Methods of selective treatment of tendinopathy using interleukin-17 (IL-17) antagonists

Abstract

The present disclosure relates to methods of treating tendon cases, such as rotator cuff tendinopathy, using an IL-17 antagonist, such as secukinumab. Also disclosed herein are the use of IL-17 antagonists, such as IL-17 antibodies, such as secukinumab, for the treatment of tendinopathy patients, as well as medicaments, dosing regimens, pharmaceutical formulations, dosage forms, and kits for use in the disclosed uses and methods.

Description

Technical Field

[0001] The present disclosure relates to methods of using an IL-17 antagonist (e.g., an IL-17 antibody or antigen-binding fragment thereof, such as secukinumab or ixekizumab; or an IL-17 receptor antibody or antigen-binding fragment thereof, such as brodalumab) to treat tendinopathy and induce regeneration of tendon tissue, and promote tendon repair in patients with moderate to severe and / or subacute (e.g., rotator cuff) tendinopathy. Background Art

[0002] Overuse tendinopathy is a complex, multifaceted disorder of the tendons that is diagnosed clinically after the onset of activity-related pain, decreased function, and sometimes localized swelling of the tendon (Riley G (2005) Expert Rev Mol Med; 7:1-25; Riley G (2008) Nat Clin Pract Rheumatol; 4:82-9). In the past, the terms "tendinitis" and "tendinosis" were used interchangeably with the term "tendinopathy", however, these definitions are now included within the scope of human tendon disorders ("tendinopathy"). Tendinopathy is a common overuse injury in athletes and working people; it is the most common reason for consultation for musculoskeletal complaints, corresponding to approximately 30% of all such consultations with general practitioners (Forde et al. (2005) J. of Occupational and Environmental Hygiene; 2:203-12; Riley (2008), supra).

[0003] The exact incidence of overuse tendon injuries is unknown, but in sports medicine, they account for 30% to 50% of all injuries (Scott and Ashe (2006) Current Sports Medicine Reports; 5:233-241). In general, for manual laborers, the prevalence of musculoskeletal symptoms increases with the duration of work (Forde et al. (2005), supra).

[0004] Upper limb tendinopathy

[0005] Systematic reviews show that the incidence of rotator cuff tendinopathy ranges from 0.3% to 5.5% / year, and the annual prevalence ranges from 0.5% to 7.4% (Littlewood et al. (2013) Physiotherapy;98:101-9). The incidence is higher in manual laborers and athletes (15%-20%), and in wheelchair users (31%-73%). It is commonly seen in swimmers, baseball players, tennis players, and volleyball players (Kaux et al. (2011) J Sports Sci Med;10:238-253).

[0006] Tennis elbow (lateral epicondylitis) is another common tendinopathy and is common in athletes of all ages who participate in sports involving overhead or repetitive arm motions (Hume et al. (2006) Sports Medicine 36, 151-170). Its prevalence is as high as 9% to 40% in tennis players (Maffulli et al. (2003) Clinics in Sports Medicine 22, 675-692; Scott and Ashe (2006), supra). The condition affects approximately 1% to 3% of the general population. Another elbow tendinopathy is golfer's elbow (medial epicondylitis), which is a typical complaint in javelin throwing, baseball, and golf (supra).

[0007] Lower limb tendinopathy

[0008] Achilles tendinopathy is the most common lower limb tendinopathy, with a prevalence of 5.9% in sedentary populations and approximately 50% in high-level endurance athletes (Scott and Ashe (2006) supra; Fredberg U and Stengaard-Pedersen K (2008) Scandinavian Journal of Medicine & Science in Sports 18, 3-15).

[0009] Approximately one-third of sports injuries treated in sports clinics involve the knee, and one-quarter of athletes treated for knee injuries are diagnosed with tendinopathy (Maffulli et al. (2003), supra). The most common knee disorder is jumper's knee (insertion patellar tendinitis), and its incidence has been reported to range from 7% to 40% (Fredberg and Stengaard-Pedersen (2008), supra; Scott and Ashe (2006), supra).

[0010] treat

[0011] Current treatments for tendinopathy are rest, ice packs, and physical therapy (including therapeutic ultrasound, laser therapy, hyperthermia, and extracorporeal shock wave therapy). Evidence supporting widespread use of these therapies for tendinopathy remains inconsistent (Alfredson and Cook (2007) Br J Sports Med; 41: 211-216). Nonsteroidal anti-inflammatory drugs (NSAIDs) or local corticosteroid injections may provide transient pain relief, but long-term benefits are questionable (Mohamadi et al. (2017) Clin. Orthop. Relat. Res.; 475: 232-243; Coombes et al. (2010) Lancet; 376: 1751-67). It has even been shown that repeated steroid injections may accelerate tendon degeneration, thereby increasing the risk of tendon rupture (ibid.). Autologous platelet-rich plasma (PRP) injections are currently used, however the evidence for long-term efficacy is weak and therefore the benefit of PRP for tendinopathy remains controversial, with several trials showing no efficacy compared with saline (Krogh TP et al. (2013) Am JSports Med 41:625-35; de Vos RJ et al. (2010) JAMA [Journal of the American Medical Association]; 303:144-9).

[0012] Overall, overuse tendinopathy is a condition with a high medical need and inadequate treatment options. Summary of the invention

[0013] There is evidence that tendon-resident immune cells expressing IL-17 are present in human overuse tendinopathy, and IL-17 mRNA and protein expression levels are increased in early human tendinopathy samples (Millar et al. (2017) Nat Rev Rheumatol [Nature Review - Rheumatology]; 13: 110-122). In human tendinocytes, IL-17 regulates proinflammatory cytokines, key apoptotic mediators, and tendon matrix changes toward a mechanically inferior type III collagen phenotype (ibid). It is speculated that IL-17 is involved in the pathogenesis of overuse tendinopathy as a mediator of tendon inflammation, tendon matrix breakdown, and tenocyte apoptosis (ibid).

[0014] Secukinumab is a selective, high-affinity, fully human monoclonal antibody that neutralizes IL 17A and is approved for the treatment of plaque psoriasis, psoriatic arthritis (PsA), and ankylosing spondylitis (AS). We have now established that IL-17 antagonists (e.g., IL-17 antibodies such as secukinumab) can be used systemically to treat certain patient populations with tendinopathy and address the pain, swelling, and / or loss of function associated therewith, as well as to induce regeneration of tenocytes and promote tendon repair.

[0015] Thus, disclosed herein are methods of reducing inflammation, structural damage, and pain in the affected tendon of a tendinopathy patient with moderate to severe and / or subacute tendinopathy, methods of inducing tendon tissue regeneration in a tendinopathy patient, methods of promoting tendon repair in a tendinopathy patient, and methods of treating a patient with moderate to severe and / or subacute tendinopathy (e.g., overuse tendinopathy), comprising administering an IL-17 antagonist (e.g., an anti-IL-17 antibody or antigen-binding fragment thereof) to a patient in need thereof. In some embodiments, the patient has one, one or more or all of the following criteria: disease duration ≤ 6 months and (WORC score ≤ 40 or Sein ≥ 2 or Bauer tear ≥ 1). In some embodiments, the patient has rotator cuff tendinopathy (e.g., unilateral) with symptoms lasting ≥6 weeks and / or ≤6 months; has night pain in the affected shoulder for at least 4 of the 7 days prior to the start of treatment; has a total WORC percent score ≤40 prior to the start of treatment; has an NRS pain score ≥5 for 3 of the 7 days prior to the start of treatment; and / or the patient is refractory (or intolerant) to 2 months of standard treatment (e.g., NSAIDs and / or physical therapy).

[0016] Disclosed herein are methods, uses, pharmaceutical compositions, and kits for inducing regeneration of tendon tissue or promoting tendon repair in patients with moderate to severe and / or subacute tendinopathy, comprising subcutaneously administering to a patient in need thereof about 150 mg to about 300 mg (e.g., a fixed dose of about 150 mg, a fixed dose of about 300 mg) of an IL-17 antibody or an antigen-binding fragment thereof, wherein the IL-17 antibody or antigen-binding fragment thereof is conjugated to a cytokine having two mature human IL-17 protein chains. The IL-17 antibody or antigen-binding fragment thereof binds to an epitope of a human IL-17 homodimer, 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, wherein the IL-17 antibody or antigen-binding fragment thereof has a K for human IL-17 Dis about 100-200 pM, and wherein the IL-17 antibody or antigen-binding fragment thereof has an in vivo half-life of about 4 weeks.

[0017] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the IL-17 antibody or antigen-binding fragment thereof is administered to the patient only once.

[0018] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the IL-17 antibody or antigen-binding fragment thereof is administered to the patient weekly.

[0019] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, during weeks 0, 1, 2, 3, and 4, the IL-17 antibody or antigen-binding fragment thereof is administered to the patient.

[0020] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the IL-17 antibody or antigen-binding fragment thereof is administered to the patient every 4 weeks.

[0021] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the IL-17 antibody or antigen-binding fragment thereof is administered to the patient for a total treatment duration of at least two months.

[0022] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the IL-17 antibody or antigen-binding fragment thereof is administered to the patient weekly during weeks 0, 1, 2, 3, and 4, and then every 4 weeks.

[0023] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the IL-17 antibody or antigen-binding fragment thereof is administered to the patient during weeks 0, 1, 2, 3, 4, 8, and 12.

[0024] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the IL-17 antibody or antigen-binding fragment thereof is administered to the patient weekly during weeks 0, 1, 2, 3, and 4, and every 4 weeks thereafter for a total treatment duration of at least three months.

[0025] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, prior to treatment with the IL-17 antibody or antigen-binding fragment thereof, the patient did not respond, had an inadequate response, or was intolerant to a previous tendinopathy treatment selected from the group consisting of: local injection of steroids into the affected tendon, treatment with an NSAID, treatment with acetaminophen, physical therapy, and combinations thereof; or the patient was refractory or intolerant to, for example, two months of NSAID treatment and / or physical therapy.

[0026] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient is undergoing physical therapy treatment, the patient is not a candidate for tendinopathy surgery, and prior to treatment with the IL-17 antibody or antigen-binding fragment thereof, the patient did not respond, had an inadequate response, or was intolerant to a previous tendinopathy treatment selected from the group consisting of local injection of steroids into the affected tendon, treatment with an NSAID, treatment with acetaminophen, and combinations thereof.

[0027] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient is undergoing physical therapy treatment, the patient is a candidate for tendinopathy surgery, and prior to treatment with the IL-17 antibody or antigen-binding fragment thereof, the patient did not respond, had an inadequate response, or was intolerant to a previous tendinopathy treatment selected from the group consisting of local injection of steroids into the affected tendon, treatment with an NSAID, treatment with acetaminophen, and combinations thereof.

[0028] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient suffers from overuse tendinopathy.

[0029] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient suffers from a subacute tendinopathy.

[0030] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient suffers from subacute moderate to severe tendinopathy.

[0031] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient suffers from subacute moderate to severe rotator cuff tendinopathy.

[0032] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, treatment with the IL-17 antibody or antigen-binding fragment thereof slows progression to chronic tendinopathy.

[0033] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient suffers from an active tendinopathy.

[0034] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient has a partially torn tendon.

[0035] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient has a partial thickness tear of less than or equal to 50%, for example confirmed by MRI or ultrasound.

[0036] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, treatment with the IL-17 antibody or antigen-binding fragment thereof slows progression to a complete tendon tear.

[0037] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient suffers from moderate to severe and / or subacute plantar fasciitis, Achilles tendinopathy, patellar tendinopathy, rotator cuff tendinopathy, jumper's knee, lateral epicondylitis, medial epicondylitis, supraspinatus syndrome, or any combination thereof.

[0038] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, following treatment with the IL-17 antibody or antigen-binding fragment thereof, the patient experiences at least 20% reduction in pain, at least 20% reduction in inflammation, at least 20% improved tendon regeneration and / or repair, and / or at least 20% improved motion of the affected tendon.

[0039] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, after treatment with the IL-17 antibody or antigen-binding fragment thereof, the patient experiences at least 20% pain relief as determined by VAS score.

[0040] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient suffers from rotator cuff tendinopathy and, following treatment with the IL-17 antibody or antigen-binding fragment thereof, the patient experiences at least a 20% improvement in shoulder-related quality of life (QoL) as determined by a WORC score, a QuickDASH score, or an ASES score.

[0041] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, after treatment with the IL-17 antibody or antigen-binding fragment thereof, the patient experiences at least a 20% overall improvement as determined by PGA score.

[0042] In some embodiments, the disclosed methods, uses, pharmaceutical compositions, and kits further comprise administering a steroid, an NSAID, or acetaminophen to the patient.

[0043] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, after treatment with an IL-17 antibody or antigen-binding fragment thereof, the patient's need for physical therapy is reduced, or the patient's tendinopathy symptoms are alleviated, thereby improving the effectiveness of physical therapy.

[0044] In some embodiments of the disclosed uses, methods and kits, the IL-17 antagonist is an IL-17 antibody or an antigen-binding fragment thereof. In some embodiments of the disclosed uses, methods and kits, the IL-17 antibody or antigen-binding fragment thereof is selected from the group consisting of: a) an IL-17 antibody or antigen-binding fragment thereof that binds to an epitope of IL-17 comprising Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129; b) an IL-17 antibody or antigen-binding fragment thereof that binds to an epitope of IL-17 comprising Tyr43, Tyr44, Arg46, Ala79, Asp80; c) an IL-17 antibody or antigen-binding fragment thereof that binds to an epitope of an IL-17 homodimer having two mature IL-17 protein chains, the epitope comprising Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129; s86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain; d) an IL-17 antibody or an antigen-binding fragment thereof that binds to an epitope of an IL-17 homodimer having two mature 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, wherein the IL-17 antibody or antigen-binding fragment thereof has a K for human IL-17 D The invention relates to an IL-17 antibody or an antigen-binding fragment thereof, wherein the IL-17 antibody or an antigen-binding fragment thereof has an in vivo half-life of about 23 to about 35 days (e.g., about 27 days); and e) an IL-17 antibody or an antigen-binding fragment thereof, which comprises: i) an immunoglobulin heavy chain variable domain (V H ) comprising the amino acid sequence set forth in SEQ ID NO: 8; H );ii) an immunoglobulin light chain variable domain (V L );iii) an immunoglobulin V comprising the amino acid sequence set forth in SEQ ID NO: 8 H Domain and an immunoglobulin V comprising the amino acid sequence listed in SEQ ID NO: 10 Ldomain; iv) an immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 H domain; v) an immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 L domain; vi) an immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 H vii) an immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 H domains and immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 L viii) an immunoglobulin V domain comprising the hypervariable regions listed in SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13 H domains and immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 L domain; ix) an immunoglobulin light chain comprising the amino acid sequence set forth in SEQ ID NO: 14; x) an immunoglobulin heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 15; or xi) an immunoglobulin light chain comprising the amino acid sequence set forth in SEQ ID NO: 14 and an immunoglobulin heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 15.

[0045] In some embodiments of the disclosed uses, methods and kits, the IL-17 antibody or antigen-binding fragment thereof is secukinumab (AIN457), a high-affinity recombinant fully human monoclonal anti-human interleukin-17A antibody of the IgG1 / κ class.

[0046] Also disclosed herein are methods, uses, pharmaceutical compositions, and kits for treating a patient with active overuse tendinopathy, comprising administering to the patient about 300 mg of secukinumab by subcutaneous injection at weeks 0, 1, 2, 3, and 4, and every four weeks thereafter for a total treatment duration of at least three months.

[0047] Also disclosed herein are methods, uses, pharmaceutical compositions, and kits for treating a patient with active overuse tendinopathy, comprising administering to the patient about 150 mg of secukinumab by subcutaneous injection at weeks 0, 1, 2, 3, and 4, and every four weeks thereafter for a total treatment duration of at least three months.

[0048] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, prior to treatment with secukinumab, the patient did not respond, had an inadequate response, or was intolerant to a previous tendinopathy treatment selected from the group consisting of local injection of steroids into the affected tendon, treatment with an NSAID, treatment with acetaminophen, physical therapy, and combinations thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 Rat tail tendon fascicle biomechanics are shown. Rat tail tendon fascicles were cultured in 1.67 nM IL-17A for 8 days (N=1; 4 fascicles / group).

[0050] Figure 2 Shown are the levels of IL-6 and CXCL1 mRNA in rat Achilles tendon cells after 72 hours of treatment with IL-17A.

