Method for selectively treating tendon disorders using interleukin-17 (IL-17) antagonists

Abstract

The present disclosure relates to a method of treating tendon disorders, such as rotator cuff tendon disorders, using an IL-17 antagonist, such as secukinumab. Also disclosed herein are the use of an IL-17 antagonist, such as an IL-17 antibody, such as secukinumab, to treat patients with tendon disorders, and pharmaceutical compositions, dosage regimens, pharmaceutical formulations, dosage forms, and kits for use in the disclosed uses and methods.

Description

Technical Field

[0001] The present disclosure relates to a method of treating tendinopathy in patients having a tendinopathy, such as a tendinous disorder of the rotator cuff, which is moderate to severe and / or subacute, and inducing regeneration of tendon tissue and promoting tendon repair, using an IL-17 antagonist, such as an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab or ixekizumab, or an IL-17 receptor antibody or an antigen-binding fragment thereof, such as brodalumab.

Background Art

[0002] Overuse tendinopathy is a complex and multifaceted tendon disease that is clinically diagnosed after a gradual onset of pain associated with activity, functional decline, and sometimes local swelling of the tendon (Riley G (2005) Expert Rev Mol Med; 7:1-25; Riley G (2008) Nat Clin Pract Rheumatol; 4:82-9). Historically, the terms "tendinitis" and "tendinosis" have been used interchangeably with the term "tendinopathy". However, these definitions are now included within the scope of disorders of human tendons ("tendinopathy"). Tendinopathy is a common overuse injury in the athlete and worker populations. Tendinopathy is the most common reason for consultation regarding musculoskeletal complaints and accounts for approximately 30% of all such consultations to 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 accounts for 30% to 50% of all injuries in sports medicine (Scott and Ashe (2006) Current Sports Medicine Reports; 5:233-241). In general, for manual workers, the prevalence of musculoskeletal symptoms increases with length of employment (Forde et al (2005), supra).

[0004] Upper limb tendinopathy Systematic reviews have shown that the incidence of rotator cuff tendon disorders ranges from 0.3% to 5.5% per 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 workers and athletes (15 - 20%) and in wheelchair users (31 - 73%). This is typically seen in swimmers, baseball, tennis, and volleyball players (Kaux et al(2011) J Sports Sci Med;10:238-253).

[0005] Tennis elbow (lateral epicondylitis) is another common tendon disorder and is common among athletes of all ages who participate in sports involving overhead or repetitive arm movements (Hume et al.(2006) Sports Medicine 36,151-170). The incidence in tennis players is as high as 9% - 40% (Maffulli et al(2003) Clinics in Sports Medicine 22,675-692; Scott and Ashe(2006), supra). This condition affects approximately 1 - 3% of the general population. Another elbow joint tendon disorder is golfer's elbow (medial epicondylitis), which is a typical complaint in pitching, baseball, and golf (ibid).

[0006] Lower limb tendon disorders Achilles tendon disorders are the most common lower limb tendon disorders, with a frequency of 5.9% in people who sit a lot and approximately 50% in elite athletes who require endurance (Scott and Ashe(2006), supra; Fredberg U and Stengaard-Pedersen K(2008) Scandinavian Journal of Medicine&Science in Sports 18,3-15).

[0007] Approximately one-third of sports injuries treated in sports clinics are related to the knee, and one-quarter of athletes being treated for knee injuries are diagnosed with tendon disorders (Maffulli et al (2003), supra). The most common knee disorder is jumper's knee (patellar tendinitis at the attachment site), and its incidence has been reported to be in the range of 7% - 40% (Fredberg and Stengaard-Pedersen (2008), supra; Scott and Ashe (2006), supra).

[0008] Treatment Current treatments for tendon disorders are rest, ice packs, and physical therapy (including therapeutic ultrasound, laser therapy, heat therapy, and extracorporeal shock wave therapy). The evidence supporting the widespread use of these treatment methods in tendon disorders remains inconsistent (Alfredson and Cook (2007) Br J Sports Med;41:211 - 216). Non-steroidal anti-inflammatory drugs (NSAIDs) or local corticosteroid injections can provide temporary pain relief, but the long-term benefits are doubtful (Mohamadi et al (2017) Clin.Orthop.Relat.Res.;475:232 - 243; Coombes et al. (2010) Lancet;376:1751 - 67). Furthermore, repeated steroid injections have been shown to have the potential to accelerate tendon degeneration, increasing the risk of tendon rupture (ibid). Autologous platelet-rich plasma (PRP) injections have been used, but the evidence regarding long-term effectiveness is scarce. Therefore, the benefits of PRP for tendon disorders remain controversial, and some studies have shown no effectiveness compared to saline (Krogh TP et al (2013) Am J Sports Med 41:625 - 35; de Vos RJ et al (2010) JAMA;303:144 - 9).

[0009] Overall, overuse tendon disorders are diseases with high medical needs and no appropriate treatment options.

Summary of the Invention

[0010] There is evidence that immune cells resident in tendons expressing IL-17 are present in human overuse tendon disorders and that IL-17 mRNA and protein expression levels are increased in early human tendon disorder samples (Millar et al. (2017) Nat Rev Rheumatol;13:110-122). In human tendon cells, IL-17 regulates pro-inflammatory cytokines, major apoptosis mediators and tendon matrix changes to a mechanically inferior type III collagen phenotype (ibid.). It is hypothesized that IL-17, a mediator of tendon inflammation, non-repair of the tendon matrix and tendon cell apoptosis, is involved in the etiology of overuse tendon disorders (ibid.).

[0011] 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). The inventors have now identified that an IL-17 antagonist, such as an IL-17 antibody, such as secukinumab, can be used systemically to treat a specific patient population having a tendon disorder and to restore pain, swelling and / or associated loss of function and to induce tendon cell regeneration and to promote tendon repair.

[0012] Accordingly, disclosed herein is a method for reducing inflammation, structural damage, and pain in tendons affected by tendon disorders in tendon disorder patients having moderate to severe and / or subacute tendon disorders, inducing tendon tissue regeneration in tendon disorder patients, promoting tendon repair in tendon disorder patients, and treating patients having moderate to severe and / or subacute tendon disorders (e.g., overuse tendon disorders), the method comprising administering an IL-17 antagonist (e.g., an anti-IL-17 antibody or an antigen-binding fragment thereof) to a patient in need thereof. In some embodiments, the patient has one or more or all of the following reference diseases for a period of 6 months or less and (WORC score ≤ 40 or Sein ≥ 2 or Bauer tear ≥ 1). In some embodiments, the patient has a rotator cuff tendon disorder (e.g., unilateral) with a symptom duration of 6 weeks or more and / or 6 months or less, nighttime pain in the affected shoulder on at least 4 days out of 7 days prior to the start of treatment, a total WORC percentage score ≤ 40 prior to the start of treatment, an NRS pain score ≥ 5 over 3 days out of 7 days prior to the start of treatment, and / or the patient is resistant (or intolerant) to 2 months of standard treatment such as NSAIDs and / or physical therapy.

[0013] Disclosed herein is a method, use, pharmaceutical composition, and kit for inducing tendon tissue regeneration or promoting tendon repair in a patient having a moderate to severe and / or subacute tendon disorder, the method comprising subcutaneously administering to a patient in need thereof an IL-17 antibody or an antigen-binding fragment thereof at about 150 mg to about 300 mg (e.g., a fixed dose of about 150 mg, a fixed dose of about 300 mg), wherein the IL-17 antibody or an antigen-binding fragment thereof binds to an epitope of a human 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, and the IL-17 antibody or an antigen-binding fragment thereof has a K for human IL-17 of about 100 - 200 pM Dand the IL-17 antibody or antigen-binding fragment thereof has a half-life in vivo of about 4 weeks.

