at weeks 0, 1, 2, and 3 once weekly at about 150 mg to about 300 mg (e.g., about 150 mg or about 300 mg), and then starting at week 4 at about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) once monthly (every 4 weeks) SC to the patient. In some embodiments, the instructions will provide for dose escalation (e.g., from a dose of about 150 mg or about 300 mg to a higher dose of about 450 mg as determined by a physician as needed).

[0128] General matters In preferred embodiments of the disclosed methods, treatments, medicaments, regimens, uses, and kits, the IL-17 antagonist is an IL-17 binding molecule. In preferred embodiments, the IL-17 binding molecule is an IL-17 antibody or an antigen-binding fragment thereof. In some embodiments of the disclosed methods, treatments, regimens, uses, and kits, the IL-17 antibody or an antigen-binding fragment thereof binds to an epitope of human IL-17 comprising a) Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129, b) Tyr43, Tyr44, Arg46, Ala79, A In preferred embodiments of the disclosed methods, treatments, medicaments, regimens, uses, and kits, the IL-17 antagonist is an IL-17 binding molecule. In preferred embodiments, the IL-17 binding molecule is an IL-17 antibody or an antigen-binding fragment thereof. In some embodiments of the disclosed methods, treatments, regimens, uses, and kits, the IL-17 antibody or an antigen-binding fragment thereof binds to an epitope of human IL-17 comprising a) Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129, b) Tyr43, Tyr44, Arg46, Ala79, A In preferred embodiments of the disclosed methods, treatments, medicaments, regimens, uses, and kits, the IL-17 antagonist is an IL-17 binding molecule. In preferred embodiments, the IL-17 binding molecule is an IL-17 antibody or an antigen-binding fragment thereof. In some embodiments of the disclosed methods, treatments, regimens, uses, and kits, the IL-17 antibody or an antigen-binding fragment thereof binds to an epitope of human IL-17 comprising a) Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129, b) Tyr43, Tyr44, Arg46, Ala79, A In some embodiments of the disclosed methods, treatments, regimens, uses, and kits, the IL-17 antibody or an antigen-binding fragment thereof binds to an epitope of human IL-17 comprising a) Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129, b) Tyr43, Tyr44, Arg46, Ala79, A In some embodiments of the disclosed methods, treatments, regimens, uses, and kits, the IL-17 antibody or an antigen-binding fragment thereof binds to an epitope of human IL-17 comprising a) Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129, b) Tyr43, Tyr44, Arg46, Ala79, A In some embodiments of the disclosed methods, treatments, regimens, uses, and kits, the IL-17 antibody or an antigen-binding fragment thereof binds to an epitope of human IL-17 comprising a) Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129, b) Tyr43, Tyr44, Arg46, Ala79, A In some embodiments of the disclosed methods, treatments, regimens, uses, and kits, the IL-17 antibody or an antigen-binding fragment thereof binds to an epitope of human IL-17 comprising a) Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129, b) Tyr43, Tyr44, Arg46, Ala79, A In some embodiments of the disclosed methods, treatments, regimens, uses, and kits, the IL-17 antibody or an antigen-binding fragment thereof binds to an epitope of human IL-17 comprising a) Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129, b) Tyr43, Tyr44, Arg46, Ala79, A An IL-17 antibody that binds to an epitope of human IL-17 containing sp80 or its antigen-binding fragment, c) an IL-17 antibody that binds to an epitope of an IL-17 homodimer having two mature human IL-17 protein chains or its antigen-binding fragment (provided that , the epitope contains Leu74, Tyr85, His86, Met87, A sn88, Val124, Thr125, Pro126, Ile127, Val128, His129 on one chain and Tyr43, Tyr44, Arg46, Ala79, As p80 on the other chain), d) an IL-17 antibody that binds to an epitope of an IL-17 homodimer having two mature human IL-17 protein chains or its antigen-binding fragment (provided that , the epitope contains Leu74, Tyr85, His86, Met87, A , the epitope contains Leu74, Tyr85, His86, Met87, A sn88, Val124, Thr125, Pro126, Ile127, Val128, His129 on one chain and Tyr43, Tyr44, Arg46, Ala79, As p80 on the other chain, and the IL-17 binding molecule has a K of about 100-200 pM, and the IL-17 D binding molecule has an in vivo half-life of about 23 to about 35 days) and e) i) an immunoglobulin heavy chain variable domain (V ) containing the amino acid sequence shown as SEQ ID NO: 8, ii) an immunoglobulin light chain variable domain (V ) containing the amino acid sequence shown as SEQ ID NO: 10, iii) an immunoglobulin V H domain containing the amino acid sequence shown as SEQ ID NO: 8 and an immunoglobulin V domain containing the amino acid sequence shown as SEQ ID NO: 10, iv L ), and iv) an immunoglobulin containing the hypervariable regions shown as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 , iii) an immunoglobulin V domain containing the amino acid sequence shown as SEQ ID NO: 8 and H and an immunoglobulin V domain containing the amino acid sequence shown as SEQ ID NO: 10, iv ), and iv) an immunoglobulin containing the hypervariable regions shown as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 L domain, iv ) an immunoglobulin containing the hypervariable regions shown as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 Lymphocyte V H domain, v) immunoglobulin V containing hypervariable regions shown as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 domain, vi) immunoglobulin V containing hypervariable regions shown as SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID L ID NO: 13 domain, vii) immunoglobulin V containing hypervariable regions shown as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 H domain, and immunoglobulin V containing hypervariable regions shown as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 domain, viii) immunoglobulin V containing hypervariable regions shown as SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID H ID NO: 13 domain, and immunoglobulin V containing hypervariable regions shown as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 L domain, ix) immunoglobulin light chain containing the amino acid sequence shown as SEQ ID NO: 14, x) immunoglobulin heavy chain containing the amino acid sequence shown as SEQ ID NO: 15, or xi) H immunoglobulin light chain containing the amino acid sequence shown as SEQ ID NO: 14 and immunoglobulin heavy chain containing the amino acid sequence shown as SEQ ID NO: 15 selected from the group consisting of an IL-17 antibody or an antigen-binding fragment thereof L domain, ix) immunoglobulin light chain containing the amino acid sequence shown as SEQ ID NO: 14, x) immunoglobulin heavy chain containing the amino acid sequence shown as SEQ ID NO: 15, or xi) immunoglobulin light chain containing the amino acid sequence shown as SEQ ID NO: 14 and immunoglobulin heavy chain containing the amino acid sequence shown as SEQ ID NO: 15 selected from the group consisting of an IL-17 antibody or an antigen-binding fragment thereof In some embodiments of the disclosed methods, kits or uses, the IL-17 antibody or