[0051] Figure 3 It is shown that the antagonist IL-17A antibody BZN035 inhibits IL-17A-induced IL-6 and CXCL1 mRNA in rat Achilles tendon cells.

[0052] Figure 4 A clinical study design for tendinopathy for Example 3 is provided. The study consists of a 4-week screening period, a 2-week run-in period, a 12-week treatment period, and a 12-week follow-up period after the last treatment. Note that due to protocol changes, the pretreatment period was modified as follows: screening period (Day -49 to Day -22), run-in period (Day -21 to Day -8), baseline (Day -7 to Day -1).

[0053] Figure 5 The patient distribution for the study described in Example 3 is shown.

[0054] Figure 6 The (A) Western Ontario Rotator Cuff (WORC) total index score and (B) pain visual analog scale (VAS) score for the secukinumab group and the placebo group in the overall population up to day 169 in the study described in Example 3 are shown, adjusted means (SE), note: two-sided p value, i.e., statistical significance p<0.1

[0055] Figure 7The adjusted means (SE) for ASES, QuickDASH, EQ5D index, and patient and physician global assessments for secukinumab treatment versus placebo in the overall population through Day 169 in the study described in Example 3 are shown.

[0056] Figure 8 The adjusted means (SE) for active and passive range of motion for secukinumab treatment versus placebo in the overall population up to Day 169 in the study described in Example 3 are shown.

[0057] Fig. 9 Post hoc analysis of (A) total WORC score and (B) pain (VAS) score results in the secukinumab and placebo groups in the subacute, early moderate to severe subpopulation (disease duration ≤ 6 months and (WORC score ≤ 40 or Sein ≥ 2 or Bauer tear ≥ 1); N = 37) in the Example 3 study up to Day 169, adjusted means (SE). Two-sided p value, i.e., statistically significant p < 0.1.

[0058] Fig.10 Shown are the WORC subscores, adjusted means (SE) for physical symptoms, work, mood, lifestyle, sports and recreation scores in the subpopulations in Example 3 (disease duration ≤ 6 months and (WORC score ≤ 40 or Sein ≥ 2 or Bauer tear ≥ 1); N = 37).

[0059] Fig.11 Shown are adjusted means (SE) for ASES, QuickDASH, EQ5D Index, PGA, and PhGA assessments for secukinumab treatment versus placebo in the subpopulation (disease duration ≤ 6 months and (WORC score ≤ 40 or Sein ≥ 2 or Bauer tear ≥ 1); N = 37) in Example 3 up to Day 169.

[0060] Fig.12 Shown are adjusted means (SE) for active and passive range of motion for secukinumab treatment versus placebo in the subpopulation (disease duration ≤ 6 months and (WORC score ≤ 40 or Sein ≥ 2 or Bauer tear ≥ 1); N = 37) in Example 3 up to Day 169. DETAILED DESCRIPTION

[0061] As used herein, "tendinopathy" is a term used to describe complex, multifaceted tendon pathology.

[0062] It is characterized by pain, decreased function, and reduced exercise tolerance (Millar et al. (2017), supra). The disease is diagnosed clinically after the onset of activity-related pain, decreased function, and sometimes localized swelling, and clinical examination reveals pain in the area of ​​pathology on extension and palpation. Ultrasound and MRI are helpful in diagnosing active tendinopathy. Tendinopathy can occur in almost any tendon (e.g., Achilles, patella, infraspinatus, epicondyle, adductor, plantar fasciopathy, subscapularis, teres minor, supraspinatus, wrist extensors, wrist flexors, hip, gluteal muscles, etc.). As used herein, the term "tendinopathy" includes tendinopathy of all positions and forms, such as plantar fasciitis, Achilles tendinopathy, patellar tendinopathy, rotator cuff (infraspinatus, teres minor, supraspinatus and subscapularis) tendinopathy, tennis elbow (lateral epicondylitis), golfer's elbow (medial epicondylitis), hamstring tendinopathy, jumper's knee, supraspinatus syndrome, etc. It includes single-position tendinopathy as well as multi-position tendinopathy. Tendinopathy patients may suffer from mid-substance (middle of the tendon) tendinopathy or terminal (attachment) tendinopathy. As used herein, the term "tendinopathy" excludes tendinopathy caused by systemic inflammatory diseases and includes those tendinopathy developed due to injury or overuse. Tendinopathy patients may suffer from acute, subacute, or chronic disease (Blazina et al. (1973) Orthop. Clin. North Am. [North American Orthopedic Clinic] 4, 665–678). In the past, the terms "tendinitis" and "tendinosis" were used interchangeably with the term "tendinopathy", however, these definitions are now included within the scope of human tendon disorders ("tendinopathy").

[0063] As used herein, "overuse tendinopathy" refers to a tendinopathy characterized by pain and tenderness at rest and / or with movement, and with reduced range of motion. The tendon may swell. Overuse tendinopathy is usually due to continuous and repetitive use of the tendon, and often occurs in workers and amateur athletes. Thus, "overuse tendinopathy" is distinct from enthesitis seen in systemic inflammatory diseases, such as psoriatic arthritis or ankylosing spondylitis. In some embodiments, the patient suffers from overuse tendinopathy.

[0064] As used herein, "affected tendon" refers to a tendon in which a patient suffers from tendinopathy.

[0065] As used herein, "chronic tendinopathy" and the like refers to a tendinopathy that has been present for at least 6 weeks, preferably at least 12 weeks. In a clinical setting, a tendinopathy is considered chronic when physical therapy, NSAIDs, and steroids have failed, and pain and reduced range of motion persist. In some embodiments, the patient suffers from overuse tendinopathy.

[0066] As used herein, the phrase "active tendinopathy" means that the patient is currently experiencing tendinopathy. In some embodiments, the patient suffers from active tendinopathy, such as active chronic overuse tendinopathy.

[0067] As used herein, the phrase "partially torn tendon" refers to a tendon injury (rupture or tear) that damages the tendon but does not completely disconnect the tendon from its associated bone. In some embodiments, the patient has a partially torn tendon, preferably no more than a 50% tear, as confirmed by, for example, ultrasound and / or MRI (e.g., assessed using the Sein tendinopathy scoring system and / or the Bauer tendon thickness score). In some embodiments, the patient has a partially torn tendon.

[0068] As used herein, the phrase "complete tear of a tendon" refers to a tendon injury (rupture or tear) that separates all of the tendon from its associated bone.

[0069] As used herein, the term "NSAID" and the phrase "nonsteroidal anti-inflammatory drug" refer to a class of drugs that collect drugs that relieve pain, reduce fever, and, at higher doses, reduce inflammation. The most prominent members of this group of drugs are aspirin, ibuprofen, and naproxen. NSAIDs include salicylates (e.g., aspirin), propionic acid derivatives (e.g., ibuprofen), acetic acid derivatives (e.g., indomethacin), enolic acid derivatives (e.g., piroxicam), anthranilic acid derivatives (e.g., mefenamic acid), selective COX-2 inhibitors (e.g., celecoxib), sulfonanilides (e.g., nimesulide), clonixin, licofelone, and h-harpagide.

[0070] As used herein, the phrase "is unresponsive to" is used to mean that the patient's symptoms are not eliminated, treated, alleviated, etc. in response to a particular tendinopathy treatment. In some embodiments, the patient has not responded to a previous tendinopathy treatment (e.g., NSAIDs, steroids (e.g., local injections of steroids into the affected tendon), acetaminophen, physical therapy, or a combination thereof).

[0071] As used herein, the phrase "has had an inadequate response to" is used to mean that the patient's symptoms are not adequately eliminated, treated, alleviated, etc. in response to a particular tendinopathy treatment. In some embodiments, the patient has had an inadequate response to a previous tendinopathy treatment (e.g., NSAIDs, steroids (e.g., local injections of steroids into the affected tendon), acetaminophen, physical therapy, or a combination thereof).

[0072] As used herein, the phrase "intolerant to" is used to mean that a patient has an adverse reaction to a particular tendinopathy treatment. In some embodiments, the patient is intolerant to a previous tendinopathy treatment (e.g., NSAIDs, steroids (e.g., local injections of steroids into the affected tendon), acetaminophen, physical therapy, or a combination thereof).

[0073] As used herein, "fixed dose" refers to a steady dose, i.e., a dose that is not modified based on the patient's characteristics. Thus, a fixed dose is different from, for example, a dose based on body surface area or a dose based on body weight (usually given in mg / kg). In a preferred embodiment, the dose used in the disclosed methods, uses, instructions, kits, etc. is a fixed dose. In a most preferred embodiment, a fixed dose of an IL-17 antibody, such as a fixed dose of secukinumab, such as a fixed dose of about 75 mg, about 150 mg, or about 300 mg of secukinumab is administered to the patient.

[0074] As used herein, IL-17 refers to interleukin-17A (IL-17A).

[0075] As used herein, IL-17AF refers to a heterodimer composed of monomers of IL-17A and IL-17F.

[0076] The term "comprising" encompasses "including" as well as "consisting of", for example, a composition "comprising" X may consist of X only or may include other substances, such as X+Y.

[0077] As used herein, the phrase "TNF-α antagonist" refers to small molecules and biomolecules that can inhibit, reduce and / or block TNF-α signaling, transduction, and / or activity. Examples of TNF-α antagonists include (etanercept), (Adalimumab), (infliximab) and (golimumab).

[0078] Unless otherwise specifically stated or apparent from the context, as used herein, the term "about" with respect to a numerical value should be understood to be within the normal tolerance of the art, e.g., within two standard deviations of the mean. Thus, "about" can be within + / -10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.1%, 0.05%, or 0.01% of the value, preferably within + / -10% of the value. When used before a numerical range or a list of numbers, the term "about" applies to each number in the series, e.g., the phrase "about 1-5" should be understood to be "about 1-about 5", or, for example, the phrase "about 1, 2, 3, 4" should be understood to be "about 1, about 2, about 3, about 4, etc."

[0079] The word "substantially" does not exclude "completely", for example, a composition "substantially free of" Y may be completely free of Y. If necessary, the word "substantially" may be omitted from the definitions of the present disclosure.

[0080] The term "antibody" as used herein includes naturally occurring and intact antibodies. A naturally occurring "antibody" is a glycoprotein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain consists of a heavy chain variable region (abbreviated herein as V H ) and a heavy chain constant region. The heavy chain constant region contains three domains, namely CH1, CH2 and CH3. Each light chain consists of a light chain variable region (abbreviated herein as V L ) and a light chain constant region. The light chain constant region comprises a domain, namely CL. V H and V L The V region can be further subdivided into hypervariable regions, termed hypervariable regions or complementarity determining regions (CDRs), interspersed with more conserved regions, termed framework regions (FRs). H and V L It is composed of three CDRs and four FRs arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigens. The constant region of an antibody can mediate the binding of immunoglobulins to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. Exemplary antibodies include secukinumab (Table 1) and ixekizumab (U.S. Patent No. 7,838,638).

[0081] As used herein, the term "antigen-binding fragment" of an antibody refers to a fragment of an antibody that retains the ability to specifically bind to an antigen (e.g., IL-17). It has been shown that fragments of a full-length antibody can perform the antigen-binding function of an antibody. Examples of binding fragments encompassed within the term "antigen-binding portion" of an antibody include a Fab fragment, a V-binding fragment, and a Fab fragment. L 、V H A monovalent fragment consisting of the V, CL and CH1 domains; a F(ab)2 fragment, a bivalent fragment comprising two Fab fragments connected by a disulfide bridge at the hinge region; an Fd fragment, which consists of the V H and CH1 domains; Fv fragment, which consists of the V L and V H Domain composition; composed of V HdAb fragments composed of domains (Ward et al., 1989, Nature 341:544-546); and isolated CDRs. Exemplary antigen binding sites include the CDRs of secukinumab listed in SEQ ID NOs: 1-6 and 11-13 (Table 1), preferably the heavy chain CDR3. In addition, although the two domains V L and V H are encoded by separate genes, but recombinant methods can be used to connect the two domains via a synthetic linker that enables them to form a single protein chain, where V L Area and V H The domains are paired to form monovalent molecules (referred to as single-chain Fvs (scFvs); see, e.g., Bird et al., 1988 Science 242:423-426; and Huston et al., 1988 Proc. Natl. Acad. Sci. 85:5879-5883). Such single-chain antibodies are also intended to be encompassed within the term "antibody". Single-chain antibodies and antigen-binding portions are obtained using techniques known to those skilled in the art.

[0082] As used herein, an "isolated antibody" refers to an antibody that is substantially free of other antibodies with different antigenic 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 refers to a preparation of antibody molecules having a single molecular composition. As used herein, the term "human antibody" is intended to include antibodies having variable regions in which both the framework region and the CDR region are derived from sequences of human origin. "Human antibodies" do not need to be produced by humans, human tissues, or human cells. The human antibodies disclosed herein may include amino acid residues that are not encoded by human sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro, by N-nucleotide additions at junctions in vivo during antibody gene recombination, or by somatic mutations in vivo). In some embodiments of the disclosed procedures and compositions, the IL-17 antibody is a human antibody, an isolated antibody, and / or a monoclonal antibody.

[0083] The term "IL-17" refers to IL-17A, previously known as CTLA8, and includes wild-type IL-17A, polymorphic variants of IL-17A, and functional equivalents of IL-17A from different species (e.g., humans, mice, and monkeys). The functional equivalents of IL-17A according to the present disclosure preferably have at least about 65%, 75%, 85%, 95%, 96%, 97%, 98%, or even 99% overall sequence identity with wild-type IL-17A (e.g., human IL-17A), and substantially retain the ability to induce human dermal fibroblasts to produce IL-6.

[0084] The term "K D " is intended to refer to the dissociation rate of a particular antibody-antigen interaction. As used herein, the term "K D " is intended to refer to d With K a The ratio (K d / K a ) and expressed as a dissociation constant of molar concentration (M). The K of an antibody can be determined using methods well established in the art. D Used to determine the K value of an antibody D The method is to use surface plasmon resonance, or use biosensor systems such as In some embodiments, the IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab) has a K of about 1-250 pM, preferably about 100-200 pM (e.g., about 200 pM). D Binds human IL-17.

[0085] The term "affinity" refers to the strength of 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 many sites through weak non-covalent forces; the more interactions, the stronger the affinity. Standard assays for assessing the binding affinity of antibodies to IL-17 of various species are known in the art and include, for example, ELISA, Western blot, and RIA. The binding kinetics (e.g., binding affinity) of an antibody can also be assessed by assays known in the art, such as by analyze.

[0086] An antibody that "inhibits" one or more of these IL-17 functional properties (e.g., biochemical, immunochemical, cellular, physiological or other biological activity, etc.) as determined by methods known in the art and described herein will be understood to involve a statistically significant reduction in a particular activity relative to that observed in the absence of the antibody (or when a control antibody of irrelevant specificity is present). An antibody that inhibits IL-17 activity affects a statistically significant reduction, e.g., a reduction of at least about 10% of a measured parameter, a reduction of at least 50%, 80% or 90%, and in certain embodiments of the disclosed methods and compositions, the IL-17 antibodies used may inhibit greater than 95%, 98% or 99% of IL-17 functional activity.

[0087] As used herein, "inhibition of IL-6" refers to the ability of an IL-17 antibody or an antigen-binding fragment thereof (e.g., secukinumab) to reduce the ability of primary human dermal fibroblasts to produce IL-6. The production of IL-6 in primary human (dermal) fibroblasts is dependent on IL-17 (Hwang et al., (2004) Arthritis Res Ther; 6: R120-128). Briefly, human dermal fibroblasts were stimulated with recombinant IL-17 in the presence of varying concentrations of an IL-17 binding molecule or a human IL-17 receptor with an Fc portion. A chimeric anti-CD25 antibody may be used. (basiliximab) is conveniently used as a negative control. The supernatant was taken after 16 h stimulation and IL-6 was measured by ELISA. When tested as above, IL-17 antibodies or antigen-binding fragments thereof (e.g., secukinumab) typically have an IC of 2.0 for inhibition of IL-6 production (in the presence of 1 nM human IL-17). 50 The inhibitory activity is measured on IL-6 production induced by hu-IL-17 in human dermal fibroblasts. In some embodiments of the disclosed methods and compositions, as defined above, the IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab) and its functional derivatives have an IC of inhibiting IL-6 production. 50 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.