[0014] In some embodiments of the disclosed methods, uses, pharmaceutical compositions and kits, the patient is administered the IL-17 antibody or antigen-binding fragment thereof only once.

[0015] In some embodiments of the disclosed methods, uses, pharmaceutical compositions and kits, the patient is administered the IL-17 antibody or antigen-binding fragment thereof weekly.

[0016] In some embodiments of the disclosed methods, uses, pharmaceutical compositions and kits, the patient is administered the IL-17 antibody or antigen-binding fragment thereof during weeks 0, 1, 2, 3 and 4.

[0017] In some embodiments of the disclosed methods, uses, pharmaceutical compositions and kits, the patient is administered the IL-17 antibody or antigen-binding fragment thereof every 4 weeks.

[0018] In some embodiments of the disclosed methods, uses, pharmaceutical compositions and kits, the patient is administered the IL-17 antibody or antigen-binding fragment thereof over a total treatment period of at least 2 months.

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

[0020] In some embodiments of the disclosed methods, uses, pharmaceutical compositions and kits, the patient is administered the IL-17 antibody or antigen-binding fragment thereof during weeks 0, 1, 2, 3, 4, 8 and 12.

[0021] In some embodiments of the disclosed methods, uses, pharmaceutical compositions and kits, the patient is administered the IL-17 antibody or antigen-binding fragment thereof weekly during weeks 0, 1, 2, 3 and 4 over a total treatment period of at least 3 months and then every 4 weeks thereafter.

[0022] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, prior to treatment with an IL-17 antibody or an antigen-binding fragment thereof, the patient did not respond, had an inadequate response, or was intolerant to a previous tendon disorder treatment selected from the group consisting of local steroid injection into the affected tendon, treatment with an NSAID, treatment with acetaminophen, physical therapy, and combinations thereof, or the patient was resistant or intolerant to, for example, treatment with an NSAID for two months and / or physical therapy.

[0023] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient has received physical therapy treatment, the patient is ineligible for tendon disorder surgery, and prior to treatment with an IL-17 antibody or an antigen-binding fragment thereof, the patient did not respond, had an inadequate response, or was intolerant to a previous tendon disorder treatment selected from the group consisting of local steroid injection into the affected tendon, treatment with an NSAID, treatment with acetaminophen, and combinations thereof.

[0024] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient has received physical therapy treatment, the patient is eligible for tendon disorder surgery, and prior to treatment with an IL-17 antibody or an antigen-binding fragment thereof, the patient did not respond, had an inadequate response, or was intolerant to a previous tendon disorder treatment selected from the group consisting of local steroid injection into the affected tendon, treatment with an NSAID, treatment with acetaminophen, and combinations thereof.

[0025] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient has an overuse tendon disorder.

[0026] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient has a subacute tendon disorder.

[0027] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient has a subacute moderate to severe tendon disorder.

[0028] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient has a subacute moderate to severe rotator cuff tendon disorder.

[0029] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, treatment with an IL-17 antibody or an antigen-binding fragment thereof reduces progression to a chronic tendon disorder.

[0030] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient has an active tendon disorder.

[0031] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient has a partially torn tendon.

[0032] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient has a partial tear of 50% or less, for example, by MRI or ultrasound.

[0033] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, treatment with an IL-17 antibody or an antigen-binding fragment thereof reduces progression to a completely torn tendon.

[0034] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient has moderate to severe and / or subacute plantar fasciitis, Achilles tendon disorder, patellar tendon disorder, rotator cuff tendon disorder, jumper's knee, lateral epicondylitis, medial epicondylitis, supraspinatus syndrome, or any combination thereof.

[0035] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, after treatment with an IL-17 antibody or an antigen-binding fragment thereof, the patient experiences at least a 20% reduction in pain, at least a 20% reduction in inflammation, at least a 20% improvement in tendon regeneration and / or repair, and / or at least a 20% improvement in the movement of the affected tendon.

[0036] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, after treatment with an IL-17 antibody or an antigen-binding fragment thereof, the patient experiences at least a 20% reduction in pain as determined by the VAS score.

[0037] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient has a rotator cuff tendon disorder, and after treatment with an IL-17 antibody or an antigen-binding fragment thereof, the patient experiences at least a 20% improvement in shoulder-related quality of life (QoL) as determined by the WORC score, QuickDASH score, or ASES score.

[0038] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, after treatment with an IL-17 antibody or an antigen-binding fragment thereof, the patient experiences at least a 20% overall improvement as determined by the PGA score.

[0039] In some embodiments, the disclosed methods, uses, pharmaceutical compositions, and kits further comprise administering to the patient a steroid, NSAID, or acetaminophen.

[0040] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, after treatment with an IL-17 antibody or an antigen-binding fragment thereof, the patient has a reduced need for physical therapy, or the patient has reduced symptoms of the tendon disorder, thereby improving the effectiveness of physical therapy.

[0041] 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 an antigen-binding fragment thereof is selected from the group consisting of: a) an IL-17 antibody or an 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 an antigen-binding fragment thereof that binds to an epitope of IL-17 comprising Tyr43, Tyr44, Arg46, Ala79, Asp80; c) an epitope of an IL-17 homodimer having two mature IL-17 protein chains, the epitope binding to Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 on one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain, an IL-17 antibody or an antigen-binding fragment thereof; d) an epitope of an IL-17 homodimer having two mature IL-17 protein chains, the epitope binding to Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 on one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain, an IL-17 antibody or an antigen-binding fragment thereof (wherein the IL-17 antibody or an antigen-binding fragment thereof has a K D of about 100 to 200 pM (e.g., about 200 pM) for human IL-17, and 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 comprising: i) an immunoglobulin heavy chain variable domain (V H ) comprising the amino acid sequence described as SEQ ID NO: 8, ii) an immunoglobulin light chain variable domain (V L ) comprising the amino acid sequence described as SEQ ID NO: 10, iii) an immunoglobulin V HAn immunoglobulin V domain comprising the amino acid sequence described as domain and SEQ ID NO: 10 L An immunoglobulin V domain, iv) comprising the hypervariable regions described as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 H An immunoglobulin V domain, v) comprising the hypervariable regions described as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 L An immunoglobulin V domain, vi) comprising the hypervariable regions described as SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13 H An immunoglobulin V domain, vii) comprising the hypervariable regions described as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 H An immunoglobulin V domain and comprising the hypervariable regions described as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 L An immunoglobulin V domain, viii) comprising the hypervariable regions described as SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13 H An immunoglobulin V domain and comprising the hypervariable regions described as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 L An immunoglobulin light chain comprising the amino acid sequence described as SEQ ID NO: 14, an immunoglobulin heavy chain comprising the amino acid sequence described as SEQ ID NO: 15, or xi) an immunoglobulin light chain comprising the amino acid sequence described as SEQ ID NO: 14 and an immunoglobulin heavy chain comprising the amino acid sequence described as SEQ ID NO: 15.

[0042] In some embodiments of the disclosed uses, methods, and kits, the IL-17 antibody or antigen-binding fragment thereof is secukinumab (AIN457), i.e., an IgG 1 / κ class recombinant high-affinity fully human monoclonal anti-human interleukin-17A antibody.