[0129] its antigen-binding fragment is a monoclonal antibody. In some embodiments of the disclosed methods, kits or uses, the IL-17 antibody or its antigen-binding fragment is a human antibody or a humanized antibody, preferably a human antibody. In the disclosed methods, kits or uses In some embodiments of use, the IL-17 antibody or its antigen-binding fragment is I a human antibody of the IgG1 isotype. In some of the disclosed methods, kits or uses embodiments, the antibody or its antigen-binding fragment is secukinumab.

[0130] The details of one or more embodiments of the present disclosure are set forth in the accompanying description above. Any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, but the preferred methods and materials are described below. Other features, objects, and advantages of the present disclosure will become apparent from the description and claims. In this specification and the appended patent claims, the singular forms include references to the plural unless the context clearly dictates otherwise. Unless defined otherwise, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications listed herein are incorporated by reference. The following examples are presented to illustrate more specifically the preferred embodiments of the present disclosure. These examples should in no way be construed as limiting the scope of the disclosed subject matter as defined by the appended patent claims.

EXAMPLE

EXAMPLE

[0131] Example 1: Imiquimod Skin and Ear Inflammation Imiquimod is used for the topical treatment of genital warts and perineal warts caused by human papillomavirus. The clinical indications for this therapy include other virus-related skin abnormalities, as well as precancerous and cancerous skin lesions, such as actinic keratosis and superficial basal cell carcinoma. has been further expanded to include treatment. Clinically, imiquimod has been found to exacerbate psoriasis in patients who had previously had good disease control during local treatment of actinic keratosis and superficial basal cell carcinoma. Imiquimod-induced exacerbation of psoriasis occurs in both the treated area and, interestingly, in distant skin sites that had not previously been affected by the disease. Therefore, treatment of mice with imiquimod cream, which produces skin lesions similar to psoriasis, can be used to study putative anti-psoriatic therapies early in the disease process (van der Fits et al. (2009) J. Immunol 182:5836-5845). process (van der Fits et al. (2009) J. Immunol 182:5836-5845). .