[0088] Unless otherwise indicated, according to the present disclosure, the term "derivative" is used to define amino acid sequence variants and covalent modifications (e.g., pegylation, deamidation, hydroxylation, phosphorylation, methylation, etc.) of, for example, a specific sequence (e.g., variable domain) of an IL-17 antibody or its antigen-binding fragment (e.g., secukinumab). "Functional derivatives" include molecules having the same qualitative biological activity as the disclosed IL-17 antibodies. Functional derivatives include fragments and peptide analogs of IL-17 antibodies as disclosed herein. Fragments contain regions within a polypeptide sequence according to the present disclosure (e.g., a specified sequence). The functional derivatives of the IL-17 antibodies disclosed herein (e.g., functional derivatives of secukinumab) preferably include the following V H and / or V L Domain: The domain is related to the V domain of the IL-17 antibody and its antigen-binding fragment disclosed herein. H and / or V LThe sequences have at least about 65%, 75%, 85%, 95%, 96%, 97%, 98%, or even 99% overall sequence identity and substantially retain the ability to bind to human IL-17, or, for example, inhibit IL-17-induced IL-6 production by human dermal fibroblasts.

[0089] The phrase "substantially identical" means that the amino acid or nucleotide sequence (e.g., V H or V L domain) or have insubstantial differences therefrom (e.g., by conservative amino acid substitutions). Insubstantial differences include minor amino acid changes, such as in a particular region (e.g., V H or V L domain). In the case of an antibody, the second antibody has the same specificity and has at least 50% of its affinity. Sequences substantially identical to the sequences disclosed herein (e.g., having at least about 85% sequence identity) are also part of this application. In some embodiments, the sequence identity of a derivative IL-17 antibody (e.g., a derivative of secukinumab, such as a secukinumab biosimilar antibody) relative to the disclosed sequence can be about 90% or higher, such as 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher.

[0090] "Identity" with respect to a natural polypeptide and its functional derivatives is defined herein as the percentage of amino acid residues in a candidate sequence that are identical to the residues of the corresponding natural polypeptide, after aligning the sequences and introducing gaps, if necessary, to achieve maximum percent identity, and without considering any conservative substitutions as part of the sequence identity. Neither N-terminal nor C-terminal extensions nor insertions should be construed as reducing identity. Methods and computer programs for alignment are known. Percent identity can be determined by standard alignment algorithms, such as the local alignment search tool (BLAST) described by Altshul et al. ((1990) J. Mol. Biol. [Journal of Molecular Biology], 215: 403 410); Needleman et al.'s algorithm ((1970) J. Mol. Biol. [Journal of Molecular Biology], 48: 444 453); or Meyers et al.'s algorithm ((1988) Comput. Appl. Biosci. [Computer Applications in Biological Sciences], 4: 11 17). One set of parameters can be a Blosum 62 scoring matrix with 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 or nucleotide sequences can also be determined using the algorithm of E. Meyers and W. Miller ((1989) CABIOS [Computer Applications in Biosciences], 4: 11-17), which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4.

[0091] "One or more amino acids" refers to, for example, all naturally occurring L-α-amino acids and includes D-amino acids. The phrase "amino acid sequence variant" refers to a molecule whose amino acid sequence has some differences when compared to a sequence according to the present disclosure. According to the amino acid sequence variants of the antibodies disclosed herein, for example, variants of a specific sequence still have the ability to bind to human IL-17 or, for example, the ability to inhibit IL-6 production by human dermal fibroblasts induced by IL-17. Amino acid sequence variants include substitution variants (those variants in which at least one amino acid residue is removed and different amino acids are inserted at the same position in the polypeptide according to the present disclosure), insertion variants (those variants in which one or more amino acids are inserted adjacent to the amino acid at a specific position in the polypeptide according to the present disclosure) and deletion variants (those variants in which one or more amino acids are removed in the polypeptide according to the present disclosure).

[0092] The term "pharmaceutically acceptable" means a non-toxic material that does not interfere with the effectiveness of the biological activity of one or more active ingredients.

[0093] The term "administering" with respect to a compound (eg, an IL-17 binding molecule or another agent) is used to refer to delivery of the compound to a patient by any route.

[0094] As used herein, "therapeutically effective amount" refers to an amount of an IL-17 antagonist (e.g., an IL-17 binding molecule (e.g., an IL-17 antibody or antigen-binding fragment thereof, such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 antibody or antigen-binding fragment thereof)) that, when administered to a patient (e.g., a human) in a single dose or multiple doses, is effective to treat, prevent, prevent the onset of a disorder or a recurring disorder, cure, delay, reduce the severity of a disorder or a recurring disorder, alleviate at least one symptom of a disorder or a recurring disorder, or prolong the patient's survival beyond what would be expected in the absence of such treatment. When applied to an individual active ingredient (e.g., an IL-17 antagonist, such as secukinumab) administered alone, the term refers only to that ingredient. When applied to a combination, the term refers to the combined amounts of the active ingredients (whether administered in combination, either serially or simultaneously) that produce a therapeutic effect.

[0095] The term "treatment" or "treat" is defined herein as the application or administration of an IL-17 antibody (e.g., secukinumab or ixekizumab) or a pharmaceutical composition containing the anti-IL-17 antibody according to the present disclosure to a subject or to an isolated tissue or cell line from a subject, wherein the subject suffers from a particular disease (e.g., tendinopathy), symptoms associated with a disease (e.g., tendinopathy), or a predisposition to develop a disease (e.g., tendinopathy), if applicable, wherein the purpose is to cure (if applicable) the disease, delay the onset of the disease, reduce the severity, slow, ameliorate one or more symptoms of the disease, ameliorate the disease, reduce or ameliorate any symptom associated with the disease or a predisposition to develop the disease. The term "treatment" or "treat" includes treating patients suspected of having a disease as well as patients suffering from or diagnosed with a disease or medical condition and includes arresting clinical relapse.

[0096] As used herein, "selection (selecting)" and "selected (selected)" about patients are used to mean that specific patients are specially selected from a larger group of patients based on (due to) having predetermined criteria. Similarly, "selective treatment" refers to providing treatment to patients with specific diseases, wherein the patient is specially selected from a larger group of patients based on specific patients with predetermined criteria. Similarly, "selective administration" refers to administering drugs to patients, and the patient is specially selected from a larger group of patients based on (due to) having predetermined criteria. By selection, selective treatment and selective administration, it is meant that personalized treatment is delivered to patients based on the patient's personal medical history (e.g., previous therapeutic interventions, such as previous treatment with biological agents), biological characteristics (e.g., specific genetic markers), and / or performance (e.g., not meeting specific diagnostic criteria), rather than delivering standard treatment regimens based solely on the patient's membership in a larger group. With reference to the treatment method used herein, selection does not refer to the accidental treatment of patients with specific criteria, but refers to the intentional selection of patients treated based on patients with specific criteria. Thus, selective treatment / administration is distinguished from standard treatment / administration, which delivers a particular drug to all patients with a particular disease, regardless of those patients' individual medical history, disease presentation, and / or biological characteristics.

[0097] IL-17 antagonists

[0098] Various disclosed processes, kits, uses and methods utilize IL-17 antagonists. IL-17 antagonists are capable of blocking, reducing and / or inhibiting IL-17 signals, activity and / or transduction. Examples of IL-17 antagonists include, for example, IL-17 binding molecules (e.g., soluble IL-17 receptors, IL-17 antibodies or antigen binding fragments thereof, such as secukinumab and ixekizumab) and IL-17 receptor binding molecules (e.g., IL-17 receptor antibodies or antigen binding fragments thereof, such as broadalumab). In some embodiments, the IL-17 antagonist is an IL-17 binding molecule, preferably an IL-17 antibody or an antigen binding fragment thereof. As used herein, the IL-17 antibody and its antigen binding fragment may be fully human, CDR-grafted or chimeric. The constant region domains of the antibodies or antigen-binding fragments thereof preferably for use in the disclosed methods, uses, kits, etc. preferably comprise suitable human constant region domains, for example, as described in "Sequences of Proteins of Immunological Interest" (Kabat EA et al., US Department of Health and Human Services, Public Health Service, National Institute of Health).

[0099] Particularly preferred IL-17 antibodies or antigen-binding fragments thereof for use in the disclosed methods are human antibodies, in particular secukinumab as described in Examples 1 and 2 of WO 2006 / 013107 (which is incorporated herein by reference in its entirety). Secukinumab is a recombinant high affinity fully human monoclonal anti-human interleukin-17A (IL-17A, IL-17) antibody of the IgG1 / κ isotype. Secukinumab has a high affinity for IL-17, i.e., a K of about 100-200 pM (e.g., about 200 pM). D , neutralizing the biological activity of human IL-17A with an IC of approximately 0.67 nM in vitro 50 It is about 0.4 nM, and the half-life is about 4 weeks.

[0100] For ease of reference, the amino acid sequence of the hypervariable region of the secukinumab monoclonal antibody is provided in Table 1 below, based on the Kabat definition and as determined by X-ray analysis and using the method of Chothia and colleagues.

[0101]

[0102]

[0103] Table 1: Amino acid sequence of the hypervariable region of secukinumab. L The DNA sequence of is listed in SEQ ID NO: 9. V encoding secukinumab H The DNA is listed in SEQ ID NO:7.

[0104] In one embodiment, the IL-17 antibody or antigen-binding fragment thereof comprises at least one immunoglobulin heavy chain variable domain (V H ), 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. In one embodiment, the IL-17 antibody or antigen-binding fragment thereof comprises at least one immunoglobulin light chain variable domain (V L’ ), 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. In one embodiment, the IL-17 antibody or antigen-binding fragment thereof comprises at least one immunoglobulin heavy chain variable domain (V H ), the CDR1-x has the amino acid sequence of SEQ ID NO:11, the CDR2-x has the amino acid sequence of SEQ ID NO:12, and the CDR3-x has the amino acid sequence of SEQ ID NO:13.

[0105] 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, wherein: a) the immunoglobulin V H The structural domain comprises (for example, in order): i) hypervariable regions CDR1, CDR2 and CDR3, wherein CDR1 has an amino acid sequence of SEQ ID NO: 1, CDR2 has an amino acid sequence of SEQ ID NO: 2, and CDR3 has an amino acid sequence of SEQ ID NO: 3; or ii) hypervariable regions CDR1-x, CDR2-x and CDR3-x, wherein CDR1-x has an amino acid sequence of SEQ ID NO: 11, CDR2-x has an amino acid sequence of SEQ ID NO: 12, and CDR3-x has an amino acid sequence of SEQ ID NO: 13; and b) immunoglobulin V LThe domain comprises (eg in order) hypervariable regions CDR1', CDR2' and CDR3', 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.

[0106] 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 listed in SEQ ID NO: 8; H ); b) an immunoglobulin light chain variable domain (V L ); c) an immunoglobulin V comprising the amino acid sequence listed in SEQ ID NO: 8 H domain and an immunoglobulin V comprising the amino acid sequence listed in SEQ ID NO: 10 L domain; d) an immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 H e) an immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 L f) an immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 H g) an immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 H domains and immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 L domain; or h) an immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 H domains and immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 L Structural domain.

[0107] In some embodiments, the IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab) comprises three CDRs of SEQ ID NO: 10. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 8. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 10 and 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 ​​in the light chain (CysL97) can be seen in SEQ ID NO: 6.

[0108] In some embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises a light chain of SEQ ID NO: 14. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises a heavy chain of SEQ ID NO: 15 (with or without a C-terminal lysine). In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises a light chain of SEQ ID NO: 14 and a heavy chain domain of SEQ ID NO: 15. In some embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 14. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 15. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 14 and three CDRs of SEQ ID NO: 15. Multiple CDRs of SEQ ID NO: 14 and SEQ ID NO: 15 can be found in Table 1.

[0109] Hypervariable regions can be associated with any type of framework region, but are preferably human. Suitable framework regions are described in Kabat EA et al. (supra). A preferred heavy chain framework is a human heavy chain framework, such as the framework of the secukinumab antibody. The framework is composed of, for example, FR1 (amino acids 1 to 30 of SEQ ID NO: 8), FR2 (amino acids 36 to 49 of SEQ ID NO: 8), FR3 (amino acids 67 to 98 of SEQ ID NO: 8) and FR4 (amino acids 117 to 127 of SEQ ID NO: 8) regions in sequence. Taking into account the hypervariable regions of secukinumab determined by X-ray analysis, another preferred heavy chain framework is composed of FR1-x (amino acids 1 to 25 of SEQ ID NO: 8), FR2-x (amino acids 36 to 49 of SEQ ID NO: 8), FR3-x (amino acids 61 to 95 of SEQ ID NO: 8) and FR4 (amino acids 119 to 127 of SEQ ID NO: 8) regions in sequence. In a similar manner, the light chain framework is composed of the FR1' (amino acids 1 to 23 of SEQ ID NO: 10), FR2' (amino acids 36 to 50 of SEQ ID NO: 10), FR3' (amino acids 58 to 89 of SEQ ID NO: 10), and FR4' (amino acids 99 to 109 of SEQ ID NO: 10) regions in sequence.

[0110] In one embodiment, the IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab) is selected from a human IL-17 antibody, the antibody comprising at least: a) an immunoglobulin heavy chain or a fragment thereof, the immunoglobulin heavy chain or a fragment thereof comprising a variable domain and a constant part of a human heavy chain or a fragment thereof, the variable domain comprising, in sequence, hypervariable regions CDR1, CDR2, and CDR3; the CDR1 has an amino acid sequence of SEQ ID NO: 1, the CDR2 has an amino acid sequence of SEQ ID NO: 2, and the CDR3 has an amino acid sequence of SEQ ID NO: 3; and b) an immunoglobulin light chain or a fragment thereof, the immunoglobulin light chain or a fragment thereof comprising a variable domain and a constant part of a human light chain or a fragment thereof, the variable domain comprising, in sequence, hypervariable regions CDR1', CDR2', and CDR3', the CDR1' having an amino acid sequence of SEQ ID NO: 4, the CDR2' having an amino acid sequence of SEQ ID NO: 5, and the CDR3' having an amino acid sequence of SEQ ID NO: 6.

[0111] In one embodiment, the IL-17 antibody or its antigen-binding fragment is selected from a single-chain antibody or its antigen-binding fragment comprising an antigen-binding site, wherein the antigen-binding site comprises: a) a first domain comprising hypervariable regions CDR1, CDR2 and CDR3 in sequence, wherein CDR1 has an amino acid sequence of SEQ ID NO: 1, wherein CDR2 has an amino acid sequence of SEQ ID NO: 2, and wherein CDR3 has an amino acid sequence of SEQ ID NO: 3; and b) a second domain comprising hypervariable regions CDR1', CDR2' and CDR3' in sequence, wherein CDR1' has an amino acid sequence of SEQ ID NO: 4, wherein CDR2' has an amino acid sequence of SEQ ID NO: 5, and wherein CDR3' has an amino acid sequence of SEQ ID NO: 6; and c) a peptide linker that binds to the N-terminal end of the first domain and the C-terminal end of the second domain or binds to the C-terminal end of the first domain and the N-terminal end of the second domain.

[0112] Alternatively, the IL-17 antibody or antigen-binding fragment thereof used in the disclosed methods may comprise a derivative of the IL-17 antibody listed herein by sequence (e.g., a PEGylated variant of secukinumab). Alternatively, the V of the IL-17 antibody or antigen-binding fragment thereof used in the disclosed methods may be H or V L The domain may have the same V as set forth in SEQ ID NOs: 8 and 10. H or V L The domains are essentially the same as V H or V L Domain. The human IL-17 antibody disclosed herein may comprise a heavy chain substantially identical to the heavy chain listed in SEQ ID NO: 15 and / or a light chain substantially identical to the light chain listed in SEQ ID NO: 14. The human IL-17 antibody disclosed herein may comprise: a heavy chain comprising SEQ ID NO: 15 and a light chain comprising SEQ ID NO: 14. The human IL-17 antibody disclosed herein may comprise: a) a heavy chain comprising a variable domain having an amino acid sequence substantially identical to the amino acid sequence shown in SEQ ID NO: 8 and a constant portion of a human heavy chain; and b) a light chain comprising a variable domain having an amino acid sequence substantially identical to the amino acid sequence shown in SEQ ID NO: 10 and a constant portion of a human light chain.