[0043] Disclosed herein are also a method, use, pharmaceutical composition, and kit for treating a patient having an active overuse tendinopathy, comprising administering to the patient by subcutaneous injection about 300 mg of secukinumab at weeks 0, 1, 2, 3, and 4 and then every 4 weeks thereafter for a total treatment period of at least 3 months.

[0044] Disclosed herein are also a method, use, pharmaceutical composition, and kit for treating a patient having an active overuse tendinopathy, comprising administering to the patient by subcutaneous injection about 150 mg of secukinumab at weeks 0, 1, 2, 3, and 4 and then every 4 weeks thereafter for a total treatment period of at least 3 months.

[0045] In some embodiments of the disclosed method, use, pharmaceutical composition, and kit, prior to treatment with secukinumab, the patient did not respond, had an inadequate response, or was intolerant to prior tendinopathy treatment selected from the group consisting of local steroid injection into the affected tendon, treatment with an NSAID, treatment with acetaminophen, physical therapy, and combinations thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0046]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Mode for Carrying Out the Invention

[0047] As used herein, the term "tendinopathy" is used to describe a complex and multifaceted condition of tendons characterized by pain, reduced function, and reduced exercise tolerance (Millar et al. (2017), supra). Tendinopathy is clinically diagnosed after a gradual onset of pain with activity, reduced function, and sometimes local swelling, and pain becomes apparent on clinical examination with stretching and palpation of the affected area. Ultrasonography and MRI are useful for diagnosing tendinopathy during the active phase. Tendinopathy can occur in almost any tendon (e.g., Achilles, patellar, infraspinatus, supratrochlear, adductor, plantar fasciitis, subscapularis, teres minor, supraspinatus, extensor carpi, flexor carpi, gluteal, hip, etc.). As used herein, the term "tendinopathy" includes tendinopathies of all locations and morphologies, 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. This includes tendinopathies at a single location as well as tendinopathies at multiple locations. A patient with tendinopathy may have a tendinopathy of the substance (central part of the tendon) or an enthesial (insertional) tendon disorder at the attachment site. As used herein, the term "tendinopathy" does not include tendon conditions resulting from systemic inflammatory diseases and does include tendon conditions that occur due to injury or overuse. A patient with tendinopathy may have an acute, subacute, or chronic condition (Blazina et al. (1973) Orthop. Clin. North Am. 4, 665-678). Historically, the terms "tendinitis" and "tendosis" have been used interchangeably with the term "tendinopathy," but these definitions are now included within the scope of disorders of human tendons ("tendinopathy").

[0048] As used herein, "overuse tendon disorder" refers to a tendon disorder characterized by pain and tenderness at rest and / or during movement, accompanied by a decrease in range of motion. The tendon can become swollen. Overuse tendon disorders generally result from continuous and repeated use of the tendon and often occur in workers and amateur athletes. Thus, "overuse tendon disorder" is different from enthesitis seen in systemic inflammatory diseases, such as psoriatic arthritis or ankylosing spondylitis. In some embodiments, a patient has an overuse tendon disorder.

[0049] As used herein, "affected tendon" refers to a tendon in which a patient has a tendon disorder.

[0050] As used herein, terms such as "chronic tendon disorder" refer to a tendon disorder that has been present for at least 6 weeks, preferably at least 12 weeks. In clinical practice, when physical therapy, NSAIDs, and steroids are unsuccessful and pain and a decrease in range of motion persist, the tendon disorder is considered chronic. In some embodiments, a patient has an overuse tendon disorder.

[0051] As used herein, the expression "active tendon disorder" means that a patient is currently experiencing a tendon disorder. In some embodiments, a patient has an active tendon disorder, such as an active chronic overuse tendon disorder.

[0052] As used herein, the expression "partially torn tendon" refers to a tendon injury (rupture or tear) in which the tendon is not completely detached from the bone to which it is attached but is damaged. In some embodiments, a patient has a partially torn tendon, preferably having a tear of 50% or less, as confirmed, for example, by ultrasound and / or MRI (e.g., evaluated using the Sein MRI tendon disorder scoring system and / or the Bauer tendon thickness score). In some embodiments, a patient has a partially torn tendon.

[0053] As used herein, the expression "completely ruptured tendon" refers to a tendon injury (rupture or break) that separates the entire tendon from the bone to which the tendon is attached.

[0054] As used herein, the term "NSAID" and the expression "non-steroidal anti-inflammatory drug" refer to a drug class that encompasses drugs that relieve pain, reduce fever, and at high doses, reduce inflammation. The most well-known 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.

[0055] As used herein, the expression "did not respond to" is used to mean, for example, that the patient's symptoms were not suppressed, treated, or alleviated in response to a particular tendon disorder treatment. In some embodiments, a patient with a tendon disorder did not respond to a previous tendon disorder treatment, such as an NSAID, a steroid (e.g., a local steroid injection into the affected tendon), acetaminophen, physical therapy, or a combination thereof.

[0056] As used herein, the expression "had an inadequate response to" is used to mean, for example, that the patient's symptoms were not sufficiently suppressed, treated, or alleviated in response to a particular tendon disorder treatment. In some embodiments, a patient with a tendon disorder had an inadequate response to a previous tendon disorder treatment, such as an NSAID, a steroid (e.g., a local steroid injection into the affected tendon), acetaminophen, physical therapy, or a combination thereof.

[0057] As used herein, the expression "was intolerant to" is used to mean that the patient experienced an adverse reaction to a particular tendon disorder treatment. In some embodiments, the tendon disorder patient was intolerant to a previous tendon disorder treatment, such as an NSAID, a steroid (e.g., a local steroid injection into the affected tendon), acetaminophen, physical therapy, or a combination thereof.

[0058] As used herein, "fixed dose" refers to a constant dose, i.e., a dose that is not modified based on the characteristics of the patient. Thus, a fixed dose is different from, for example, a dose based on body surface area or a dose based on body weight (typically given as mg / kg). In preferred embodiments, the doses used in the disclosed methods, uses, indications, kits, etc. are fixed doses. In the most preferred embodiments, the patient is administered 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.

[0059] As used herein, IL-17 refers to interleukin-17A (IL-17A).

[0060] As used herein, IL-17AF refers to a heterodimer consisting of monomers of IL-17A and IL-17F.

[0061] The term "comprising" encompasses "being included" and "consisting of", e.g., a composition "comprising" X can consist solely of X or can include something additional (e.g., X+Y).

[0062] As used herein, the expression "TNF-α antagonist" refers to small molecules and biological molecules that are capable of inhibiting, weakening, and / or blocking TNF-α signaling, transmission, and / or activity. Examples of TNF-α antagonists include Enbrel® (etanercept), Humira® (adalimumab), Remicade® (infliximab), and Simponi® (golimumab).

[0063] Unless a statement to the contrary is specific or clear from the context, as used herein, the term "about" with respect to a numerical value is understood to be within the normal tolerance in the art, for example within two standard deviations of the mean value. Thus, "about" can be within + / - 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.1%, 0.05% or 0.01% of the stated value, preferably + / - 10% of the stated value. When used before a numerical range or list of numbers, the term "about" applies to each number in the series. For example, the expression "about 1 to 5" should be construed as "about 1 to about 5", or for example, the expression "about 1, 2, 3, 4" should be construed as "about 1, about 2, about 3, about 4, etc.".

[0064] The word "substantially" does not exclude "completely". For example, a composition that is "substantially free of" Y may be completely free of Y. If desired, the word "substantially" can be omitted from the definitions of the present disclosure.