[0132] A. Systemic delivery Female Balb / c mice (8-10 weeks old) were used in a skin inflammation model. A 5% imiquimod containing cream or a vehicle cream was applied daily to the shaved backs of the mice (total imiquimod dose 12.5 mg / mouse). Skin thickness on the back was measured daily using digital calipers .

[0133] Anti-IL-17 Ab was administered by intraperitoneal injection on days -3, 0, 4, 7, and 11 relative to the first application of the cream. Skin thickness was calculated as the % change at each time point relative to day 0 (baseline), and area under the curve (AUC) graphs were obtained for the vehicle cream, imiquimod cream, and Ab treatment groups. The percent inhibition of individual animals in the AUC of each treatment group was calculated relative to the imiquimod group AUC ( 0% inhibition) using an Excel spreadsheet. As shown in Figure 1, treatment with anti-IL-17 Ab administered i.p . at 100 mg / kg on days -3, 0, 4, 7, and 11 resulted in an AUC of skin swelling

[0134] As shown in Figure 1, treatment with anti-IL-17 Ab administered i.p . at 100 mg / kg on days -3, 0, 4, 7, and 11 resulted in an AUC of skin swelling[0~14日間] was 22. was inhibited by 94 ± 12.25%. Therefore, early systemic treatment with an IL-17 antibody reduces skin thickness in this model.

[0135] B. Local delivery Female Balb / c mice (8 - 10 weeks old) were used in an ear inflammation model. A cream containing 5% imiquimod was applied daily to both ears of the mice (total imiquimod dose 12.5 mg / mouse). The ear thickness of both ears was measured daily using a digital caliper and averaged.

[0136] Anti - IL - 17Ab was administered as a single dose by subcutaneous injection at 100 mg / kg on day - 3 relative to the first application of the cream. The % change in ear thickness was calculated at each time point relative to day 0 (baseline), and the area under the curve (AUC) graphs for the imiquimod cream and Ab treatment groups were obtained. The percent inhibition of AUC for individual animals in each treatment group was calculated relative to the imiquimod group AUC (0% inhibition) using an Excel spreadsheet.

[0137] As shown in Figure 2, treatment with anti - IL - 17Ab administered s.c. at 100 mg / kg only on day - 3 resulted in an AUC of ear swelling [0~10日間] that was inhibited by 25.50 ± 2.28%. * p < 0.05 (unpaired t - test). Therefore, early local treatment with an IL - 17 antibody reduces ear thickness in this model.

[0138] In summary, early treatment (local or systemic delivery) of psoriasis vulgaris with an IL - 17 antibody is associated with inflammation related to the plaque - type skin lesions that occur in psoriasis (e.g., thickness and / or It is suggested from the data of imiquimod model tests that it may be possible to reduce (or swelling).

[0139] Example 2: IL23-induced auricular swelling Cytokine IL-23, which drives the generation of Th17 cells that produce IL-17 and IL22, has been proposed to be functionally involved in the pathogenesis of psoriasis. (For example, see van der Fits et al. (2009) J. Immunol 182:583 6-5845). In psoriatic skin lesions, the expression of IL-23 increases, and there are increased numbers of Th17 cells. Intradermal injection of IL-23 into mouse skin results in erythema, mixed inflammatory infiltrates, and epidermal hyperplasia, and swelling occurs at the injection site after repeated injections. Both IL-23 and IL-17 have been shown to be critical for the progression of psoriasis, so an IL-23 ear injection mouse model can also be used as a convenient and rapid method to study therapies that may be useful for the treatment of early psoriasis. On day 0, 1 μg of IL-23 in 10 μl of PBS was injected i.d. into the right auricle of female Balb / c mice (approximately 20 g), and 10 μl of PBS alone was injected into the left auricle (control ear). Ear injections with IL-23 and PBS were repeated on days 2, 5, and 7. Ear thickness was measured using digital calipers on days 0, 5, 7, and

[0140] 8. One day before the first ear injection on day 0, an anti-IL-17 Ab therapeutic agent or an isotype control Ab therapeutic agent was administered i.p. as a single dose at 30 mg / kg. The right auricular swelling was calculated as the ratio of the right auricular swelling to the left auricular swelling, and the R / L auricular swelling ratio was plotted against time to obtain the control group and

[0141] The area under the curve (AUC) graphs of the treatment groups were obtained. Using an Excel spreadsheet, the percent inhibition of AUC for individual animals in each treatment group was calculated compared to the control group AUC (0% inhibition).