[0113] Alternatively, the IL-17 antibody or antigen-binding fragment thereof used in the disclosed methods may be an amino acid sequence variant of the reference IL-17 antibody listed herein (as long as it contains CysL97). The present disclosure also includes IL-17 antibodies or antigen-binding fragments thereof (e.g., secukinumab), wherein the V of secukinumab (but not CysL97) is H or V L Typically only a few (e.g., 1-10) of one or more amino acid residues of the domain are changed; for example, by mutation, for example, site-directed mutagenesis of the corresponding DNA sequence. In the case of all such derivatives and variants, the IL-17 antibody or antigen-binding fragment thereof is capable of inhibiting the activity of about 1 nM (= 30 ng / ml) human IL-17 by 50% at a concentration 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 of the molecule, as described in Example 1 of WO 2006 / 013107 for IL-6 production induced by hu-IL-17 in human dermal fibroblasts.

[0114] In some embodiments, an IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab) binds to an epitope of mature human IL-17 comprising Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129. In some embodiments, an IL-17 antibody (e.g., secukinumab) binds to an epitope of mature human IL-17 comprising Tyr43, Tyr44, Arg46, Ala79, Asp80. In some embodiments, an IL-17 antibody (e.g., secukinumab) binds to an epitope of an IL-17 homodimer having two mature human IL-17 chains, 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. The residue numbering scheme used to define IL-17 epitopes herein is based on the residue that is the first amino acid of the mature protein (i.e., IL-17A lacking the 23 amino acid N-terminal signal peptide and starting with glycine). The sequence of immature IL-17A is listed in Swiss-Prot entry Q16552.

[0115] In some embodiments, the IL-17 antibody has a K of about 100-200 pM. DIn some embodiments, the IL-17 antibody has an IC of about 0.4 nM for in vitro neutralization of the biological activity of about 0.67 nM human IL-17A. 50 In some embodiments, the absolute bioavailability of the IL-17 antibody administered by subcutaneous injection (SC) has a range of about 60% to about 80%, such as about 73%, about 76%. In some embodiments, the IL-17 antibody (such as secukinumab) has an elimination half-life of about 4 weeks (e.g., about 23 to about 35 days, about 23 to about 30 days, such as about 30 days). In some embodiments, the IL-17 antibody (such as secukinumab) has a T max For about 7 to 8 days.

[0116] Other preferred IL-17 antagonists for use in the disclosed methods, kits and protocols include KHK4872 (Kyowa Hakko Kirin), ABT-122 (Abbvie), BCD-085 (JCS Biomedical), vidofludimus (4SC-101), NI-1401 (RG7624; MCAF5352A - NovImmune), ANB004 (Anaptys Bio Inc.), E-036041 (Ensemble Therapeutics Corp.), Qβ-IL-17 (virus-like particle-based vaccine), PRS-190 (Pieris AG), bimegezumab (UCB 4940 - UCB), ALX-0761, CNTO 6785 (Janssen Pharmaceuticals), LY3074828 (Eli Lilly), LY3114062 (Eli Lilly), SCH-900117, MSB0010841 (ALX-0761—Merck), ABT-122, COVA322 (Covagen), ixekizumab and brolucumab, and those listed in the following U.S. Patent Nos.: 9,193,788; 8,057,794; 7,767,206; 8,003,099; 8,110,191; and 7,838,638 and U.S. Published Patent Application Nos.: 20120034656 and 20110027290, the disclosures of which regarding the sequences and / or structures of IL-17 antagonists are incorporated herein by reference.

[0117] In some embodiments of the disclosed uses, methods and kits, the IL-17 antibody or antigen-binding fragment thereof is selected from the group consisting of: a) an IL-17 antibody or antigen-binding fragment thereof that binds to an epitope between residues Arg 55 and Trp 67 of IL-17; b) an IL-17 antibody or antigen-binding fragment thereof that binds to an epitope of IL-17 comprising Arg 55, Glu 57, and Trp67; c) an IL-17 antibody or antigen-binding fragment thereof that binds to an epitope of IL-17 comprising: Arg 55, Glu 57, Trp 67, Tyr 62, and Arg 101; d) an IL-17 antibody or antigen-binding fragment thereof that binds to an epitope of IL-17 comprising Arg 55, Glu 57, Trp 67, Tyr 62, Arg 101, Pro 59, Ser 64, and Val 64. 65; e) an IL-17 antibody or an antigen-binding fragment thereof that binds to an epitope of IL-17, the epitope comprising Arg 55, Glu 57, Trp 67, Tyr 62, Arg 101, Pro 59, Ser 64, Val 65, Val 22*, Leu 26, Asp 58, Glu 60, Pro 63, Pro107, Phe 110, and Lys 114*, wherein the amino acids marked with (*) represent residues contributed by the second IL-17 subunit of the IL-17A homodimer, wherein the IL-17 antibody or the antigen-binding fragment thereof has a K of 0.05 for human IL-17. D The invention relates to an IL-17 antibody or an antigen-binding fragment thereof, wherein the IL-17 antibody or an antigen-binding fragment thereof has an in vivo half-life of about 14-23 days, for example, about 20 days; and f) an IL-17 antibody or an antigen-binding fragment thereof, which comprises: i) an immunoglobulin heavy chain variable domain (V H ) comprising the amino acid sequence set forth in SEQ ID NO: 30; H );ii) an immunoglobulin light chain variable domain (V L );iii) an immunoglobulin V comprising the amino acid sequence listed in SEQ ID NO: 30 H domain and an immunoglobulin V comprising the amino acid sequence set forth in SEQ ID NO: 22 L domain; iv) an immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 24, SEQ ID NO: 26 and SEQ ID NO: 28 H domain; v) an immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 16, SEQ ID NO: 18 and SEQ ID NO: 20L domain; vi) an immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 25, SEQ ID NO: 27, and SEQ ID NO: 29 H vii) an immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 17, SEQ ID NO: 19 and SEQ ID NO: 21 L h) an immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 24, SEQ ID NO: 26 and SEQ ID NO: 28 H domains and immunoglobulin V domains comprising the hypervariable regions listed in SEQ ID NO: 16, SEQ ID NO: 18, and SEQ ID NO: 20 L domain; ix) an immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 25, SEQ ID NO: 27, and SEQ ID NO: 29 H Domains and immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 17, SEQ ID NO: 19 and SEQ ID NO: 21 L domain; x) a light chain comprising SEQ ID NO:23; xi) a heavy chain comprising SEQ ID NO:31; or xii) a light chain comprising SEQ ID NO:23 and a heavy chain comprising SEQ ID NO:31.

[0118] In some embodiments of the disclosed uses, methods and kits, the IL-17 antibody or antigen-binding fragment thereof is CJM112, a high-affinity recombinant fully human monoclonal anti-human IL-17 antibody of the IgG1 / κ class. CJM112 also binds to IL-17AF and antagonizes this cytokine (see, e.g., U.S. Pat. No. 9,193,788, which is incorporated herein by reference in its entirety).

[0119] IL-17AF antagonists can also be used to treat tendinopathy and induce regeneration of tendon tissue and promote tendon repair in patients with tendinopathy. These antagonists (including antibodies that cross-react with IL-17A and IL-17F, and bispecific anti-IL-17A / F antibodies FynomAb (e.g., COVA322), nanobodies (e.g., ALX-0761), etc.) can be found in U.S. Published Patent Application Nos. 20140314763, 2013 / 0195872, 20160326241, U.S. Patent Nos. 8496936, 8945553, and published PCT Application No. WO / 2016 / 070062.

[0120] Methods of treatment and use of Il-17 antagonists for tendinopathy

[0121] The disclosed IL-17 antagonists (e.g., IL-17 binding molecules (e.g., IL-17 antibodies or antigen-binding fragments thereof, such as secukinumab)) or IL-17 receptor binding molecules (e.g., IL-17 receptor antibodies or antigen-binding fragments thereof) can be used in vitro, ex vivo, or incorporated into pharmaceutical compositions and administered in vivo to treat tendinopathy (e.g., human patients suffering from tendinopathy).

[0122] It is contemplated that all representative forms of tendinopathy may be treated using the disclosed uses, compositions, methods and kits, such as plantar fasciitis, Achilles tendinopathy, patellar tendinopathy, rotator cuff (infraspinatus, teres minor, supraspinatus and subscapularis) tendinopathy, tennis elbow (lateral epicondylitis), golfer's elbow (medial epicondylitis), jumper's knee, supraspinatus syndrome, etc. In a preferred embodiment, the patient suffers from rotator cuff (infraspinatus, teres minor, supraspinatus and subscapularis) tendinopathy.

[0123] In some embodiments, the patient has no tear or a partial tear of the affected tendon [maximum 50% tendon thickness (Bauer tendon thickness score maximum 2); AP tear dimension [length] of the tendon maximum 10 mm (Bauer tendon length score maximum 2)] (e.g., as confirmed using ultrasound and / or MRI). MRI scoring schemes for partial tears are known (see, e.g., Bauer et al. (2014) J Orthop Surg Res. [Journal of Orthopedic Surgery and Research] 9:128).

[0124] In some embodiments, the patient has a positive "Painful Arc Test" (see, e.g., O'Kane and Toresdahl (2014) Curr Sports Med Rep. 13(5):307-13) on examination, and / or has night pain in the affected shoulder on at least 4 of the 7 days in a given week. In some embodiments, the patient has pain in the affected shoulder (at rest or during exercise) on at least 3 of the 7 days in a given week, and the pain visual analog scale (VAS) scores ≥ 4 (out of 10).

[0125] In some embodiments, the patient's symptoms (e.g., pain, motor inhibition, and / or swelling) have been present for ≥6 weeks. In some embodiments, the patient's symptoms (e.g., pain, motor inhibition, and / or swelling) have been present for <12 months. In some embodiments, the patient's symptoms (e.g., pain, motor inhibition, and / or swelling) have been present for ≥6 weeks and <12 months.

[0126] In some embodiments, the patient has MRI-positive overuse (non-systemic inflammatory) rotator cuff (infraspinatus, teres minor, supraspinatus, and subscapularis) tendinopathy. In some embodiments, the patient has rotator cuff (infraspinatus, teres minor, supraspinatus, and subscapularis) tendinopathy and no systemic inflammatory disease.

[0127] In some embodiments, the patient is refractory (i.e., the patient did not respond or had an inadequate (suboptimal) response [e.g., as determined by a VAS pain score, e.g., a VAS pain score ≥ 4]) to or intolerant of a prior tendinopathy treatment (e.g., steroid treatment (e.g., local injection of a steroid into the affected tendon), treatment with an NSAID, treatment with acetaminophen, physical therapy, or a combination thereof).

[0128] In some embodiments, the patient has previously had an inadequate response to a previous tendinopathy surgery.

[0129] Treatment of tendinopathy with steroids, NSAIDs, acetaminophen, physical therapy, and combinations thereof are referred to herein as "standard of care" treatment for tendinopathy. Patients treated with physical therapy are referred to as "physical therapy treated."

[0130] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, a patient with rotator cuff tendinopathy is being treated with standard of care treatments for tendinopathy and is not suitable or willing to undergo surgery. Whether a patient is suitable for surgery can be based on biochemical characteristics and / or physical characteristics, such as heart health, lung health, advanced age, etc., which can be determined by a physician.

[0131] In some embodiments, the patient is steroid-naive. In some embodiments, the patient is previously treated with one or more local steroid injections into the affected tendon. In some embodiments, the patient has tendinopathy at multiple sites.

[0132] In some embodiments, the patient is not a candidate for tendinopathy surgery.

[0133] In some embodiments, the patient does not wish to undergo tendinopathy surgery.

[0134] In some embodiments, the patient is not a candidate for or is unwilling to undergo tendinopathy surgery.

[0135] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient is undergoing physical therapy treatment, the patient is not a candidate for tendinopathy surgery, and prior to treatment with the IL-17 antibody or antigen-binding fragment thereof, the patient did not respond, had an inadequate response, or was intolerant to a previous tendinopathy treatment selected from the group consisting of local injection of steroids into the affected tendon, treatment with an NSAID, treatment with acetaminophen, and combinations thereof.

[0136] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient is undergoing physical therapy treatment, the patient is a candidate for tendinopathy surgery, and prior to treatment with the IL-17 antibody or antigen-binding fragment thereof, the patient did not respond, had an inadequate response, or was intolerant to a previous tendinopathy treatment selected from the group consisting of local injection of steroids into the affected tendon, treatment with an NSAID, treatment with acetaminophen, and combinations thereof.

[0137] Patient-reported outcomes (PROs), clinician-reported outcomes, imaging techniques, etc. can be used to measure the patient's response to the treatment disclosed herein. Clinician-reported outcomes include, for example, a physician's global assessment (PhGA) of disease activity (e.g., using a VAS score), a range of motion test (e.g., using a goniometer or digital assessment), and an arm muscle strength test (e.g., using a digital pressure gauge or rotator cuff functional index). Imaging techniques include, for example, MRI (e.g., used to determine MRI Sein scores, MRI Bauer scores, supraspinatus tendon thickness, bursitis in the rotator cuff region, supraspinatus tendon quality, the presence of diseased biceps tendon); ultrasound; and shear wave elastography (SWE) (e.g., used to assess the biomechanical properties [stiffness] of the supraspinatus tendon). PROs include, for example, the Patient Global Assessment (PGA) of disease activity (e.g., using a VAS score); the Western Ontario Rotator Cuff (WORC) patient-reported outcome score; the Disability of Arm, Shoulder and Hand Questionnaire (QuickDASH) score; the American Shoulder and Elbow Surgeons Shoulder Evaluation Form (ASES) score, and the EQ5D-5L score.

[0138] The WORC score is a patient-reported outcome tool uniquely developed by Kirkley and colleagues for rotator cuff disease (Kirkley et al. (2003) Clin J Sport Med; 13:84–92). It is a quality of life questionnaire designed for patients with rotator cuff injuries. The minimal clinically important change (MCIC) in WORC is calculated as 275 points or 12.8% (if displayed in WORC% format). In some embodiments, when a patient population with rotator cuff tendinopathy is treated according to the disclosed methods (e.g., using a fixed dose of about 150 mg of secukinumab or a fixed dose of about 300 mg of secukinumab, given monthly, with or without a loading dose), at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the patients in the population achieve the MCID in the WORC score. In preferred embodiments, when a patient population with rotator cuff tendinopathy is treated according to the disclosed methods (e.g., using a fixed dose of about 150 mg of secukinumab or a fixed dose of about 300 mg of secukinumab, administered monthly, with or without a loading dose), at least 40%, preferably at least 60%, of the patients in the population achieve the MCID in the WORC score.

[0139] Quick DASH is an abbreviated form of DASH (Patient-Reported Outcome Tool) and has been developed by the American Academy of Orthopedic Surgeons in conjunction with the Institute for Work & Health (Toronto, Ontario, Canada).

[0140] The Society of the American Shoulder and Elbow Surgeons has developed the ASES score for the assessment of shoulder function (Richards et al. (1994) J Shoulder Elbow Surg 3:347-352).

[0141] The EuroQuol 5D (EQ-5D-5L) (euroqol.org / eq-5d-instruments / eq-5d-5l-about / ), a self-administered questionnaire designed to assess the health status of adults, is widely used. In this study, the EQ-5D-5L was designed to assess the general health status of the patients.

[0142] The MRI Sein score is primarily used to grade supraspinatus tendinosis (Sein et al. (2007) Br J Sports Med [British Journal of Sports Medicine]; 41(8):e9) and to monitor changes in this grade over time. Tendinopathy is characterized by thickened, uneven rotator cuff tendons with increased signal intensity on all pulsed MRI sequences, but still not as bright as fluid on typical T2-weighted images. Because tendinitis and partial-thickness rotator cuff injuries are common in athletic and middle-aged populations, another grading system, the Bauer score, can be used to evaluate partial supraspinatus tears and tendinitis (Bauer et al. (2014) J. Orthopaedic Surg. Res [Journal of Orthopaedic Surgery and Research] 9:128). These images can be used to measure the thickness of the rotator cuff tendons and assess the presence of bursitis in the rotator cuff area. In some embodiments, when a tendinopathy population is treated according to the disclosed methods, at least 40%, at least 50%, at least 60%, at least 70%, or at least 90% of the patients have less progression of tendon rupture (partial / complete) as measured by MRI Bauer score. In preferred embodiments, when a tendinopathy population is treated according to the disclosed methods, at least 50% of the patients have less progression of tendon rupture (partial / complete) as measured by MRI Bauer score. In some embodiments, when a tendinopathy population is treated according to the disclosed methods, at least 40%, at least 50%, at least 60%, at least 70%, or at least 90% of the patients have at least one grade improvement in tendon structure (i.e., less damage) as measured by MRI Sein score. In some embodiments, when a tendinopathy population is treated according to the disclosed methods, at least 50% of the patients have at least one grade improvement in tendon structure (i.e., less damage) as measured by MRI Sein score.