[0065] As used herein, the term "antibody" includes intact antibodies of natural origin. An "antibody" of natural origin 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 consists of three domains, 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 consists of one domain, CL. V H and V L regions can be further subdivided into regions of high frequency variability or regions of complementarity determining regions (CDRs), which are regions of high frequency variability that interrupt more conserved regions referred to as framework regions (FRs). Each V H and V LIt consists of three CDRs and four FRs arranged in the following order from the amino terminus to the carboxy 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 regions of the 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 of the classical complement system (C1q). Exemplary antibodies include secukinumab (Table 1) and ixekizumab (U.S. Patent No. 7,838,638).

[0066] 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 the antigen-binding function of an antibody can be performed by fragments of the full-length antibody. Examples of binding fragments included within the term "antigen-binding portion" of an antibody include Fab fragments, i.e., monovalent fragments consisting of V L , V H , CL and CH1 domains, F(ab)2 fragments, i.e., divalent fragments containing two Fab fragments linked by a disulfide bridge in the hinge region, Fd fragments consisting of V H and CH1 domains, Fv fragments consisting of the V L and V H domains of a single arm of an antibody, dAb fragments consisting of V H domains (Ward et al., 1989 Nature 341:544-546), and isolated CDRs. Exemplary antigen-binding sites include the CDRs of secukinumab as described in SEQ ID NOs: 1-6 and 11-13 (Table 1), preferably the heavy chain CDR3. Further, the two domains of the Fv fragment, V L and V H are encoded by separate genes, but when they are a single protein chain, where the V L region and the V HThey can be linked using recombinant methods by a synthetic linker that allows them to act as a monovalent molecule (known as single-chain Fv (scFv), see, for example, Bird et al., 1988 Science 242:423-426 and Huston et al., 1988 Proc. Natl. Acad. Sci. 85:5879-5883) that pairs with the domain. Such single-chain antibodies are also intended to be encompassed by the term "antibody". Single-chain antibodies and antigen-binding portions can be obtained using techniques known to those of skill in the art.

[0067] "Isolated antibody", as used herein, refers to an antibody that is substantially free of other antibodies having different antigen specificities (e.g., an isolated antibody that specifically binds to IL-17 is substantially free of antibodies that specifically bind to antigens other than IL-17). The term "monoclonal antibody" or "monoclonal antibody composition" as used herein refers to the preparation of antibody molecules of a single molecular composition. The term "human antibody", as used herein, is intended to include antibodies having variable regions derived from sequences of human origin in both their framework and CDR regions. A "human antibody" need not be produced by a human, a human tissue, or a human cell. The human antibodies of the present disclosure may contain amino acid residues not encoded by human sequences (e.g., mutations introduced by random or site-directed mutagenesis in vitro, N-nucleotide addition at junctions in vivo during recombination of antibody genes, or somatic mutations in vivo). In some embodiments of the disclosed processes and compositions, the IL-17 antibody is a human antibody, an isolated antibody, and / or a monoclonal antibody.

[0068] The term "IL-17" refers to IL-17A, which was previously known as CTLA8, and includes wild-type IL-17A from various species (e.g., human, mouse, and monkey), polymorphic variants of IL-17A, and functional equivalents of IL-17A. Functional equivalents of IL-17A according to the present disclosure preferably have at least about 65%, 75%, 85%, 95%, 96%, 97%, 98%, and even 99% overall sequence identity with wild-type IL-17A (e.g., human IL-17A) and substantially retain the ability to induce IL-6 production by human skin fibroblasts.

[0069] The term "K D " is intended to refer to the dissociation rate of a particular antibody-antigen interaction. The term "K D ", as used herein, is the ratio of K d to K a (i.e., K d / K a ) and is intended to refer to the dissociation constant expressed as molar concentration (M). The K D value for an antibody can be determined using methods established in the art. Methods for determining the K D of an antibody are by using surface plasmon resonance or a biosensor system such as the Biacore® system. In some embodiments, an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab, binds to human IL-17 with a K D of about 1-250 pM, preferably about 100-200 pM (e.g., about 200 pM).

[0070] The term "affinity" refers to the strength of the interaction between an antibody and an antigen at a single antigenic site. Within each antigenic site, the variable regions of the antibody "arms" interact with the antigen through weak non-covalent forces at multiple sites, and the greater the number of interactions, the stronger the affinity. Standard assays for evaluating the binding affinity of antibodies to various species of IL-17 are known in the art, including, for example, ELISA, Western blot, and RIA. The binding kinetics of an antibody (e.g., binding affinity) can also be evaluated by assays known in the art, such as Biacore® analysis.

[0071] An antibody that is determined according to methodologies known in the art and that "inhibits" one or more of these IL-17 functional properties (e.g., biochemical, immunochemical, cellular, physiological, or other biological activities) described herein will be understood to be associated with a statistically significant decrease in that particular activity relative to what is seen in the absence of the antibody (or in the presence of a control antibody of unrelated specificity). An antibody that inhibits IL-17 activity will, for example, result in a statistically significant decrease of at least about 10%, at least 50%, 80%, or 90% of the measured parameter, and in certain embodiments of the disclosed methods and compositions, the IL-17 antibodies used can inhibit greater than 95%, 98%, or 99% of IL-17 functional activity.

[0072] As used herein, "inhibiting IL-6" refers to the ability of an IL-17 antibody or an antigen-binding fragment thereof (e.g., secukinumab) to reduce IL-6 production from primary human dermal fibroblasts. IL-6 production in primary human dermal fibroblasts is IL-17-dependent (Hwang et al., (2004) Arthritis Res Ther; 6:R120-128). Briefly, human dermal fibroblasts are stimulated with recombinant IL-17 in the presence of various concentrations of an IL-17-binding molecule having an Fc portion or human IL-17 receptor. The chimeric anti-CD25 antibody Simulect® (basiliximab) can be conveniently used as a negative control. After 16 hours of stimulation, the supernatant is removed and IL-6 is quantified by ELISA. An IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab, is tested as described above, i.e., when the inhibitory activity is measured with respect to IL-6 production induced by human IL-17 in human dermal fibroblasts, typically has an IC50 for inhibition of IL-6 production of about 50 nM or less (e.g., about 0.01 to about 50 nM) (in the presence of 1 nM human IL-17). In some embodiments of the disclosed methods and compositions, an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab and its functional derivatives, has an IC50 for inhibition of IL-6 production as defined above of about 20 nM or less, more preferably about 10 nM or less, more preferably about 5 nM or less, more preferably about 2 nM or less, more preferably about 1 nM or less.

[0073] The term "derivative" is used, unless otherwise indicated, to define, for example, specific sequences (e.g., variable domains), amino acid sequence variants and covalent modifications (e.g., pegylation, deamidation, hydroxylation, phosphorylation, methylation, etc.) of an IL-17 antibody or antigen-binding fragment thereof, such as secukinumab, according to the present disclosure. "Functional derivatives" include molecules that have a qualitative biological activity in common with the disclosed IL-17 antibodies. Functional derivatives include fragments and peptide analogs of the IL-17 antibodies disclosed herein. Fragments include regions within the sequence of a polypeptide, for example, of a specific sequence, according to the present disclosure. Functional derivatives of the IL-17 antibodies disclosed herein (e.g., functional derivatives of secukinumab) include, for example, the V domains of the IL-17 antibodies and antigen-binding fragments thereof disclosed herein. H and / or V L V having at least about 65%, 75%, 85%, 95%, 96%, 97%, 98%, or even 99% overall sequence identity with the sequence H and / or V L Preferably, the antibody comprises a IL-17 domain and substantially retains the ability to bind human IL-17 or inhibit IL-6 production in human skin fibroblasts induced by IL-17, for example.