[0142] As shown in Figure 3, treatment with anti-IL-1 7Ab administered i.p. at 30 mg / kg only on day -1 resulted in an inhibition of ear swelling AUC [0 - 8 days] of 38.57 ± 3.98%. *** p < 0.001 (paired t-test). This suggests that early treatment of initial psoriasis with an IL-17 antibody can reduce inflammation associated with plaque-type skin lesions that occur in psoriasis (e.g.,

[0143] Example 3: Analysis of the response of psoriasis patients to secukinumab treatment according to disease duration The details and results of the design of two Phase 3 double-blind 52-week trials, ERASURE (Response Efficacy and Safety of Two Fixed Secukinumab Regimens in Psoriasis, CAIN457A2302) and FIXTURE E (A Year-Round Study of Secukinumab Versus Etanercept Using Two Dosage Regimens to Determine Efficacy in Psoriasis, CAIN457A2303), are presented in Langley et al. (2014) N Engl J Med 371:326 -38. The percentage of patients who met the PASI75 criterion at 12 weeks was higher for each secukinumab dosage than for placebo or etanercept: in the ERASUR E trial, the PASI75 rate was 81.6% for 300 mg of secukinumab, 71.6% for 150 mg of secukinumab, and 4.5% for placebo, and in the F IXTURE trial, the rate was 77.1% for 300 mg of secukinumab, 15 For secukinumab at 0 mg, it was 67.0%, for etanercept it was 44.0% and for placebo it was 4.9% (P < 0 .001 for each secukinumab dose vs comparator). The proportion of patients with a modified global assessment (IGA) response of 0 or 1 at 12 weeks was higher for each secukinumab dose than for placebo or etanercept: In the ERASURE trial, the rates were 65.3% for 300 mg of secukinumab, 51.2% for 150 mg of secukinumab and 2.4% for placebo, and in the FIXTURE trial, the rates were 62.5% for 300 mg of secukinumab, 51.1% for 150 mg of secukinumab, 27.2% for etanercept and 2.8% for placebo (P < 0.001 for each secukinumab dose vs comparator). The infection rate for secukinumab was higher than for placebo in both trials and was similar to that for etanercept. To determine whether the effects of 150 mg and 300 mg of secukinumab on PASI75, PASI90 and PASI100 and the response rate of IGA 0 / 1 vary by subgroup of patients in different stages of psoriasis disease history, the data from ERASURE and FI XTURE were reanalyzed. The following three subgroups were analyzed. Namely, those diagnosed with moderate to severe psoriasis at study enrollment with a disease duration of ≤2 years, 2 to ≤10 years, and ≥10 years. Table 3 below gives a summary of the period (number of years) since patients in ERASURE and FIXTURE were first diagnosed with psoriasis. For secukinumab at 0 mg, it was 67.0%, for etanercept it was 44.0% and for placebo it was 4.9% (P < 0 .001 for each secukinumab dose vs comparator). The proportion of patients with a modified global assessment (IGA) response of 0 or 1 at 12 weeks was higher for each secukinumab dose than for placebo or etanercept: In the ERASURE trial, the rates were 65.3% for 300 mg of secukinumab, 51.2% for 150 mg of secukinumab and 2.4% for placebo, and in the FIXTURE trial, the rates were 62.5% for 300 mg of secukinumab, 51.1% for 150 mg of secukinumab, 27.2% for etanercept and 2.8% for placebo (P < 0.001 for each secukinumab dose vs comparator). The infection rate for secukinumab was higher than for placebo in both trials and was similar to that for etanercept. To determine whether the effects of 150 mg and 300 mg of secukinumab on PASI75, PASI90 and PASI100 and the response rate of IGA 0 / 1