[0143] Enhancement of the subacromial bursa can be assessed by the method of Hodgson et al. ((2012) Br. J. Radiology; 85:1482-1487).

[0144] Improved Achilles tendon pain and function can be assessed using the Victorian Institute of Sport Assessment-Achilles (VISA-A) questionnaire.

[0145] Improved patellar tendon pain and function can be assessed using the Victorian Institute of Sport Assessment-Patellar (VISA-P) questionnaire.

[0146] Improved epicondylar tendon pain and function were assessed using the Patient-Rated Tennis Elbow Evaluation (PRTEE) questionnaire.

[0147] Other MRI measurements may also be considered as markers of tendon “quality / integrity”, such as MRI techniques based on ultrashort echo time (UTE) pulse sequences, and contrast mechanisms based on T2* relaxation rate (Juras et al. (2013) Eur Radiol [European Radiology] 23:2814-2822) and / or based on magnetization transfer ratio (MTR) (Syha et al. (2011) Fortschr Rontgenstra; 183:1043-1050).

[0148] Due to the elastic properties of tendons in the body, they can withstand large muscle forces with minimal deformation and force transmission loss by absorbing and releasing energy during movement. In tendinopathy, changes in tendon morphology and composition can lead to alterations in its mechanical characteristics. Shear wave elastography (SWE) is a non-invasive ultrasonographic imaging technique that can assess the elastic properties of soft tissues, including tendons (Chen et al. (2013) J Ultrasound Med; 32:449-455). Rotator cuff tendon stiffness can be measured by SWE.

[0149] The Visual Analog Scale (VAS) is a tool that measures a characteristic or condition whose values ​​are thought to range across a continuum. For example, the amount of pain a patient feels ranges from none across a continuum of extreme amounts of pain. From the patient's perspective, this range appears continuous ± their pain does not have discrete jumps, as the categories of none, mild, moderate, and severe would imply. The VAS pain scale is often used as an outcome measure to characterize pain intensity in clinical studies. It typically exists as a 100-mm horizontal line with points between the extremes of "no pain at all" and "worst pain imaginable" (etc.) where the patient's pain intensity lies. The respondent is asked to place a line perpendicular to the VAS line at the location that best represents their pain at the moment. This tool is scored in millimeters (although scores are often recorded in tenths of centimeters using a 10-point scale); scores below 40 millimeters (or 4 points if measured in centimeters) are generally considered desirable for chronic pain management.

[0150] In some embodiments, after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months (preferably 1, 2 or 3 months) of treatment according to the claimed methods, the patient experiences at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% pain relief, reduced inflammation, improved tendon regeneration and / or repair, and / or improved motion. In a preferred embodiment, after treatment according to the claimed methods, the patient experiences at least 20% pain relief, reduced inflammation, improved tendon regeneration and / or repair, and / or improved motion.

[0151] In some embodiments, after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months (preferably 1, 2 or 3 months) of treatment according to the claimed methods, the patient experiences at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% improvement in VAS score, WORC score, QuickDASH score, ASES score, and / or EQ5D-5L score. In a preferred embodiment, after treatment according to the claimed methods, the patient experiences at least 20% pain relief as determined by VAS score. In preferred embodiments, after treatment according to the claimed methods, the patient experiences at least a 20% improvement in shoulder-related quality of life (QoL), as determined by a WORC score, a QuickDASH score, or an ASES score. In preferred embodiments, after treatment according to the claimed methods, the patient experiences at least a 20% improvement in overall quality of life, as determined by a PGA score.

[0152] When used in combination with a pharmaceutically acceptable carrier, an IL-17 antagonist (e.g., 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 antibody or an antigen-binding fragment thereof)) can be used as a pharmaceutical composition. In addition to the IL-17 antagonist, such a composition may also contain a carrier, various diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials. The characteristics of the carrier will depend on the route of administration. The pharmaceutical composition for use in the disclosed methods may also contain other therapeutic agents for treating specific targeted disorders. For example, the pharmaceutical composition may also include an anti-inflammatory agent. Such additional factors and / or agents may be included in the pharmaceutical composition together with the IL-17 binding molecule to produce a synergistic effect or minimize the side effects caused by the IL-17 antagonist (e.g., 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 antibody or an antigen-binding fragment thereof)).

[0153] The pharmaceutical composition for use in the disclosed method can be prepared in a known manner. In one embodiment, the pharmaceutical composition is provided in a lyophilized form. For immediate administration, it is dissolved in a suitable aqueous carrier, such as sterile water for injection or sterile buffered saline. If it is considered necessary to constitute a larger volume of solution for administration by infusion rather than a single rapid intravenous injection, it may be advantageous to incorporate human serum albumin or the patient's own heparinized blood into the saline during formulation. The presence of an excess of this physiologically inert protein prevents the loss of antibodies by adsorption to the walls of the container and the tubing used to infuse the solution. If albumin is used, a suitable concentration is from 0.5% to 4.5% by weight of the saline solution. Other formulations include liquid or lyophilized formulations.

[0154] Antibodies, such as antibodies to IL-17, are typically formulated in aqueous form for parenteral administration, or as lyophilisates for reconstitution with a suitable diluent prior to administration. In some embodiments of the disclosed methods and uses, the IL-17 antagonist (e.g., an IL-17 antibody such as secukinumab) is formulated as a ready-to-use liquid pharmaceutical composition. Suitable lyophilized formulations can be reconstituted in a small liquid volume (e.g., 2 ml or less) to allow subcutaneous administration, and can provide a solution with low levels of antibody aggregation. Antibodies are now widely used as active ingredients in drugs, including the product HERCEPTIN TM (trastuzumab), RITUXAN TM (rituximab), SYNAGIS TM(Palivizumab) and the like. The technology for purifying antibodies to pharmaceutical grade is known. When 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 (e.g., an IL-17 antibody or an antigen-binding fragment thereof) is administered by intravenous, percutaneous or subcutaneous injection, the IL-17 antagonist will be in the form of a pyrogen-free, parenterally acceptable solution. In addition to the IL-17 antagonist, the pharmaceutical composition for intravenous, percutaneous or subcutaneous injection may contain an isotonic vehicle, such as sodium chloride, Ringer's solution, dextrose, dextrose and sodium chloride, lactated Ringer's solution, or other vehicles known in the art.

[0155] In preferred embodiments of the disclosed methods, uses, kits, etc., the IL-17 molecule (e.g., IL-17 antibody or antigen-binding fragment thereof) or the IL-17 receptor binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof) is secukinumab, which is provided in a stable liquid pharmaceutical formulation comprising about 25 mg / mL to about 150 mg / mL secukinumab, about 10 mM to about 30 mM histidine (pH 5.8), about 200 mM to about 225 mM trehalose, about 0.02% polysorbate 80, and about 2.5 mM to about 20 mM methionine, wherein the liquid formulation is not reconstituted from a lyophilisate. A preferred drug product for use in the disclosed methods, uses, kits, etc. comprises a stable liquid formulation having 150 mg / ml secukinumab, 200 mM trehalose, 0.02% polysorbate 80, and 5 mM L-methionine in 20 mM histidine buffer (pH 5.8), provided in a pre-filled syringe or autoinjector (i.e., having 1 mL or 2 mL of the formulation).

[0156] The appropriate dosage will vary depending on, for example, the specific IL-17 antagonist used, such as an IL-17 binding molecule (e.g., an IL-17 antibody or antigen-binding fragment thereof, such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 antibody or antigen-binding fragment thereof); the host; the mode of administration and the nature and severity of the condition being treated and the nature of the treatment that the patient has previously undergone. Ultimately, the attending healthcare provider will determine the amount of IL-17 antagonist used to treat each individual patient. In some embodiments, the attending healthcare provider can 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 titrated down until signs of relapse appear. Larger doses of the IL-17 antagonist may be administered until the optimal therapeutic effect for the patient is obtained, and the dose is generally not increased further.

[0157] In practicing some of the methods of treatment or uses disclosed herein, a therapeutically effective amount of an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody or antigen-binding fragment thereof, such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 antibody or antigen-binding fragment thereof) is administered to a patient (e.g., a mammal (e.g., a human)). While it should be understood that the disclosed methods provide for the treatment of a tendinopathy patient using an IL-17 antagonist (e.g., secukinumab), this does not preclude that if the patient is to be ultimately treated with an IL-17 antagonist, such IL-17 antagonist therapy is necessarily a monotherapy. Indeed, if a patient is selected for treatment with an IL-17 antagonist, the IL-17 antagonist (e.g., secukinumab) may be administered alone or in combination with other agents and therapies (e.g., other tendinopathy standard of care therapies, e.g., steroids, NSAIDs, acetaminophen, physical therapy, etc.) according to the methods disclosed herein. Additional therapies for use in combination with the disclosed IL-17 antagonists (e.g., secukinumab) to treat tendinopathy include rest, ice, massage therapy, extracorporeal shock wave therapy (ESWT), ultrasound, laser therapy, eccentric exercise, LIPUS, electrotherapy, taping, sclerotherapy injections, glyceryl trinitrate, and other forms of physical therapy and physical therapy. Tendinopathy agents for use in combination with the disclosed IL-17 antagonists (e.g., secukinumab) to treat tendinopathy include steroids (e.g., corticosteroids, glucocorticoids, methylprednisolone, betamethasone) (oral, IV, or IM), autologous blood, platelet-rich plasma (PRP), deproteinized hemodialysate, aprotinin, polysulfated glycosaminoglycans, acetaminophen, NSAIDs (salicylates [e.g., aspirin], propionic acid derivatives [e.g., ibuprofen], acetic acid derivatives [e.g., diclofenac], enolic acid (oxicam) derivatives [e.g., meloxicam], anthranilic acid derivatives (fenamates) [e.g., meclofenamic acid], selective COX-2 inhibitors [e.g., celecoxib], sulfonanilides [e.g., nimesulide] and others [clonixin, licoricellon, h-harpagoside]).Additional tendinopathy agents for use in combination with the disclosed IL-17 antagonists (e.g., secukinumab) to treat tendinopathy include growth hormone, hyaluronic acid, insulin-like growth factor I, autologous conditioned plasma, lidocaine, tetracaine patch, ethoxysclerotol, polidocanol, SM04755, betamethasone, ketorolac, autologous mesenchymal stem cells, sodium thiosulfate, depomedrol, RCT-01, ketamine, MRX-7EAT, ketoprofen, TNF-α inhibitors (infliximab, adalimumab, pegol-certolizumab pegol), golimumab, etanercept), IL-1 inhibitors (anakinra, rilanacept, canakinumab), IL-23 inhibitors (ustekinumab, guselkmab), IL-17 inhibitors (ixekizumab, buladezumab), aliviador, gelol, triamcinolone acetonide, xylocaine, doxycycline, ketorolac, etoricoxib, oxycodone, bupivacaine, hydrocodone, and codeine.

[0158] When co-administered with one or more additional tendinopathy agents, the IL-17 antagonist can be administered simultaneously with the other agents, or sequentially. If used sequentially, the attending physician will determine the appropriate order of administering the IL-17 antagonist in combination with the other agents and the appropriate doses for co-delivery. The IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody or antigen-binding fragment thereof, such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody or antigen-binding fragment thereof) is conveniently administered parenterally, such as intravenously (e.g., in an antecubital or other peripheral vein), intramuscularly, or subcutaneously.

[0159] The duration of the therapy using the pharmaceutical composition of the present disclosure will vary according to the severity of the disease being treated and the illness and personal response of each individual patient. A healthcare provider will use the pharmaceutical composition of the present disclosure to determine the appropriate duration of therapy and the administration time of the therapy. As used herein, the phrase "total duration of treatment" refers to the total amount of time during the treatment of a patient with an IL-17 antagonist, including (if applicable) an induction phase (e.g., initial weekly administration). Therefore, for example, if during the 0th, 1st, 2nd, 3rd, and 4th week, an IL-17 antagonist is administered to the patient weekly, and then the administration is performed every 4 weeks and the total duration of treatment lasts for 2 months, then the administration is performed to the patient during the 0th, 1st, 2nd, 3rd, 4th, and 8th week. Similarly, for example, if during the 0th, 1st, 2nd, 3rd, and 4th week, an IL-17 antagonist is administered to the patient weekly, and then the administration is performed every 4 weeks and the total duration of treatment lasts for 3 months, then the administration is performed to the patient during the 0th, 1st, 2nd, 3rd, 4th, and 8th week.

[0160] The preferred total duration of treatment is between 1-3 months, 3-6 months, 6-9 months, or 9-12 months. In some embodiments, the patient is treated for 3 months or less, such as 1, 2, or 3 months. In other embodiments, the patient is treated for up to 12 months, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months. The most preferred total duration of treatment is 1, 2, or 3 months.

[0161] Preferred SC treatment regimens with secukinumab (including both induction and maintenance regimens) that may be used to treat patients with tendinopathy are provided in PCT Application Nos. PCT / US2011 / 064307 and PCT / IB 2014 / 063902, which are incorporated herein by reference in their entirety, as appropriate.

[0162] In some embodiments, a single SC dose of about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) 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 (e.g., an IL-17 receptor antibody or an antigen-binding fragment thereof) can be administered to the patient.

[0163] In some embodiments, an IL-17 antagonist, e.g., 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 SC to the patient weekly during weeks 0, 1, 2, 3, and 4 at about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg).

[0164] In a preferred embodiment, an IL-17 antagonist (e.g., 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 to the patient SC at a fixed dose of about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) per week during weeks 0, 1, 2, 3, and 4, and about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) of the antagonist is administered to the patient SC every 4 weeks (monthly) thereafter. In this way, about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) of an IL-17 antagonist (e.g., secukinumab) is administered to the patient SC during weeks 0, 1, 2, 3, 4, 8, etc.

[0165] In other embodiments, an IL-17 antagonist (e.g., 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 to the patient (without a loading regimen), for example, the antagonist can be administered to the patient SC at a fixed dose of about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) every 4 weeks (monthly). In this way, about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) of an IL-17 antagonist (e.g., secukinumab) is administered to the patient SC during weeks 0, 4, 8, 12, etc. Ideally, an IL-17 antagonist (e.g., secukinumab) is administered monthly (every 4 weeks) to a patient (e.g., a patient with rotator cuff tendinopathy or Achilles tendinopathy (preferably rotator cuff tendinopathy)) for a total of four doses (weeks 0, 4, 8, and 12).

[0166] In other preferred embodiments, the 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 to the patient twice a month (every 2 weeks, every other week), every other month, quarterly (every three months), twice a year (every 6 months), or annually.

[0167] The preferred SC dose (e.g., fixed dose) is about 150 mg-about 300 mg, preferably about 150 mg or about 300 mg. However, it should be understood that for some patients, such as patients who show an inadequate 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, such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody or an antigen-binding fragment thereof)), dose escalation may be required (e.g., during the induction and / or maintenance phase). Therefore, the SC dose of an IL-17 antagonist (e.g., secukinumab) may be greater than about 150 mg-about 300 mg, such as about 175 mg, about 200 mg, about 250 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, etc. It should also be understood that for certain patients, such as patients who exhibit adverse events or adverse reactions to treatment with an IL-17 antagonist (e.g., an IL-17 antibody or antigen-binding fragment thereof, such as secukinumab), a dose reduction may also be required (e.g., during the induction and / or maintenance phase). Thus, the dose of an IL-17 antagonist (e.g., an IL-17 antibody or antigen-binding fragment thereof, such as secukinumab) may be less than about 150 mg to about 300 mg SC, such as about 75 mg, about 100 mg, about 125 mg, about 175 mg, about 200 mg, about 250 mg, about 275 mg, etc. In some embodiments, the IL-17 antagonist (e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen binding fragment thereof, such as secukinumab) or IL-17 receptor binding molecule (e.g., IL-17 receptor antibody or antigen binding fragment thereof)) can be administered to the patient at an initial dose (or multiple initial doses) of 150 mg SC delivery, as determined by a physician, and then the dose is increased to about 300 mg if necessary. In some embodiments, the IL-17 antagonist (e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen binding fragment thereof, such as secukinumab) or IL-17 receptor binding molecule (e.g., IL-17 receptor antibody or antigen binding fragment thereof)) can be administered to the patient at an initial dose (or multiple initial doses) of 300 mg SC delivery, as determined by a physician, and then the dose is increased to about 450 mg if necessary.