[0074] The phrase "substantially identical" refers to a related amino acid or nucleotide sequence (e.g., H Or V L It means that a particular region (e.g., a V domain) is identical to a particular reference sequence or has insubstantial differences (e.g., by conservative substitution of amino acids). Insubstantial differences include those that are not identical to a particular region (e.g., a V domain) compared to a particular reference sequence. H Or V LMinor amino acid changes are included, such as one or two substitutions in the 5 - amino acid sequence of the (domain). In the case of an antibody, the second antibody has the same specificity and has at least 50% of the affinity. Sequences that are substantially identical to the sequences disclosed herein (e.g., 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, e.g., a secukinumab biosimilar antibody) can be about 90% or more, such as 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more, relative to the disclosed sequence.

[0075] As used herein, "identity" with respect to a native polypeptide and its functional derivatives is defined as the percentage of amino acid residues in a candidate sequence that are identical to the residues of the corresponding native polypeptide, after aligning the sequences as needed to obtain the maximum percent identity and introducing gaps, with no conservative substitutions being considered part of the sequence identity. N- or C-terminal extensions or insertions are not to be construed as decreasing identity. Methods and computer programs for alignment are well known. Percent identity can be determined by standard alignment algorithms, such as the Basic Local Alignment Search Tool (BLAST) described by Altshul et al. ((1990) J. Mol. Biol., 215:403-410); the algorithm of Needleman et al. ((1970) J. Mol. Biol., 48:444-453) or the algorithm of Meyers et al. ((1988) Comput. Appl. Biosci., 4:11-17). A set of parameters can be the Blosum 62 score matrix with a 12 gap penalty, a 4 gap extension penalty and a 5 frameshift gap penalty. Percent identity between two amino acid or nucleotide sequences can also be determined using the algorithm of E. Meyers and W. Miller ((1989) CABIOS, 4:11-17) incorporated into the ALIGN program (version 2.0), using the PAM120 weight residue table, a 12 gap length penalty and a 4 gap penalty.

[0076] "Amino acid" refers to all naturally occurring L-α-amino acids and includes, for example, D-amino acids. The expression "amino acid sequence variant" refers to a molecule whose amino acid sequence is somewhat different when compared to the sequences according to the present disclosure. For example, an amino acid sequence variant of an antibody according to the present disclosure of a particular sequence still has the ability to bind to human IL-17 or inhibits, for example, the production of IL-6 by human skin fibroblasts induced by IL-17. Amino acid sequence variants include substitution variants (where at least one amino acid residue in a polypeptide according to the present disclosure is removed and another amino acid is inserted in its place at the same position), insertion variants (where one or more amino acids are inserted immediately adjacent to an amino acid at a particular position in a polypeptide according to the present disclosure), and deletion variants (where one or more amino acids in a polypeptide according to the present disclosure are removed).

[0077] The term "pharmaceutically acceptable" means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredient.

[0078] The term "administering" with respect to a compound, such as an IL-17 binding molecule or another agent, is used to refer to the delivery of that compound to a patient by any route.

[0079] As used herein, "therapeutically effective amount" refers to the 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), that is effective to treat, prevent, prevent the onset of, cure, delay, reduce the severity of, reverse, or prolong the survival of a patient (such as a human) beyond that expected in the absence of such treatment when administered as a single dose or as repeated doses to the patient, to treat at least one symptom of a disorder or a recurrent disorder. When applied to an individual active ingredient administered alone (e.g., an IL-17 antagonist, such as secukinumab), the term refers to that ingredient alone. When applied to a combination, the term refers to the combined amount of the active ingredients that produces a therapeutic effect, whether administered in combination, continuously, or simultaneously.

[0080] The terms "treatment" or "treating" are defined herein as the application or administration to a subject or to an isolated tissue or cell line derived from a subject of an IL-17 antibody according to the present disclosure, such as secukinumab or ixekizumab, or a pharmaceutical composition comprising said anti-IL-17 antibody, where the subject has a predisposition to a particular disease (e.g., tendon disorder), a symptom associated with said disease (e.g., tendon disorder), or the onset of said disease (e.g., tendon disorder, if applicable), and the purpose is to cure (if applicable), delay the onset, reduce the severity, alleviate, reverse, improve the disease, reduce or improve any associated symptom of the disease or the predisposition to the onset of the disease. The terms "treatment" or "treating" include treating patients suspected of having a disease and patients diagnosed as being ill or suffering from a disease or medical condition, and include suppression of clinical recurrence.

[0081] As used herein, "selecting" and "selected" with respect to a patient are used to mean that a particular patient is individually selected from a larger group of patients based on (due to) that particular patient having pre - defined criteria. Similarly, "selectively treating" refers to providing treatment to a patient having a particular disease, where the patient is individually selected based on that particular patient having pre - defined criteria. Similarly, "selectively administering" refers to administering a drug to a patient individually selected from a larger group of patients based on (due to) that particular patient having pre - defined criteria. Selecting, selectively treating, and selectively administering mean that the patient receives an individualized treatment based on the patient's individual medical history (e.g., previous treatment interventions, e.g., previous treatment with a biologic), biology (e.g., specific gene markers), and / or symptoms (e.g., not meeting certain diagnostic criteria), rather than a standard treatment regimen delivered based only on the patient's membership within the larger group. Selecting as used herein with respect to a method of treatment does not refer to the fortunate treatment of patients having particular criteria, but rather to an intentional selection to treat a patient based on the patient having particular criteria. Thus, selective treatment / administration is different from standard treatment / administration that delivers a particular drug to all patients having a particular disease regardless of their individual medical history, disease symptoms, and / or biology.

[0082] IL - 17 antagonist The various processes, kits, uses, and methods disclosed utilize an IL-17 antagonist. An IL-17 antagonist is capable of blocking, weakening, and / or inhibiting IL-17 signaling, activity, and / or transmission. 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 brodalumab). In some embodiments, the IL-17 antagonist is an IL-17 binding molecule, preferably an IL-17 antibody or antigen-binding fragment thereof. The IL-17 antibodies and antigen-binding fragments thereof used herein can be fully human, CDR-grafted, or chimeric. The constant region domain of the antibody or antigen-binding fragment thereof for use in the disclosed methods, uses, kits, etc. preferably includes a suitable human constant region domain, for example, as described in ‘‘Sequences of Proteins of Immunological Interest’’, Kabat E.A. et al, US Department of Health and Human Services, Public Health Service, National Institute of Health.

[0083] A particularly preferred IL-17 antibody or antigen-binding fragment thereof used in the disclosed methods is a human antibody, in particular secukinumab, described in Examples 1 and 2 of WO 2006 / 013107 pamphlet, the entire content of which is incorporated herein by reference. Secukinumab is an IgG 1 / κ isotype recombinant high-affinity fully human monoclonal anti-human interleukin-17A (IL-17A, IL-17) antibody. Secukinumab has a high affinity for IL-17, i.e., a K D of about 100 - 200 pM (e.g., about 200 pM), an IC 50 of about 0.4 nM for neutralization of the biological activity of about 0.67 nM human IL-17A in vitro, and a half-life of about 4 weeks.