[0144] vary by subgroup of patients in different stages of psoriasis disease history, the data from ERASURE and FI XTURE were reanalyzed. The following three subgroups were analyzed. Namely, those diagnosed with moderate to severe psoriasis at study enrollment with a disease duration of ≤2 years, 2 to ≤10 years, and ≥10 years. Table 3 below gives a summary of the period (number of years) since patients in ERASURE and FIXTURE were first diagnosed with psoriasis. years, 2 to ≤10 years, and ≥10 years. Table 3 below gives a summary of the period (number of years) since patients in ERASURE and FIXTURE were first diagnosed with psoriasis. years, 2 to ≤10 years, and ≥10 years. Table 3 below gives a summary of the period (number of years) since patients in ERASURE and FIXTURE were first diagnosed with psoriasis. For secukinumab at 0 mg, it was 67.0%, for etanercept it was 44.0% and for placebo it was 4.9% (P < 0 .001 for each secukinumab dose vs comparator). The proportion of patients with a modified global assessment (IGA) response of 0

[0145]

Table 3

[0146] As shown in Figure 5, at 52 weeks, with secukinumab 150 mg treatment, PASI 10 Except for 0, the percentage of responses was highest in the short-term subgroup (i.e., patients diagnosed with psoriasis within ≤ 2 years before treatment). Consistently, the intermediate patient subgroup (i.e., patients diagnosed with psoriasis between 2 and ≤ 10 years) and the long-term patient subgroup (i.e., patients diagnosed with psoriasis ≥ 10 years) followed. Therefore, after treatment with 150 mg secukinumab, the rate of responders among short-term patients achieving PASI 75 / 90 and IGA 0 / 1 improvement is greater compared to patients with more advanced disease. Fourteen out of 30 patients (n = 30) with a psoriasis duration of ≤ 2 years before treatment had been previously treated with non-biological systemic therapy, and the patients were all biologic-naive and topical-naive. In further analysis, it was shown that 2 out of 7 patients (n = 7) with a psoriasis duration of ≤ 1 year before treatment had been previously treated with non-biological systemic therapy, and the patients were all biologic-naive and topical-naive. As shown in Figure 6, at 52 weeks, with secukinumab 300 mg treatment, for PASI 75 and PASI 100, the difference in the responder rate between short-term (≤ 2 years) vs. non-short-term (> 2 years) was only 1.1%. However, for PASI 90 and IGA 0 / 1 the percentage of responders in the short-term subgroup was higher than that in the intermediate and long-term subgroups. Therefore, after treatment with 300 mg secukinumab, patients with more advanced disease had been previously treated with non-biological systemic therapy, and the patients were all biologic-naive and topical-naive. had been previously treated with non-biological systemic therapy, and the patients

[0147] As shown in Figure 6, at 52 weeks, with secukinumab 300 mg treatment, for PASI 75 and PASI 100, the difference in the responder rate between short-term (≤ 2 years) vs. non-short-term (> 2 years) was only 1.1%. However, for PASI 90 and IGA 0 / 1 the percentage of responders in the short-term subgroup was higher than that in the intermediate and long-term subgroups. Therefore, after treatment with 300 mg secukinumab, patients with more advanced disease had been previously treated with non-biological systemic therapy, and the patients had a higher percentage of responders in the short-term subgroup compared to those in the intermediate and long-term subgroups. Therefore, after treatment with 300 mg secukinumab, patients with more advanced disease Response of short-term patients achieving improvement in PASI90 and IGA0 / 1 compared to patients with a higher rate of clearance. Among patients (n = 33) with a psoriasis duration of ≤2 years before treatment, 22 of them had been previously treated with non-biological systemic therapy, and all patients were naive to biologics or topical agents. In further analysis, among patients (n = 11) with a psoriasis duration of ≤1 year before treatment, 8 of them had been previously treated with non-biological systemic therapy, and it was shown that all patients were naive to biologics and topical agents.