[0168] The timing of dosing is usually measured from the day of the first dose of medication (also called “baseline”). However, healthcare providers often use different nomenclature to determine dosing schedules, as shown in Table 2.

[0169]

[0170] Table 2: General nomenclature used for dosing regimens. Items in bold refer to the nomenclature used herein.

[0171] It is noteworthy that Week 0 may be referred to as Week 1 by some healthcare providers, while Day 0 may be referred to as Day 1 by some healthcare providers. Therefore, it is possible that different physicians will indicate that the dosage is given, for example, in Week 3 / during Day 21, in Week 3 / during Day 22, in Week 4 / during Day 21, in Week 4 / during Day 22, and refer to the same dosing schedule. For consistency, the first week of administration will be referred to as Week 0 herein, and the first day of administration will be referred to as Day 1. However, it will be understood by those skilled in the art that the naming convention is only used for consistency and should not be interpreted as limiting, i.e., weekly administration is to provide a weekly dose of IL-17 antibody, regardless of whether the physician refers to a specific week as "Week 1" or "Week 2". In one dosing regimen, antibodies are administered monthly during Weeks 0, 4, 8, 12, etc. In one dosing regimen, antibodies are administered during Weeks 0, 1, 2, 3, 4, 8, 12, etc. Some providers may refer to this regimen as weekly for five weeks and monthly (or every 4 weeks) thereafter beginning during week 8, while others may refer to this regimen as weekly for four weeks and monthly (or every 4 weeks) thereafter beginning during week 4. One skilled in the art will appreciate that administering injections to a patient at weeks 0, 1, 2, and 3, followed by monthly dosing (or every 4 weeks) beginning during week 4, is the same as: 1) administering injections to a patient at weeks 0, 1, 2, 3, and 4, followed by monthly dosing beginning at week 8; 2) administering injections to a patient at weeks 0, 1, 2, 3, and 4, followed by every 4 weeks; and 3) administering injections to a patient at weeks 0, 1, 2, 3, and 4, followed by monthly dosing.

[0172] Disclosed herein are methods of treating a patient suffering from tendinopathy, comprising administering to a patient in need thereof a therapeutically effective amount of an IL-17 antibody or an antigen-binding fragment thereof, wherein the IL-17 antibody or antigen-binding fragment thereof binds to an epitope of an IL-17 homodimer having two mature 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, wherein the IL-17 antibody or antigen-binding fragment thereof has a Kp of 0.05 for human IL-17. D The IL-17 antibody or antigen-binding fragment thereof has an in vivo half-life of about 4 weeks.

[0173] In addition, disclosed herein is a therapeutically effective amount of an IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) for use in treating a patient with tendinopathy, wherein 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 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, wherein the IL-17 antibody or antigen-binding fragment thereof has a Kp of 0.05 for human IL-17. D is about 100-200 pM, and wherein the IL-17 antibody or antigen-binding fragment thereof has an in vivo half-life of about 4 weeks.

[0174] Additionally, 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 treating a patient with tendinopathy, wherein 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 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, wherein the IL-17 antibody or antigen-binding fragment thereof has a Kp of 0.05 for human IL-17. D is about 100-200 pM, and wherein the IL-17 antibody or antigen-binding fragment thereof has an in vivo half-life of about 4 weeks.

[0175] Additionally, disclosed herein are IL-17 antagonists (e.g., IL-17 antibodies or antigen-binding fragments thereof, such as secukinumab) for use in the manufacture of a medicament for treating a patient suffering from tendinopathy, wherein the medicament is formulated to comprise containers, each container having a sufficient amount of the IL-17 antagonist (e.g., IL-17 antibody or antigen-binding fragment thereof, such as secukinumab) to allow 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., IL-17 antibody or antigen-binding fragment thereof, such as secukinumab) per unit dose, and further wherein the IL-17 antagonist (e.g., IL-17 antibody or antigen-binding fragment thereof, such as secukinumab) is administered to a subject in a manner consistent with the present invention. 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 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, wherein the IL-17 antibody or antigen-binding fragment thereof has a K of 0.05 for human IL-17. D is about 100-200 pM, and wherein the IL-17 antibody or antigen-binding fragment thereof has an in vivo half-life of about 4 weeks.

[0176] As used herein, the phrase "a container having a sufficient amount of IL-17 antagonist to allow delivery of [a specified dose]" is used to indicate that a given container (e.g., a vial, a pen, a syringe) has been configured therein a volume of IL-17 antagonist that can be used to provide the desired dose (e.g., as part of a pharmaceutical composition). As an example, if the desired dose is 300 mg, then the clinician might use 2 ml from a container containing an IL-17 antibody formulation at a concentration of 150 mg / ml, 1 ml from a container containing an IL-17 antibody formulation at a concentration of 300 mg / ml, 0.5 ml from a container containing an IL-17 antibody formulation at a concentration of 600 mg / ml, etc. In each such case, these containers have a sufficient amount of IL-17 antagonist to allow delivery of the desired 300 mg dose. In one embodiment, 1 ml of a formulation containing 150 mg / ml of secukinumab has been configured in the container. In another embodiment, 2 ml of a formulation containing 150 mg / ml of secukinumab has been configured in the container. A preferred formulation is a liquid pharmaceutical composition comprising about 25 mg / mL to about 150 mg / mL of secukinumab, about 10 mM to about 30 mM histidine (pH 5.8), about 200 mM to about 225 mM trehalose, about 0.02% polysorbate 80, and about 2.5 mM to about 20 mM methionine.

[0177] Furthermore, 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 treating a patient suffering from tendinopathy, wherein the medicament is formulated as a dose that allows for subcutaneous delivery of 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) to the patient, and further wherein the IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) The IL-17 antibody or antigen-binding fragment thereof binds to an epitope of an IL-17 homodimer having two mature 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, wherein the IL-17 antibody or antigen-binding fragment thereof has a K of 0.05 for human IL-17. D is about 100-200 pM, and wherein the IL-17 antibody or antigen-binding fragment thereof has an in vivo half-life of about 4 weeks.

[0178] As used herein, the phrase "formulated in a dosage that allows [route of administration] to deliver [specified dose]" is used to indicate that a given pharmaceutical composition can be used to provide a desired dose of an IL-17 antagonist, e.g., an IL-17 antibody, such as secukinumab, via a specified route of administration (e.g., SC or IV). For example, if the desired subcutaneous dose is 300 mg, then the clinician may use 2 ml of an IL-17 antibody formulation at a concentration of 150 mg / ml, 1 ml of an IL-17 antibody formulation at a concentration of 300 mg / ml, 0.5 ml of an IL-17 antibody formulation at a concentration of 600 mg / ml, and the like. In each such case, these IL-17 antibody formulations are at a sufficiently high concentration to allow subcutaneous delivery of the IL-17 antibody. Subcutaneous delivery typically requires delivery of a volume of ≤2 ml. In one embodiment, a single 2 ml SC injection of a formulation containing 150 mg / ml secukinumab is administered to a patient. In another embodiment, two 1 ml SC injections of a formulation containing 150 mg / ml secukinumab are administered to a patient.

[0179] Disclosed herein are methods, uses, pharmaceutical compositions, and kits for inducing regeneration of tendon tissue or promoting tendon repair in patients with tendinopathy, comprising subcutaneously administering to a patient in need thereof about 150 mg to about 300 mg of an IL-17 antibody or an antigen-binding fragment thereof, wherein the IL-17 antibody or antigen-binding fragment thereof binds to an epitope of a human 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, wherein the IL-17 antibody or antigen-binding fragment thereof has a K of 0.05 for human IL-17. D The IL-17 antibody or antigen-binding fragment thereof has an in vivo half-life of about 4 weeks.

[0180] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the IL-17 antibody or antigen-binding fragment thereof is administered to the patient only once.

[0181] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the IL-17 antibody or antigen-binding fragment thereof is administered to the patient weekly.

[0182] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, during weeks 0, 1, 2, 3, and 4, the IL-17 antibody or antigen-binding fragment thereof is administered to the patient.

[0183] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the IL-17 antibody or antigen-binding fragment thereof is administered to the patient every 4 weeks.

[0184] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the IL-17 antibody or antigen-binding fragment thereof is administered to the patient for a total treatment duration of at least two months.

[0185] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the IL-17 antibody or antigen-binding fragment thereof is administered to the patient for a total treatment duration of at least four months.

[0186] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the IL-17 antibody or antigen-binding fragment thereof is administered to the patient weekly during weeks 0, 1, 2, 3, and 4, and then every 4 weeks.

[0187] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the IL-17 antibody or antigen-binding fragment thereof is administered to the patient during weeks 0, 1, 2, 3, 4, 8, and 12.

[0188] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the IL-17 antibody or antigen-binding fragment thereof is administered to the patient weekly during weeks 0, 1, 2, 3, and 4, and every 4 weeks thereafter for a total treatment duration of at least three months.

[0189] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, prior to treatment with the IL-17 antibody or antigen-binding fragment thereof, the patient did not respond, had an inadequate response, or was intolerant to a previous tendinopathy treatment selected from the group consisting of local injection of steroids into the affected tendon, treatment with an NSAID, treatment with acetaminophen, physical therapy, and combinations thereof.

[0190] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient suffers from overuse tendinopathy.

[0191] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient suffers from a subacute tendinopathy.

[0192] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, treatment with the IL-17 antibody or antigen-binding fragment thereof slows progression to chronic tendinopathy.

[0193] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient suffers from a chronic tendinopathy.

[0194] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient suffers from an active tendinopathy.

[0195] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient has a partially torn tendon.

[0196] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, treatment with the IL-17 antibody or antigen-binding fragment thereof slows progression to a complete tendon tear.

[0197] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient suffers from plantar fasciitis, Achilles tendinopathy, patellar tendinopathy, rotator cuff tendinopathy, jumper's knee, lateral epicondylitis, medial epicondylitis, supraspinatus syndrome, or any combination thereof.

[0198] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, following treatment with the IL-17 antibody or antigen-binding fragment thereof, the patient experiences at least 20% reduction in pain, at least 20% reduction in inflammation, at least 20% improved tendon regeneration and / or repair, and / or at least 20% improved motion of the affected tendon.

[0199] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, after treatment with the IL-17 antibody or antigen-binding fragment thereof, the patient experiences at least 20% pain relief as determined by VAS score.

[0200] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient suffers from rotator cuff tendinopathy and, following treatment with the IL-17 antibody or antigen-binding fragment thereof, the patient experiences at least a 20% improvement in shoulder-related quality of life (QoL) as determined by a WORC score, a QuickDASH score, or an ASES score.

[0201] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, after treatment with the IL-17 antibody or antigen-binding fragment thereof, the patient experiences at least a 20% overall improvement as determined by PGA score.

[0202] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits further comprise administering a steroid, an NSAID, or acetaminophen to the patient.

[0203] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, after treatment with an IL-17 antibody or antigen-binding fragment thereof, the patient's need for physical therapy is reduced, or the patient's tendinopathy symptoms are alleviated, thereby improving the effectiveness of physical therapy.

[0204] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the IL-17 antibody or antigen-binding fragment thereof comprises: i) an immunoglobulin heavy chain variable domain (V H ) comprising the amino acid sequence set forth in SEQ ID NO: 8; H );ii) an immunoglobulin light chain variable domain (V L );iii) an immunoglobulin V comprising the amino acid sequence listed in SEQ ID NO:8 H Domain and an immunoglobulin V comprising the amino acid sequence listed in SEQ ID NO: 10 L domain; iv) an immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 H domain; v) an immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 L domain; vi) an immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 H vii) an immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 H domains and immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 L viii) an immunoglobulin V domain comprising the hypervariable regions listed in SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13 H domains and immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 Ldomain; ix) an immunoglobulin light chain comprising the amino acid sequence set forth in SEQ ID NO: 14; x) an immunoglobulin heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 15; or xi) an immunoglobulin light chain comprising the amino acid sequence set forth in SEQ ID NO: 14 and an immunoglobulin heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 15. In some embodiments of the disclosed uses, methods, and kits, the IL-17 antibody or antigen-binding fragment thereof is secukinumab.

[0205] Also disclosed herein are methods, uses, pharmaceutical compositions, and kits for treating a patient with active overuse tendinopathy, comprising administering to the patient about 300 mg of secukinumab by subcutaneous injection at weeks 0, 1, 2, 3, and 4, and every four weeks thereafter for a total treatment duration of at least three months.

[0206] Also disclosed herein are methods, uses, pharmaceutical compositions, and kits for treating a patient with active overuse tendinopathy, comprising administering to the patient about 150 mg of secukinumab by subcutaneous injection at weeks 0, 1, 2, 3, and 4, and every four weeks thereafter for a total treatment duration of at least three months.

[0207] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, prior to treatment with secukinumab, the patient was refractory to a prior tendinopathy treatment selected from the group consisting of local injection of steroids into the affected tendon, treatment with an NSAID, treatment with acetaminophen, physical therapy, and combinations thereof.

[0208] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient is undergoing physical therapy treatment, the patient is not a candidate for tendinopathy surgery, and prior to treatment with the IL-17 antibody or antigen-binding fragment thereof, the patient did not respond, had an inadequate response, or was intolerant to a previous tendinopathy treatment selected from the group consisting of local injection of steroids into the affected tendon, treatment with an NSAID, treatment with acetaminophen, and combinations thereof.

[0209] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient is undergoing physical therapy treatment, the patient is a candidate for tendinopathy surgery, and prior to treatment with the IL-17 antibody or antigen-binding fragment thereof, the patient did not respond, had an inadequate response, or was intolerant to a previous tendinopathy treatment selected from the group consisting of local injection of steroids into the affected tendon, treatment with an NSAID, treatment with acetaminophen, and combinations thereof.

[0210] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient had a suboptimal response to tendinopathy surgery prior to treatment with secukinumab.

[0211] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, a patient with rotator cuff tendinopathy is being treated with standard of care for tendinopathy and is not a candidate for surgery.

[0212] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, when a patient population suffering from rotator cuff tendinopathy is treated with secukinumab, at least 40%, preferably at least 60% of the patients achieve the MCID in the WORC score.

[0213] Reagent test kit

[0214] The present disclosure also encompasses kits for treating patients with tendinopathy. Such kits include 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 (e.g., an IL-17 antibody or an antigen-binding fragment thereof) (e.g., in liquid or lyophilized form) or a pharmaceutical composition comprising an IL-17 antagonist (as described above) in a therapeutically effective amount. In addition, such kits may include tools for administering the IL-17 antagonist (e.g., an automatic injector, a syringe and a vial, a prefilled syringe, a prefilled pen) and instructions for use. These kits may contain additional therapeutic agents for treating tendinopathy (as described above), for example, for delivery in combination with the included IL-17 antagonist (e.g., an IL-17 binding molecule, such as an IL-17 antibody, such as secukinumab). Such kits may also include instructions for administering an IL-17 antagonist (e.g., an IL-17 antibody, such as secukinumab) to treat patients with tendinopathy. Such instructions can provide a dose (e.g., about 150 mg - about 300 mg, e.g., about 150 mg, about 300 mg), route of administration (e.g., IV, SC, IM), regimen (e.g., weekly during weeks 0, 1, 2, 3, and 4; weekly during weeks 0, 1, 2, 3, and 4, and then every 4 weeks), and total duration of treatment (e.g., 1, 2, 3, 4, 6, 8, 12 months, etc. [preferably 3-12 months, e.g., 3-6 months, such as 3 months]) for use with an included IL-17 antagonist (e.g., an IL-17 binding molecule, e.g., an IL-17 antibody, such as secukinumab).

[0215] The phrase "instrument for administration" is used to indicate any available means for systemically administering a drug to a patient, including but not limited to prefilled syringes, vials and syringes, injection pens, auto-injectors, IV injection troughs and injection bags, pumps, etc. Using such items, a patient can self-administer the drug (i.e., administer the drug without the help of a physician) or a licensed physician can administer the drug. In some embodiments, a total dose of 300 mg is delivered in a total volume of 2 ml of an IL-17 antibody (e.g., secukinumab) with 150 mg / ml configured in a single PFS or auto-injector. In some embodiments, a total dose of 300 mg is delivered in a total volume of 2 ml configured in two PFS or auto-injectors, each PFS or auto-injector containing: a volume of 1 ml of an IL-17 antibody (e.g., secukinumab) with 150 mg / ml.