[0084] For ease of reference, the amino acid sequences of the hypervariable regions of the secukinumab monoclonal antibody, based on the Kabat definition, determined by X-ray analysis, and using the method of Chothia and co-workers, are provided in Table 1 below.

[0085]

Table 1

[0086] In one embodiment, the IL-17 antibody or antigen-binding fragment thereof comprises at least one immunoglobulin heavy chain variable domain (V H ) comprising hypervariable regions CDR1, CDR2 and CDR3, wherein said CDR1 has the amino acid sequence SEQ ID NO: 1, said CDR2 has the amino acid sequence SEQ ID NO: 2, and said CDR3 has the amino acid sequence 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’ ) comprising hypervariable regions CDR1′, CDR2′ and CDR3′, wherein said CDR1′ has the amino acid sequence SEQ ID NO: 4, said CDR2′ has the amino acid sequence SEQ ID NO: 5, and said CDR3′ has the amino acid sequence 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 ) comprising hypervariable regions CDR1-x, CDR2-x and CDR3-x, wherein said CDR1-x has the amino acid sequence SEQ ID NO: 11, said CDR2-x has the amino acid sequence SEQ ID NO: 12, and said CDR3-x has the amino acid sequence SEQ ID NO: 13.

[0087] 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, and a) an immunoglobulin V HThe domain includes (for example, in order) i) the hypervariable regions CDR1, CDR2, and CDR3 (where CDR1 has the amino acid sequence SEQ ID NO: 1, CDR2 has the amino acid sequence SEQ ID NO: 2, and CDR3 has the amino acid sequence SEQ ID NO: 3), or ii) the hypervariable regions CDR1-x, CDR2-x, and CDR3-x (where CDR1-x has the amino acid sequence SEQ ID NO: 11, CDR2-x has the amino acid sequence SEQ ID NO: 12, and CDR3-x has the amino acid sequence SEQ ID NO: 13), and b) immunoglobulin V L The domain includes (for example, in order) the hypervariable regions CDR1', CDR2', and CDR3' (where CDR1' has the amino acid sequence SEQ ID NO: 4, CDR2' has the amino acid sequence SEQ ID NO: 5, and CDR3' has the amino acid sequence SEQ ID NO: 6).

[0088] In one embodiment, the IL-17 antibody or its antigen-binding fragment comprises a) an immunoglobulin heavy chain variable domain (V H ) comprising the amino acid sequence shown as SEQ ID NO: 8, b) an immunoglobulin light chain variable domain (V L ) comprising the amino acid sequence shown as SEQ ID NO: 10, c) an immunoglobulin V H domain comprising the amino acid sequence shown as SEQ ID NO: 8 and an immunoglobulin V L domain comprising the amino acid sequence shown as SEQ ID NO: 10, d) an immunoglobulin V H domain comprising the hypervariable regions shown as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, e) an immunoglobulin V L domain comprising the hypervariable regions shown as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, f) an immunoglobulin V H domain comprising the hypervariable regions shown as SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13, g) an immunoglobulin V H domain comprising the hypervariable regions shown as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 and an immunoglobulin V Ldomain, or h) an immunoglobulin V domain containing the hypervariable regions shown as SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13 H domain and an immunoglobulin V domain containing the hypervariable regions shown as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 L domain.

[0089] In some embodiments, the IL-17 antibody or an antigen-binding fragment thereof (e.g., secukinumab) contains the three CDRs of SEQ ID NO: 10. In other embodiments, the IL-17 antibody or an antigen-binding fragment thereof contains the three CDRs of SEQ ID NO: 8. In other embodiments, the IL-17 antibody or an antigen-binding fragment thereof contains the three CDRs of SEQ ID NO: 10 and the three CDRs of SEQ ID NO: 8. The CDRs of SEQ ID NO: 8 and SEQ ID NO: 10 can be referred to in Table 1. The free cysteine (CysL97) within the light chain can be found in SEQ ID NO: 6.

[0090] In some embodiments, the IL-17 antibody or an antigen-binding fragment thereof contains the light chain of SEQ ID NO: 14. In other embodiments, the IL-17 antibody or an antigen-binding fragment thereof contains the heavy chain of SEQ ID NO: 15 (with or without a C-terminal lysine). In other embodiments, the IL-17 antibody or an antigen-binding fragment thereof contains the light chain of SEQ ID NO: 14 and the heavy domain of SEQ ID NO: 15. In some embodiments, the IL-17 antibody or an antigen-binding fragment thereof contains the three CDRs of SEQ ID NO: 14. In other embodiments, the IL-17 antibody or an antigen-binding fragment thereof contains the three CDRs of SEQ ID NO: 15. In other embodiments, the IL-17 antibody or an antigen-binding fragment thereof contains the three CDRs of SEQ ID NO: 14 and the three CDRs of SEQ ID NO: 15. The CDRs of SEQ ID NO: 14 and SEQ ID NO: 15 can be referred to in Table 1.

[0091] The high-frequency variable region can be associated with any type of framework region, but those of human origin are preferred. Suitable framework regions are described in Kabat E.A. et al, ibid. Preferred heavy-chain frameworks are human heavy-chain frameworks, such as the heavy-chain framework of the secukinumab antibody. This consists, in order, of, for example, the 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. Considering the determined high-frequency variable region of secukinumab by X-ray analysis, another preferred heavy-chain framework consists, in order, of the 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. Similarly, the light-chain framework consists, in order, 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.

[0092] In one embodiment, the IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab) is selected from human IL-17 antibodies comprising at least: a) an immunoglobulin heavy chain or fragment thereof comprising, in order, a variable domain comprising high-frequency variable regions CDR1, CDR2 and CDR3, and a constant region or fragment thereof of a human heavy chain (wherein said CDR1 has the amino acid sequence SEQ ID NO: 1, said CDR2 has the amino acid sequence SEQ ID NO: 2, and said CDR3 has the amino acid sequence SEQ ID NO: 3), and b) an immunoglobulin light chain or fragment thereof comprising, in order, a variable domain comprising high-frequency variable regions CDR1', CDR2' and CDR3', and a constant region or fragment thereof of a human light chain (wherein said CDR1' has the amino acid sequence SEQ ID NO: 4, said CDR2' has the amino acid sequence SEQ ID NO: 5, and said CDR3' has the amino acid sequence SEQ ID NO: 6).

[0093] In one embodiment, the IL-17 antibody or antigen-binding fragment thereof is selected from a single-chain antibody or antigen-binding fragment thereof comprising an antigen-binding site that includes: a) a first domain in order containing the hypervariable regions CDR1, CDR2, and CDR3 (wherein CDR1 has the amino acid sequence SEQ ID NO: 1, CDR2 has the amino acid sequence SEQ ID NO: 2, and CDR3 has the amino acid sequence SEQ ID NO: 3); b) a second domain in order containing the hypervariable regions CDR1', CDR2', and CDR3' (wherein CDR1' has the amino acid sequence SEQ ID NO: 4, CDR2' has the amino acid sequence SEQ ID NO: 5, and CDR3' has the amino acid sequence SEQ ID NO: 6); and c) a peptide linker that binds to the N-terminus of the first domain and the C-terminus of the second domain or to the C-terminus of the first domain and the N-terminus of the second domain).