[0148] Trial CAIN457A2317 treated moderate to severe psoriasis with 300 mg secukinumab and performed a similar analysis of patients. Interestingly, in this analysis, the rate of improvement achieved by the short-term subgroup was comparable to the rate observed in patients with more advanced disease (data not shown). However, in CAIN457A2317, only 15 patients had a psoriasis duration of ≤2 years before treatment, and it should be noted that comparison between subgroups was difficult in this trial. Among patients (n = 15) with a psoriasis duration of ≤2 years before treatment, 8 of them had been previously treated with non-biological systemic therapy, and 1 patient had been previously treated with biological systemic therapy. In further analysis, among patients (n = 5) with a psoriasis duration of ≤1 year before treatment, 4 of them had been previously treated with non-biological systemic therapy, and it was shown that all patients were

[0149]

Table 4

[0150]

Table 5

[0151]

Table 6

[0152]

Table 7

[0153]

Table 8

[0154]

Table 9

[0155]

Table 10

[0156]

Table 11

[0157]

Table 12

Claims

1. A method for treating a patient having moderate to severe plaque psoriasis, comprising administering to the patient by subcutaneous injection at 0, 1, 2, and 3 weeks, and subsequently by monthly administration starting from 4 weeks, about 150 mg or about 300 mg of secukinumab. The method according to claim 1, wherein the patient is naive to biologic agents. The method according to claim 1, comprising administering to the patient by subcutaneous injection at 0, 1, 2, and 3 weeks, and subsequently by monthly administration starting from 4 weeks, about 300 mg of secukinumab.

4. A method for reducing the number of tissue resident memory cells in the lesional skin of a patient having moderate to severe plaque psoriasis, comprising administering to the patient by subcutaneous injection at 0, 1, 2, and 3 weeks, and subsequently by monthly administration starting from 4 weeks, about 150 mg or about 300 mg of secukinumab, wherein the patient is naive to biologic agents.

5. A method for treating a patient having plaque psoriasis, comprising administering to the patient in need thereof a therapeutically effective amount of an anti-IL-17 antibody or an antigen-binding fragment thereof, wherein the anti-IL-17 antibody or an antigen-binding fragment thereof binds to an epitope of an IL-17 homodimer having two mature human IL-17 protein chains, the epitope comprising Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 on one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain, and the anti-IL-17 antibody or an antigen-binding fragment thereof has an in vivo half-life of about 4 weeks.