[0216] Disclosed herein is a kit for use in the treatment of a patient with tendinopathy, comprising an IL-17 antagonist (e.g., an IL-17 binding molecule, such as an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab). In some embodiments, the kit further comprises a tool for administering the IL-17 antagonist to the patient. In some embodiments, the kit further comprises instructions for administering the IL-17 antagonist, wherein the instructions indicate that the IL-17 antagonist (e.g., an IL-17 binding molecule, such as an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) is administered subcutaneously (SC) to the patient at a dose of about 150 mg to about 300 mg (e.g., about 150 mg, or about 300 mg). In some embodiments, the instructions indicate that the IL-17 antagonist (e.g., an IL-17 binding molecule, such as an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) is administered to the patient weekly during weeks 0, 1, 2, 3, and 4. In some embodiments, the instructions indicate that the IL-17 antagonist (e.g., IL-17 binding molecule, e.g., IL-17 antibody or antigen-binding fragment thereof, such as secukinumab) is administered to the patient every 4 weeks (monthly) for a total treatment duration of at least 2 months (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months (preferably, 2 or 3 months)). In some embodiments, the instructions indicate that the IL-17 antagonist (e.g., IL-17 binding molecule, e.g., IL-17 antibody or antigen-binding fragment thereof, such as secukinumab) is administered to the patient every week during weeks 0, 1, 2, 3, and 4, and that administration is performed every 4 weeks (monthly) thereafter for a total treatment duration of at least 3 months (i.e., 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months (preferably, 2 or 3 months)). In some embodiments, the instructions will provide for dose escalation (eg, from a dose of about 150 mg to a higher dose of about 300 mg, or from a dose of about 300 mg to a dose of about 450 mg, as needed as determined by a physician).

[0217] Overview

[0218] 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 preferred embodiments of the disclosed methods, treatments, regimens, uses and kits, the IL-17 antibody or an antigen-binding fragment thereof is a human antibody of the IgG1 isotype with a kappa light chain. In preferred embodiments of the disclosed methods, the antibody or antigen-binding fragment thereof is secukinumab.

[0219] The details of one or more embodiments of the present disclosure are set forth in the specification attached above. Preferred methods and materials are now described, but any methods and materials similar or equivalent to those described herein may also be used for the practice or testing of the present disclosure. According to the specification and according to the claims, other features, objects and advantages of the present disclosure will be clear. In this specification and the appended claims, unless the context clearly indicates otherwise, the singular form includes plural references. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those of ordinary skill in the art to which the present disclosure belongs. Unless otherwise stated, all patents and publications cited in this specification are incorporated by reference when appropriate. The following examples are provided to more fully illustrate the preferred embodiments of the present disclosure. These examples should never be interpreted as limiting the scope of the subject matter of the disclosure defined by the appended claims.

[0220] Examples

[0221] Example 1 - Tissue exposure and efficacy of IgG1 anti-IL-17 monoclonal antibody in tendinopathy

[0222] In an in vivo rat disease model, tendinopathy of the rotator cuff tendons was induced by unilateral surgical partial tenotomy of the supraspinatus tendon along the coronal plane. IgG1 anti-IL-17 monoclonal antibody (CJM112) (15 mg / kg) or vehicle was administered subcutaneously or intravenously one week before or one day before surgical induction of tendinopathy, followed by subcutaneous or intravenous administration once a week for three weeks. Four weeks after surgical induction of tendinopathy and one week after the last administration of the antibody, the exposure of the antibody in the rotator cuff tendon tissue, its pharmacological effects on tendinopathy inflammation and gait imbalance were evaluated. After tissue homogenization and protein extraction, the terminal valley exposure level of the antibody in the rotator cuff tendon tissue, skeletal muscle and skin was evaluated by enzyme-linked immunosorbent assay (ELISA). The effects of the antibody on tendinopathy inflammation were assessed by in vivo magnetic resonance imaging (MRI) (10.1136 / bjsm.2006.034421), and the effects on gait imbalance were assessed by quantifying illuminated footprints of animals moving unforced through a catwalk (10.1007 / s11916-014-0456-x).

[0223] After repeated dosing, trough exposure levels of IL-17 antibody in rotator cuff tendon were similar according to subcutaneous and intravenous administration routes (500 ng / mg total protein, n=5). Trough exposure levels of antibody in tendon tissue were similar to those in skeletal muscle and lower than those in skin (2'500 ng / mg total protein, n=5).

[0224] Induction of tendinopathy significantly increased the MRI T2 inflammatory signal from 35 ms in normal tendons to 55 ms in tendinopathic tendons (p<0.01, Student's t-test, n=4). The antibody reversed the increased MRI T2 inflammatory signal in tendinopathies (p<0.01, Student's t-test, n=4). Induction of tendinopathy triggered gait imbalance and significantly increased the front-hind ratio in the footprint contact area from 1 before induction of tendinopathy to 1.5 after induction of tendinopathy (p<0.05, ANOVA Tukey post hoc test, n=8). The antibody reversed the gait imbalance (p<0.05, ANOVA Tukey post hoc test, n=8).

[0225] The results of this in vivo testing strongly suggest that antagonist IL-17 antibodies will be useful in treating tendinopathy.

[0226] Example 2 - Ex vivo and in vitro examples of IL17-induced tendon fascicle inflammation

[0227] In an in vitro rat tail tendon fascicle model (a model of unloaded induced tendon degeneration), RNASeq analysis revealed markers of intrinsic tendon fascicle inflammation. Unloaded fascicles showed >10-fold upregulation of multiple cytokines, chemokines, and MMPs (including IL6, CXCL1, CCL2, CCL20, CSF1-3, MMP2, 3, and 9). IL-17RA and IL-17RC were found to be highly expressed in tendon fascicles, indicating that the tissue was sensitive to IL-17. Computational analysis of signal transduction pathways from an internal database identified five pathway hits that were specific for IL-17 or TH17 cell-specific features. Adding recombinant IL-17A (1.67nM) to unloaded tendon fascicles induced a further increase in the expression of cytokines, chemokines, and MMPs (IL-6, CXCL-1, PTGS-2, MMP-3). At the same time, and in accordance with tendon degeneration, tendon marker genes scleraxis and tenomodulin were sharply downregulated. Furthermore, after eight days of culture, the elastic modulus of unloaded tendon fascicles decreased compared to fresh tissue controls (ANOVA; p = 0.0001), and IL-17A treatment induced a trend toward a further decrease (Dunnett post hoc test: p = 0.0774), suggesting that inflammatory cytokines lead to a loss of biomechanical capacity ( Figure 1 ).

[0228] In vitro assays in rat tenocytes demonstrated that IL-17A induced a dose-dependent increase in IL-6 and CXCL-1 mRNA expression ( Figure 2). In addition, in rat tenocytes, 33 nM of the rodent anti-IL-17A antibody BZN035 was able to completely block IL-17A-induced induction of IL-6 and CXCL-1 expression ( Figure 3 ).

[0229] Example 3 - A randomized, double-blind, placebo-controlled, parallel-group, Phase II, 24-week study investigating the efficacy, safety, and tolerability of AIN457 in patients with active overuse tendinopathy refractory to oral NSAIDs / acetaminophen, physical therapy, or corticosteroid injections

[0230] "Enthesitis" is a term used to describe inflammation of the attachment points of tendons, ligaments, or joint capsules. It applies to diseases associated with spondyloarthritis (SpA), including AS and PsA. Enthesitis can be inflammatory or mechanically induced; both can share common features (McGonagle D and Benjamin M (2009) Reports on Rheumatic Diseases Series 6.4:1-6).

[0231] As seen in studies with secukinumab, neutralization of IL-17 has been shown to have efficacy in the inflammatory enthesitis of PsA and AS. In study CAIN457F2312, enthesitis was assessed in a subgroup of patients with disease activity at baseline. In this patient population, secukinumab significantly increased the percentage of patients with resolved enthesitis compared to placebo (CAIN457F2312). Overall, at week 24, the percentages of patients with unresolved enthesitis were 67.6%, 57.8%, 51.8%, 59.6%, and 78.5%, respectively, for secukinumab 75mg, 150mg, 300mg groups, combined secukinumab groups, and placebo groups. At Week 24, these differences versus placebo were also greater for the 150 mg and 300 mg dose groups versus placebo (p=0.0108 and p=0.0025, respectively), while similar for 75 mg versus placebo (p=0.1678).

[0232] Given the in vitro, ex vivo, and in vivo evidence for tendinopathy treatment shown in Examples 1 and 2, combined with the effects of IL-17 antagonism on enthesitis in PsA and AS patients, we believe that neutralization of IL-17 will reduce tendon inflammation and, perhaps more importantly, reduce tendon matrix breakdown and degeneration. Therefore, secukinumab was tested as a disease-modifying therapy for inducing regeneration of tenocytes and promoting tendon repair for active overuse tendinopathy.

[0233] The purpose of this Phase II study is to determine the efficacy of secukinumab in the treatment of patients diagnosed with overuse, non-systemic inflammatory rotator cuff (infraspinatus, teres minor, supraspinatus, and subscapularis) tendinopathy, and to confirm the safety and tolerability profile of secukinumab given at a dose of 300 mg sc on Day 1 (Week 0) and weekly up to and including Week 4 (Weeks 1, 2, 3, and 4), with additional injections at Weeks 8 and 12 thereafter. The efficacy of secukinumab will be evaluated at the end of Week 14 based on validated patient-reported outcomes (PROs), including improvements in signs and symptoms, physical function, quality of life, and range of motion (ROM). Changes in tendon structure reflecting tendon regeneration and repair will be studied using MRI and shear wave elastography. Patients will be followed up without treatment from Week 12 to Week 24 to investigate long-term safety. Details of the study are provided below:

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[0240] result

[0241] Patient Distribution and Baseline Characteristics

[0242] A total of 353 patients were screened, 98 were enrolled, 97 were randomized, and 96 received at least one dose, 49 in the secukinumab group and 47 in the placebo group. Of all patients treated in the study (N=96; 100%), a total of 90 patients completed the treatment phase and 88 patients completed the study including the follow-up phase ( Figure 5 ).

[0243] Demographic variables were generally comparable between the two groups. Patients in the secukinumab group were approximately 5 years younger and more likely to be male than those in the placebo group (Table R1).

[0244] Table R1

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[0248] *Number of evaluable patients: SEC, N=47; PBO, N=41; Total, N=88

[0249] ASES, American Shoulder and Elbow Surgeons Evaluation Schedule; BMI, body mass index; N, total number of patients; n, number of patients; QuickDASH, Disability of the Arm, Shoulder, and Hand Questionnaire; PBO, placebo;

[0250] SEC, secukinumab; VAS, visual analog scale; WORC, Western Ontario Rotator Cuff Index

[0251] Clinical efficacy

[0252] Key pain and functional outcomes (primary and secondary endpoints): WORC and pain scores

[0253] In the overall study population, treatment with secukinumab and placebo in combination with standard of care (SoC) resulted in clinically relevant improvements in total WORC score (primary endpoint at week 14), WORC subdomains, and pain scores (secondary endpoints), with no statistically significant differences between the two groups at week 14 and over time ( Figure 6 ).

[0254] Patient-reported outcomes: ASES, QuickDASH, EQ-5D scores

[0255] The secukinumab group showed numerical improvements in ASES scores compared with the placebo group; however, the difference was not statistically significant. Both groups showed improvements in QuickDASH scores over time, with no statistically significant differences between the two groups. There was consistent improvement in EQ-5D-5L index scores in both the secukinumab and placebo groups at all time points; however, only the difference at day 15 was significantly superior to placebo (p = 0.05) ( Figure 7 ).

[0256] Overall disease assessment: PGA, PhGA

[0257] Both the secukinumab group and the placebo group showed improvement in PGA.

[0258] Patients treated with secukinumab showed greater improvement and lower mean PhGA scores compared with those treated with placebo at all visits except day 15, which did not differ significantly between the two groups. Both the secukinumab and placebo groups showed improvement over time, with lower mean PhGA scores reflecting reduced disease activity, which did not differ significantly between the two groups ( Figure 7 ).

[0259] Imaging: MRI, Sein and Bauer scores

[0260] The MRI Sein score change chart did not show any changes compared with baseline at week 14 in the secukinumab group. In the placebo group, one patient had a change in Sein score from 2 at baseline to 1 at week 14. For the Bauer MRI score, one patient in the placebo group showed a change at week 14, worsening from a score of 1 to a score of 2.

[0261] Physical Function Assessment: Range of Mobility

[0262] At week 14 (day 99), both treatment groups showed improvements in all assessed parameters of active and passive range of motion (ROM): abduction, adduction, extension, flexion, and internal and external rotation. No significant differences or specific patterns of active and passive ROM were observed between the secukinumab and placebo groups ( Figure 8 ).

[0263] Post-mortem analysis

[0264] Since many patients (n = 77, 87.5%) had mild disease, with a WORC score above 60 (maximum 100), and / or a Sein tendinopathy score of 1 and / or a Bauer score of 0 at baseline, it was assumed based on the current literature that 1 These patients improve with standard physical therapy. Preclinical Translational Research 10,12 High tissue signaling of IL-17A in patients with early tendinopathy associated with inflammatory infiltrates was highlighted, suggesting that targeting the IL-17A pathway may be most beneficial in early disease. Additionally, 37 (42%) patients were noted to have a prolonged duration of tendinopathy symptoms >6 months; this indicates advanced disease; based on these observations, a subgroup of patients (n=37, 42%) with disease duration ≤6 months, WORC score ≤40, Sein score ≥2, or Bauer score ≥1 (indicating early moderate to severe disease) were subsequently analyzed ( Fig. 9 ).

[0265] WORC scores improved over time in both the secukinumab-treated and placebo-treated subgroups, with the secukinumab group showing clinically relevant and nominally statistically significant improvements compared with placebo at all time points (Table R2, Fig. 9 ).

[0266] Table R2 Changes from baseline in total WORC scores and pain (VAS) scores in the secukinumab-treated and placebo-treated groups in subpopulations*

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[0269] *Disease duration ≤ 6 months and (WORC score ≤ 40 or Sein ≥ 2 or Bauer tear ≥ 1); N = 37

[0270] a Baseline WORC score: SEC, 37.2; placebo, 34.5

[0271] b Baseline pain scores: SEC, 71.7; placebo, 67.6

[0272] N, total number of patients; n, number of patients; PBO, placebo; SEC, secukinumab; VAS, visual analog scale; WORC, Western Ontario Rotator Cuff Index

[0273] For the WORC subdimensions of physical symptoms, work, exercise, lifestyle, and mood scores, improvements with secukinumab were nominally statistically significantly different from placebo at all time points except for lifestyle at days 85 and 99 and mood at days 85, 99, and 169 ( Fig.10 ).

[0274] Differences in pain scores (VAS) compared with placebo were clinically meaningful at all time points and statistically significant from day 57 to day 127 (Table R2, Fig.10 ).

[0275] Similar results were observed for ASES scores, with differences from placebo being statistically significant at all time points except for Days 15, 99, and 169 (p = 0.07). For QuickDASH, secukinumab showed numerical improvements compared to placebo at all time points, with no statistically significant differences. Secukinumab showed numerical improvements compared to placebo at all time points, with the exception of Days 99 and 169 (p = 0.06 and 0.07, respectively).

[0276] The secukinumab group showed significant improvements in the EQ-5D-5L index at all time points ( Fig.11 ).

[0277] In post hoc subgroups, active and passive ROM improved in both groups, but the secukinumab group showed clinically relevant and statistically significant improvements compared with placebo ( Fig.12 ). To better understand the treatment effect in the restricted subacute, moderate to severe subpopulation analysis, the influence of different clinical characteristics on the response to secukinumab versus placebo was also investigated, showing a clear trend toward improvement with secukinumab treatment across the different subpopulations.

[0278] Security

[0279] During the 12-week period, secukinumab was generally well tolerated. The favorable safety profile of secukinumab was consistent with previous secukinumab studies. There were no serious AEs in the study (Table R3).

[0280] Table R3 AE incidence by preferred option - n (%) of patients (≥ 5% in all patients)

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[0282] Patients who experienced multiple AEs were counted only once in the 'At least one AE' row.

[0283] Patients who experienced multiple AEs by the same preference were counted only once for both preference and treatment. Preferences were ordered in descending frequency as reported in the 'Total column'.