[0094] Alternatively, the IL-17 antibody or antigen-binding fragment thereof used in the disclosed methods may include derivatives of the IL-17 antibodies described herein by sequence (e.g., pegylated species of secukinumab). Alternatively, the V H or V L domains of the IL-17 antibody or antigen-binding fragment thereof used in the disclosed methods may have V H or V L domains that are substantially identical to the described V H or V L domains (e.g., SEQ ID NOs: 8 and 10). The human IL-17 antibodies disclosed herein may include a heavy chain that is substantially identical to that shown as SEQ ID NO: 15 and / or a light chain that is substantially identical to that shown as SEQ ID NO: 14. The human IL-17 antibodies disclosed herein may include a heavy chain comprising SEQ ID NO: 15 and a light chain comprising SEQ ID NO: 14. The human IL-17 antibodies disclosed herein may include: a) one heavy chain comprising a variable domain having an amino acid sequence substantially identical to that shown in SEQ ID NO: 8 and a constant region of a human heavy chain; and b) one light chain comprising a variable domain having an amino acid sequence substantially identical to that shown in SEQ ID NO: 10 and a constant region of a human light chain.

[0095] Alternatively, the IL-17 antibody or antigen-binding fragment thereof used in the disclosed method can be an amino acid sequence variant of the reference IL-17 antibody as shown herein, as long as it contains CysL97. The present disclosure includes one or more, typically only a very small number (e.g., 1 to 10) of amino acid residues (other than CysL97) of the V H or V L domain of secukinumab that have been changed, for example, by mutation of the corresponding DNA sequence, such as site-directed mutagenesis, of an IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab). In all such cases of derivatives and variants, the IL-17 antibody or antigen-binding fragment thereof is capable of inhibiting the activity of 1 nM (= 30 ng / ml) of human IL-17 by 50% at a concentration of the molecule of about 50 nM or less, about 20 nM or less, about 10 nM or less, about 5 nM or less, about 2 nM or less, or more preferably about 1 nM or less, and the inhibitory activity is measured against IL-6 production induced by hu-IL-17 in human dermal fibroblasts as described in Example 1 of WO 2006 / 013107 pamphlet.

[0096] In some embodiments, an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab, binds to an epitope of mature human IL-17 that includes Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129. In some embodiments, an IL-17 antibody, such as secukinumab, binds to an epitope of mature human IL-17 that includes Tyr43, Tyr44, Arg46, Ala79, Asp80. In some embodiments, an IL-17 antibody, such as secukinumab, binds to an epitope of an IL-17 homodimer having two mature human IL-17 chains, the epitope including 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 the IL-17 epitopes herein is based on residue 1 being the first amino acid of the mature protein (i.e., IL-17A lacks a 23-amino acid N-terminal signal peptide and starts with glycine). The sequence of immature IL-17A is described in Swiss-Prot entry Q16552.

[0097] In some embodiments, the IL-17 antibody has a K D of about 100 - 200 pM. In some embodiments, the IL-17 antibody has an IC 50 of about 0.4 nM for the in vitro neutralization of the biological activity of about 0.67 nM human IL-17A. In some embodiments, the absolute bioavailability of an IL-17 antibody administered subcutaneously (SC) ranges from about 60% to about 80%, such as about 73%, about 76%. In some embodiments, an IL-17 antibody, such as secukinumab, has a clearance half-life of about 4 weeks (e.g., about 23 - about 35 days, about 23 - about 30 days, e.g., about 30 days). In some embodiments, an IL-17 antibody (such as secukinumab) has a T max of about 7 - 8 days.

[0098] Other preferred IL-17 antagonists for use in the disclosed methods, kits and regimens include KHK4872 (Kyowa Hakko Kirin Co., Ltd.), ABT-122 (Abbvie), BCD-085 (JCS Biopharm), Vidofludimus (4SC-101), NI-1401 (RG7624; MCAF5352A - NovImmune), ANB004 (AnaptysBio Inc.), E-036041 (Ensemble Therapeutics Corp.), Qβ-IL-17 (virus-like particle-based vaccine), PRS-190 (Pieris AG), Bimekizumab (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 Brodalumab, and those described in 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. Patent Application Publication Nos. 20120034656 and 20110027290, which are incorporated herein by reference with respect to the disclosure of the sequences and / or structures of the IL-17 antagonists.

[0099] 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 between residues Arg 55 and Trp 67; b) an IL-17 antibody or antigen-binding fragment thereof that binds to an epitope of IL-17 comprising Arg 55, Glu 57 and Trp 67; 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 65; e) 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, Val 65, Val 22 * , Leu 26, Asp 58, Glu 60, Pro 63, Pro 107, Phe 110 and Lys 114 * (wherein the amino acids marked with ( * ) mean the residues provided by the second IL-17 subunit of the IL-17A homodimer) and an IL-17 antibody or antigen-binding fragment thereof that binds to an epitope of IL-17 (wherein the IL-17 antibody or antigen-binding fragment thereof has a K of about 1-10 pM (e.g., about 6 pM) for human IL-17 D and the IL-17 antibody or antigen-binding fragment thereof has a half-life in vivo of about 14-23 days, e.g., about 20 days), and f) an IL-17 antibody or antigen-binding fragment thereof comprising: i) an immunoglobulin heavy chain variable domain (V H ) comprising the amino acid sequence described as SEQ ID NO: 30, ii) an immunoglobulin light chain variable domain (V L ) comprising the amino acid sequence described as SEQ ID NO: 22, iii) an immunoglobulin V H domain comprising the amino acid sequence described as SEQ ID NO: 30 and an immunoglobulin V Ldomain, iv) an immunoglobulin V domain comprising the hypervariable regions described as SEQ ID NO: 24, SEQ ID NO: 26, and SEQ ID NO: 28 H domain, v) an immunoglobulin V domain comprising the hypervariable regions described as SEQ ID NO: 16, SEQ ID NO: 18, and SEQ ID NO: 20 L domain, vi) an immunoglobulin V domain comprising the hypervariable regions described as SEQ ID NO: 25, SEQ ID NO: 27, and SEQ ID NO: 29 H domain, vii) an immunoglobulin V domain comprising the hypervariable regions described as SEQ ID NO: 17, SEQ ID NO: 19, and SEQ ID NO: 21 L domain, viii) an immunoglobulin V domain comprising the hypervariable regions described as SEQ ID NO: 24, SEQ ID NO: 26, and SEQ ID NO: 28 H domain and an immunoglobulin V domain comprising the hypervariable regions described as SEQ ID NO: 16, SEQ ID NO: 18, and SEQ ID NO: 20 L domain, ix) an immunoglobulin V domain comprising the hypervariable regions described as SEQ ID NO: 25, SEQ ID NO: 27, and SEQ ID NO: 29 H domain and an immunoglobulin V domain comprising the hypervariable regions described as 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.

[0100] In some embodiments of the disclosed uses, methods, and kits, the IL-17 antibody or antigen-binding fragment thereof is CJM112, namely an IgG 1 / κ class recombinant high-affinity fully human monoclonal anti-human IL-17 antibody. CJM112 also binds to IL-17AF and antagonizes this cytokine (see, e.g., U.S. Patent No. 9,193,788, the entire contents of which are incorporated herein by reference).

[0101] IL-17AF antagonists can also be used to treat tendon disorders, induce tendon tissue regeneration, and promote tendon repair in patients with tendon disorders. These antagonists include antibodies that cross-react with IL-17A and IL-17F and bispecific anti-IL-17A / F antibodies, FynomAbs (e.g., COVA322), nanobodies (e.g., ALX-0761), etc., which can be referred to in US Patent Application Publication No. 20140314763, No. 2013 / 0195872, No. 20160326241, US Patent No. 8496936, No. 8945553, and International Publication No. 2016 / 070062 Pamphlet.