6. A method of modulating the immune mechanism causing psoriasis disease chronicity in the skin of a patient having plaque psoriasis, comprising administering to the patient in need thereof a therapeutically effective amount of an anti-IL-17 antibody or an antigen-binding fragment thereof, wherein the anti-IL-17 antibody or an antigen-binding fragment thereof binds to an epitope of an IL-17 homodimer having two mature human IL-17 protein chains, the epitope comprising Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, I ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ 17 An antibody or antigen-binding fragment thereof has a K of about 100-200 pM Ｄ and said ​ ​ ​ ​ ​ ​ ​ ​ ​ Le127, Val128, His129, and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain, and the IL-17 antibody or its antigen-binding fragment has an in vivo half-life of about 4 weeks, method. wherein the IL-17 antibody or its antigen-binding fragment has an in vivo half-life of about 4 weeks. The gument has K of about 100 to 200 pM Ｄ and has the IL-17 antibody or its antigen-binding A method, wherein the IL-17 antibody or its antigen-binding fragment has an in vivo half-life of about 4 weeks. **Claim 7** The method according to claim 5 or 6, wherein the patient has moderate to severe plaque psoriasis. A method according to claim 5 or 6, wherein the patient has moderate to severe plaque psoriasis. **Claim 8** The method according to any one of claims 5 to 7, wherein the patient has not been previously treated with systemic therapy for psoriasis. A method according to any one of claims 5 to 7, wherein the patient has not been previously treated with systemic therapy for psoriasis. **Claim 9** The method according to any one of claims 5 to 7, wherein the patient is naive to biologic agents. **Claim 10** The method according to any one of claims 5 to 9, wherein the patient has not been previously treated with phototherapy for psoriasis. A method according to any one of claims 5 to 9, wherein the patient has not been previously treated with phototherapy for psoriasis. **Claim 11** Administering to the patient by subcutaneous injection at 0, 1, 2, and 3 weeks, followed by monthly administration starting at 4 weeks, about 150 mg to about 300 mg of the IL-17 antibody or its antigen-binding fragment, the method according to any one of claims 5 to 10. Administering to the patient by subcutaneous injection at 0, 1, 2, and 3 weeks, followed by monthly administration starting at 4 weeks, about 150 mg to about 300 mg of the IL-17 antibody or its antigen-binding fragment, the method according to any one of claims 5 to 10. A method according to any one of claims 5 to 10, comprising administering to the patient by subcutaneous injection at 0, 1, 2, and 3 weeks, followed by monthly administration starting at 4 weeks, about 150 mg to about 300 mg of the IL-17 antibody or its antigen-binding fragment. **Claim 12** Administering to the patient by subcutaneous injection at 0, 1, 2, and 3 weeks, followed by monthly administration starting at 4 weeks, about 150 mg of the IL-17 antibody or its antigen-binding fragment, the method according to any one of claims 5 to 11. Administering to the patient by subcutaneous injection at 0, 1, 2, and 3 weeks, followed by monthly administration starting at 4 weeks, about 150 mg of the IL-17 antibody or its antigen-binding fragment, the method according to any one of claims 5 to 11. A method according to any one of claims 5 to 11, comprising administering to the patient by subcutaneous injection at 0, 1, 2, and 3 weeks, followed by monthly administration starting at 4 weeks, about 150 mg of the IL-17 antibody or its antigen-binding fragment. **Claim 13** Administering to the patient by subcutaneous injection at 0, 1, 2, and 3 weeks, followed by monthly administration starting at 4 weeks, about 300 mg of the IL-17 antibody or its antigen-binding fragment, the method according to any one of claims 5 to 11. Administering to the patient by subcutaneous injection at 0, 1, 2, and 3 weeks, followed by monthly administration starting at 4 weeks, about 300 mg of the IL-17 antibody or its antigen-binding fragment, the method according to any one of claims 5 to 11. A method according to any one of claims 5 to 11, comprising administering to the patient by subcutaneous injection at 0, 1, 2, and 3 weeks, followed by monthly administration starting at 4 weeks, about 300 mg of the IL-17 antibody or its antigen-binding fragment. **Claim 14** The IL-17 antibody or its antigen-binding fragment i) an immunoglobulin heavy chain variable domain (V) containing the amino acid sequence shown as SEQ ID NO: 8 Ｈ ）、 ii) an immunoglobulin light chain variable domain containing the amino acid sequence shown as SEQ ID NO: 10 (V Ｌ ), iii) An immunoglobulin V domain comprising the amino acid sequence shown as SEQ ID NO: 8 Ｈ domain and an immunoglobulin V comprising the amino acid sequence shown as SEQ ID NO: 10 Ｌ domain 、 iv) an immunoglobulin containing the hypervariable regions shown as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 Roburin V Ｈ domain, v) an immunoglobulin containing the hypervariable regions shown as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 Brin V Ｌ domain, vi) an immunoglobulin containing the hypervariable regions shown as SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13 Immunoglobulin V Ｈ domain, vii) the immunoglobulin containing the hypervariable regions shown as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 Immunoglobulin V Ｈ domain, and as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 Immunoglobulin V containing the variable region shown above Ｌ domain viii) the hypervariable region shown as SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13 Immunoglobulin V domain containing a domain, and SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: Ｈ sequence number Immunoglobulin V domain containing the hypervariable region shown as 6 Ｌ domain ix) an immunoglobulin light chain comprising the amino acid sequence shown as SEQ ID NO: 14, x) an immunoglobulin heavy chain comprising the amino acid sequence shown as SEQ ID NO: 15, or xi) an immunoglobulin light chain comprising the amino acid sequence shown as SEQ ID NO: 14 and an immunoglobulin heavy chain comprising the amino acid sequence shown as SEQ ID NO: 15 The method according to any one of claims 5 to 13, comprising: The method according to any one of claims 5 to 13, comprising: **Claim 15** The method according to claim 14, wherein the IL-17 antibody or antigen-binding fragment thereof is a human antibody or a humanized antibody. The method according to claim 14, wherein the IL-17 antibody or antigen-binding fragment thereof is a human antibody or a humanized antibody. **Claim 16** The method according to claim 15, wherein the IL-17 antibody or antigen-binding fragment thereof is secukinumab. The method according to claim 15, wherein the IL-17 antibody or antigen-binding fragment thereof is secukinumab.

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