[0284] AE, adverse event; N, total number of patients; n, number of patients; PBO, placebo; SEC, secukinumab

[0285] All AEs were mild or moderate in severity and did not differ significantly between the two groups. No clinically significant changes were reported between the two groups in hematology, clinical chemistry, urinalysis, or vital signs.

[0286] No treatment-emergent antidrug antibodies were observed in any patient.

[0287] discuss

[0288] This is the first study to examine the effects of IL-17A blockade in a patient cohort with active RC tendinopathy. In the total study population, both groups had significant improvements in symptoms and function on top of SoC therapy (NSAIDs, physical therapy), but there was no clear additional benefit of secukinumab treatment compared to placebo. Secukinumab showed a good safety profile, was well tolerated, and the AEs observed were consistent with the safety profile observed with secukinumab in other indications. The current results show that patients had clinically relevant improvements after receiving SoC therapy 16 , making it difficult to detect a treatment effect compared with the SoC arm. In addition, some patients with RC tendinopathy have a long history of disease (>6 months) with underlying tissue degeneration, at which time anti-inflammatory therapy may be functionally redundant. Based on this study, it is concluded that the widespread use of secukinumab in RC tendinopathy is not justified.

[0289] This study provides an opportunity to explore in greater depth the relationship between cytokine effector pathology and clinical manifestations in and around human tendons. Given that tendon biopsies tend to be included in the Human Cell Atlas project, 17The results of this study are presented in the journal Nature and are therefore being deconstructed at the molecular level, which has important implications for future translational histopathological descriptions and rational therapeutic interventions. 18 Immunobiology of tendinopathy 19 Several IL-17A inhibitors have shown efficacy in treating multiple aspects of spondyloarthritis, including psoriasis, enthesitis, synovitis, bone erosion, new bone formation, and pain, suggesting that IL-17A plays a role in the pathophysiology of the disease in various tissues. 20 Several observations suggest that IL-17A displays plausible biological characteristics in preclinical and translational studies of tendinous tissue. Therefore, it is hypothesized that inhibition of IL-17A could show beneficial therapeutic effects in RC tendinopathy. 10 Increased IL-17 mRNA and protein expression levels were noted in the 14 samples of human tendinopathy. Interestingly, it was also noted that tendon-resident immune cells with high expression of IL-17A were expressed in early but not late stage human tendinopathy biopsies. 10 Functional IL-17A blockade significantly improved supraspinatus tendinopathy in rodent models (which, by definition, are early-stage disease models). 12 ) in tendon structure and function. Therefore, as a post hoc analysis, the cohort of patients meeting criteria for early disease was interrogated.

[0290] Therefore, we performed an exploratory post hoc analysis of 37 patients (42%) with disease duration ≤6 months and moderate to severe disease (defined as a WORC score ≤40, a Sein score ≥2, or a Bauer score ≥1). In this subgroup of patients with RC tendinopathy, secukinumab provided nominally significant but clearly clinically relevant and durable improvements in WORC scores that were above the minimal clinically important difference from baseline for the treatment group. 21 , 48 at week 14, and 56 at the end of the study. This subanalysis supports data obtained from preclinical studies and therefore provides meaningful translational insights. RC tendinopathy patients with early (<6 months) moderate to severe tendinopathy may represent a more robust inflammatory phenotype and be more likely to respond to IL-17A inhibition.

[0291] There remains a significant gap in the development of new drugs and agents that can improve tendinopathy in patients who do not respond to exercise regimens. The translation of preclinical findings remains challenging due to the multiple anatomical sites and varying phenotypes of tendinopathy, as was evident in this trial. Clinical trials in nonathletic individuals are rarely interpreted, making it difficult to determine whether certain treatment strategies are beneficial in different patient subgroups. Patient stratification was applied to post hoc analyses that showed significant improvements across a range of clinically relevant outcomes.

[0292] Limitations of the existing studies affected the ability to meet prespecified primary and secondary endpoints, including heterogeneity and a broad spectrum of disease from mild to severe, as well as long disease duration of up to 12 months at inclusion. 22 , and allowed optimal NSAID therapy, resulting in improvements in the placebo group. In addition, due to the large number of patients with mild disease, the study was not powered to detect relevant changes in MRI imaging during short-term treatment.

[0293] In conclusion, although neutralization of IL-17A with secukinumab did not benefit all patients with mild to severe RC tendinopathy, it appeared to improve pain, function, and quality of life in patients with moderate to severe disease of shorter duration. Larger prospective studies in this subpopulation are needed to confirm the results obtained in this phase 2 study.

[0294] Example 4 – A randomized, parallel-group, 24-week, double-blind, placebo-controlled, multicenter Phase 3 study to evaluate the efficacy and safety of secukinumab compared with placebo in adult participants with rotator cuff tendinopathy

[0295] Study Group

[0296] The target population is adult men and women aged 18 to 65 years with unilateral, non-acute, partial tear or no tear, moderate to severe RCT that is refractory to conservative SoC. In order to participate, participants must:

[0297] Is refractory to SoC therapy, defined as 2 months of NSAIDs (or discontinuation if not tolerated) and physical therapy (PT). Symptoms present for at least 6 weeks but no longer than 6 months.

[0298] NRS pain score of 5 or higher, equivalent to moderate to severe pain (0-10 scale with 10 being the worst possible pain), at baseline and 3 of the 7 days prior to baseline. Participants must also have had night pain in the affected shoulder for at least 4 of the 7 days in the week prior to baseline.

[0299] · A WORC total score percentile score of 40 or less at baseline (where 100 percentile is asymptomatic). Using cut-off values ​​for the WORC total score to define the target group is appropriate because it has been reported to be validated and widely cited in the RCT literature. It allows for the identification of suitable RCT participants from a broad holistic perspective, taking into account the participant's condition and the impact of the RCT on the participant's quality of life (QoL) ( Kirkley et al., 2003a ; Ekeberg et al., 2008 ; de Witte et al., 2012 ). Section 4.4This further supports a WORC overall cutoff of 40 percentiles, which identifies moderate to severe disease.

[0300] A partial-thickness tear of 50% or less as determined by MRI or ultrasound.

[0301] Goals and End Points

[0302] The primary and key secondary efficacy endpoints of the Phase 3 study are presented in Table 2-1. The primary endpoint was the proportion of participants with an improvement of at least 40 percentage points from baseline in the WORC physical symptom domain at Week 14. Secondary endpoints assessed shoulder-specific daily pain intensity and functional impact, sleep disruption due to shoulder pain, and overall sleep quality, which would support the clinical benefit of secukinumab.

[0303] Table 0-1 Primary and secondary objectives and endpoints

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[0308] NRS, Numerical Rating Scale; PSQI, Pittsburgh Sleep Quality Index; WORC, Western Ontario Rotator Cuff Index

[0309] Sequence Listing

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Claims

1. A method for inducing regeneration of tendon tissue or promoting tendon repair in a patient with moderate to severe tendinopathy, the method comprising subcutaneously administering to a patient in need thereof about 150 mg to about 300 mg of an IL-17 antibody or an antigen-binding fragment thereof, wherein the IL-17 antibody or the antigen-binding fragment thereof binds to an epitope of a human IL-17 homodimer having two mature human IL-17 protein chains, the epitope comprising Leu74, Tyr85, His86 on one chain , Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain, wherein the IL-17 antibody or its antigen-binding fragment has a KD for human IL-17 of about 100-200 pM, and wherein the IL-17 antibody or its antigen-binding fragment has an in vivo half-life of about 4 weeks.

2. The method of claim 1, wherein the IL-17 antibody or antigen-binding fragment thereof is administered to the patient only once.

3. The method of claim 1, wherein the IL-17 antibody or antigen-binding fragment thereof is administered to the patient weekly.

4. The method of claim 3, wherein the IL-17 antibody or antigen-binding fragment thereof is administered to the patient during weeks 0, 1, 2, 3, and 4.

5. The method of claim 1, wherein the IL-17 antibody or antigen-binding fragment thereof is administered to the patient every four weeks.

6. The method of claim 5, wherein the IL-17 antibody or antigen-binding fragment thereof is administered to the patient for a total treatment duration of at least two months.

7. The method of claim 5, wherein the IL-17 antibody or antigen-binding fragment thereof is administered to the patient every four weeks for a total treatment duration of four months.

8. The method of claim 3, wherein the IL-17 antibody or antigen-binding fragment thereof is administered to the patient weekly during weeks 0, 1, 2, 3, and 4, and then every 4 weeks.

9. The method of claim 8, wherein the IL-17 antibody or antigen-binding fragment thereof is administered to the patient during weeks 0, 1, 2, 3, 4, 8, and 12.

10. The method of claim 8, wherein the IL-17 antibody or antigen-binding fragment thereof is administered to the patient weekly during weeks 0, 1, 2, 3, and 4, and every 4 weeks thereafter for a total treatment duration of at least three months.

11. The method of any of the above claims, wherein prior to treatment with the IL-17 antibody or antigen-binding fragment thereof, the patient did not respond, had an inadequate response, or was intolerant to a previous tendinopathy treatment selected from the group consisting of local injection of steroids into the affected tendon, treatment with an NSAID, treatment with acetaminophen, physical therapy, and combinations thereof; or wherein the patient is refractory or intolerant to, e.g., two months of NSAID treatment and / or physical therapy.

12. The method according to any one of the preceding claims, wherein the patient has had symptoms of tendinopathy for > 6 weeks.

13. The method of any one of the preceding claims, wherein the patient suffers from subacute tendinopathy, and / or wherein treatment with the IL-17 antibody or antigen-binding fragment thereof is initiated when the patient has had symptoms of tendinopathy for ≤ 6 months.

14. The method of claim 13, wherein treatment with the IL-17 antibody or antigen-binding fragment thereof slows progression to chronic tendinopathy.

15. The method according to any of the preceding claims, wherein the patient suffers from an active tendinopathy.

16. The method according to any of the preceding claims, wherein the patient has a partially torn tendon.

17. The method of claim 16, wherein the patient has a partial thickness tear of ≤ 50%, for example, as confirmed by MRI or ultrasound.

18. The method of claim 16 or 17, wherein treatment with the IL-17 antibody or antigen-binding fragment thereof slows progression to a complete tendon tear.

19. The method of any of the above claims, wherein the patient suffers from plantar fasciitis, Achilles tendinopathy, patellar tendinopathy, rotator cuff tendinopathy, jumper's knee, lateral epicondylitis, medial epicondylitis, supraspinatus syndrome, or any combination thereof.

20. The method of any of the preceding claims, wherein the patient has rotator cuff tendinopathy, is being treated with standard of care for tendinopathy, and is not a candidate for surgery.

21. The method according to any one of the preceding claims, wherein the patient suffers from rotator cuff tendinopathy and The method comprises determining that the patient had night pain in the affected shoulder for at least 4 of the 7 days prior to initiating treatment with the IL-17 antibody or antigen-binding fragment thereof; or The patient has had night pain in the affected shoulder for at least 4 of the 7 days prior to initiating treatment with the IL-17 antibody or antigen-binding fragment thereof.

22. The method according to any one of the preceding claims, wherein the patient suffers from rotator cuff tendinopathy and Prior to starting treatment with the IL-17 antibody or antigen-binding fragment thereof, the patient's total WORC percentile score was ≤ 40; or The method includes determining that the patient's total WORC percentile score is ≤ 40 prior to initiating treatment with the IL-17 antibody or antigen-binding fragment thereof.

23. The method according to any one of the preceding claims, wherein the patient suffers from rotator cuff tendinopathy and The patient has an NRS pain score of ≥ 5 on 3 of the 7 days prior to starting treatment with the IL-17 antibody or antigen-binding fragment thereof; or The method comprises determining that the patient has an NRS pain score of ≥ 5 on 3 of the 7 days prior to initiating treatment with the IL-17 antibody or antigen-binding fragment thereof.

24. The method of any of the above claims, wherein following treatment with the IL-17 antibody or antigen-binding fragment thereof, the patient experiences at least 20% reduction in pain, at least 20% reduction in inflammation, at least 20% improved tendon regeneration and / or repair, and / or at least 20% improved motion of the affected tendon.

25. The method of any one of the preceding claims, wherein following treatment with the IL-17 antibody or antigen-binding fragment thereof, the patient experiences at least a 20% reduction in pain as determined by a VAS score.

26. The method according to any one of the preceding claims, wherein the patient suffers from rotator cuff tendinopathy, and wherein, Following treatment with the IL-17 antibody or antigen-binding fragment thereof, the patient experiences at least a 20% improvement in shoulder-related quality of life (QoL) as determined by a WORC score, a QuickDASH score, or an ASES score.

27. The method of any one of the preceding claims, wherein following treatment with the IL-17 antibody or antigen-binding fragment thereof, the patient experiences at least a 20% overall improvement as determined by PGA score.

28. The method of any of the preceding claims, further comprising administering a steroid, an NSAID, or acetaminophen to the patient.

29. The method of any of the above claims, wherein following treatment with the IL-17 antibody or antigen-binding fragment thereof, the patient's need for physical therapy is reduced, or the patient's tendinopathy symptoms are alleviated, thereby improving the efficacy of physical therapy.

30. The method according to any one of the preceding claims, wherein the IL-17 antibody or antigen-binding fragment thereof comprises: i) an immunoglobulin heavy chain variable domain (V H ); ii) an immunoglobulin light chain variable domain (V L ); iii) an immunoglobulin V comprising the amino acid sequence set forth in SEQ ID NO: 8 H domain and an immunoglobulin V comprising the amino acid sequence listed in SEQ ID NO: 10 L Structural domain; iv) an immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 H Structural domain; v) an immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 L Structural domain; vi) an immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 H Structural domain; vii) an immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 H domains and immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 L Structural domain; viii) an immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 H domains and immunoglobulin V comprising the hypervariable regions listed in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 L Structural domain; ix) an immunoglobulin light chain comprising the amino acid sequence set forth in SEQ ID NO: 14; x) an immunoglobulin heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 15; or xi) an immunoglobulin light chain comprising the amino acid sequence set forth in SEQ ID NO:14 and an immunoglobulin heavy chain comprising the amino acid sequence set forth in SEQ ID NO:

15.

31. The method of claim 30, wherein the IL-17 antibody or antigen-binding fragment thereof is secukinumab.

32. A method of treating a patient with moderate to severe tendinopathy, the method comprising administering to the patient about 300 mg of secukinumab by subcutaneous injection at weeks 0, 1, 2, 3, and 4, and every four weeks thereafter for a total treatment duration of at least three months.

33. A method of treating a patient with moderate to severe tendinopathy, the method comprising administering to the patient about 150 mg of secukinumab by subcutaneous injection at weeks 0, 1, 2, 3, and 4, and every four weeks thereafter for a total treatment duration of at least three months.

34. The method of claim 32 or 33, wherein prior to treatment with secukinumab, the patient was refractory to a tendinopathy treatment selected from the group consisting of: local injection of steroids into the affected tendon, treatment with an NSAID, treatment with acetaminophen, physical therapy, and combinations thereof; or wherein the patient was refractory or intolerant to, e.g., two months of NSAID treatment and / or physical therapy.

35. The method of claim 32 or 33, wherein the patient had a suboptimal response to tendinopathy surgery prior to treatment with secukinumab.

36. The method of any one of claims 32-35, wherein the patient suffers from rotator cuff tendinopathy.

37. The method of any one of claims 32-35, wherein the patient has rotator cuff tendinopathy, is being treated with standard of care for tendinopathy, and is not a candidate for surgery; or wherein the patient is refractory or intolerant to, e.g., two months of NSAID treatment and / or physical therapy.

38. The method according to claim 36 or 37, wherein when treating a patient population suffering from rotator cuff tendinopathy with secukinumab, at least 40%, preferably at least 60% of the patients achieve the MCID in the WORC score.

39. The method of any one of claims 32 to 38, wherein the patient has had symptoms of rotator cuff tendinopathy for at least 6 weeks prior to initiating treatment with secukinumab.

40. The method of claim 39, wherein the patient has had symptoms of rotator cuff tendinopathy for 6 months or less prior to initiating treatment with secukinumab.

41. The method of claim 39 or 40, wherein the patient has night pain in the affected shoulder on at least 4 out of 7 days prior to starting treatment with secukinumab; a total WORC percent score ≤ 40; and / or an NRS pain score ≥ 5 on 3 out of 7 days.

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