[0102] Methods of treatment and use of IL-17 antagonists for tendon disorders The disclosed IL-17 antagonists, such as 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 to treat patients with tendon disorders (e.g., human patients with tendon disorders), or incorporated into pharmaceutical compositions for in vivo administration.

[0103] All reactive forms of tendon disorders, such as plantar fasciitis, Achilles tendon disorder, patellar tendon disorder, rotator cuff (subscapularis, teres minor, supraspinatus, and infraspinatus) tendon disorder, tennis elbow (lateral epicondylitis), golfer's elbow (medial epicondylitis), jumper's knee, supraspinatus syndrome, etc., are expected to be treatable using the disclosed uses, compositions, methods, and kits. In a preferred embodiment, the patient has a rotator cuff (subscapularis, teres minor, supraspinatus, and infraspinatus) tendon disorder.

[0104] In some embodiments, the patient does not have a torn tendon (confirmed, for example, using ultrasound and / or MRI) or has a partial tear [up to 50% tendon thickness (Bauer tendon thickness score maximum 2), tendon AP tear size [length] maximum 10 mm (Bauer tendon length score maximum 2)]. MRI scoring protocols for partial tears are known (see, for example, Bauer et al. (2014) J Orthop Surg Res. 9:128).

[0105] In some embodiments, the patient has a positive "painful arc test" (see, for example, O’Kane and Toresdahl (2014) Curr Sports Med Rep. 13(5):307-13) at the time of examination and / or has night pain in the affected shoulder on at least 4 out of 7 days of a given week. In some embodiments, the patient has pain in the affected shoulder (at rest or during movement) on at least 3 out of 7 days of a given week and a score of ≥4 out of 10 on the visual analog scale (VAS) for pain.

[0106] In some embodiments, the patient's symptoms (such as pain, motion inhibition, and / or swelling) are present for more than 6 weeks. In some embodiments, the patient's symptoms (such as pain, motion inhibition, and / or swelling) are present for less than 12 months. In some embodiments, the patient's symptoms (such as pain, motion inhibition, and / or swelling) are present for more than 6 weeks and less than 12 months.

[0107] In some embodiments, the patient has a positive MRI for overuse (non-systemic inflammatory) rotator cuff (subscapularis, infraspinatus, teres minor, and supraspinatus) tendonopathy. In some embodiments, the patient has a rotator cuff (subscapularis, infraspinatus, teres minor, and supraspinatus) tendonopathy without a systemic inflammatory disease.

[0108] In some embodiments, the patient is resistant (i.e., the patient did not respond or had an inadequate (suboptimal) response [e.g., as determined by a VAS pain score, e.g., VAS pain score ≥ 4]) or intolerant to previous tendon disorder treatments such as steroid treatment (e.g., local steroid injection into the affected tendon), treatment with an NSAID, treatment with acetaminophen, physical therapy, or combinations thereof.

[0109] In some embodiments, the patient has previously shown an inadequate response to previous tendon disorder surgery.

[0110] Tendon disorder treatments that utilize steroids, NSAIDs, acetaminophen, physical therapy, and combinations thereof are referred to herein as tendon disorder "standard treatment" procedures. A patient being treated with physical therapy is referred to as "receiving a physical therapy procedure."

[0111] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient has a rotator cuff tendon disorder, has been treated using standard treatment for tendon disorder, and is ineligible or unwilling to undergo surgery. Patient eligibility for surgery can be based on biochemical and / or physical characteristics, such as heart health, lung health, advanced age, etc., that can be determined by a physician.

[0112] In some embodiments, the patient has not received steroids. In some embodiments, the patient has previously been treated with local steroid injection into the affected tendon. In some embodiments, the patient has multiple sites of tendon disorder.

[0113] In some embodiments, the patient is ineligible for surgery for tendon disorder.

[0114] In some embodiments, the patient is unwilling to undergo surgery for tendon disorder.

[0115] In some embodiments, the patient is ineligible for surgery for tendon disorder or is unwilling to undergo surgery for tendon disorder.

[0116] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient has received a physical therapy treatment, the patient is ineligible for tendon disorder surgery, and the patient did not respond, had an inadequate response, or was intolerant to previous tendon disorder treatment selected from the group consisting of local steroid injection into the affected tendon, treatment with an NSAID, treatment with acetaminophen, and combinations thereof prior to treatment with an IL-17 antibody or an antigen-binding fragment thereof.

[0117] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient has received a physical therapy treatment, the patient is eligible for tendon disorder surgery, and the patient did not respond, had an inadequate response, or was intolerant to previous tendon disorder treatment selected from the group consisting of local steroid injection into the affected tendon, treatment with an NSAID, treatment with acetaminophen, and combinations thereof prior to treatment with an IL-17 antibody or an antigen-binding fragment thereof.

[0118] The response of a patient to the treatment disclosed herein can be measured using patient-reported outcomes (PROs), physician-reported outcomes, imaging techniques, etc. Physician-reported outcomes include, for example, the Physician's Global Assessment of Disease Activity (PhGA) (e.g., using a VAS score), range of motion tests (e.g., using a goniometer or a count-based assessment), and arm muscle strength tests (e.g., using a digital pressure gauge or the rotator cuff function index). Imaging techniques include, for example, MRI (e.g., MRI Sein score, MRI Bauer score, supraspinatus tendon thickness, subacromial bursitis within the area of the rotator cuff, quality of the supraspinatus tendon, for determining the presence of an affected biceps tendon), ultrasound, and shear wave elastography (SWE) (e.g., for assessing the biomechanical properties [stiffness] of the supraspinatus tendon). PROs include, for example, the Patient's Global Assessment of Disease Activity (PGA) (e.g., using a VAS score), the Western Ontario Rotator Cuff (WORC) patient-reported outcome score, the QuickDASH score for the Disabilities of the Arm, Shoulder and Hand questionnaire, the American Shoulder and Elbow Surgeons Shoulder Evaluation Form (ASES) score, and the EQ5D-5L score.

[0119] The WORC score is a patient-reported outcome measure that was uniquely developed by Kirkley and co-researchers 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 clinically important minimum change (MCIC) of WORC has been calculated to be 275 points or 12.8% (when shown in the form of WORC%). In some embodiments, when a population of patients with rotator cuff tendon disorders is treated according to the disclosed method (e.g., using a fixed dose of about 150 mg secukinumab or about 300 mg secukinumab administered 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 reach the MCID of the WORC score. In a preferred embodiment, when a population of patients with rotator cuff tendon disorders is treated according to the disclosed method (e.g., using a fixed dose of about 150 mg secukinumab or about 300 mg secukinumab administered monthly with or without a loading dose), at least 40%, preferably at least 60% of the patients in the population reach the MCID of the WORC score.

[0120] Quick DASH is an abbreviated form of the DASH patient-reported outcome measure, developed by the American Academy of Orthopaedic Surgeons in conjunction with the Institute for Work & Health (Toronto, Ontario, Canada).

[0121] The ASES score was developed by the American Shoulder and Elbow Surgeons for the evaluation of shoulder function (Richards et al (1994) J Shoulder Elbow Surg 3:347-352).

[0122] EuroQuol 5D (EQ-5D-5L) (euroqol.org / eq-5d-instruments / eq-5d-5l-about / ) is a widely used self-administered questionnaire designed to assess the health status of adults. The purpose of the EQ-5D-5L in this study was to evaluate the overall health status of the patients.

[0123] The MRI Sein score is mainly used to grade supraspinatus tendinosis (Sein et al. (2007) Br J Sports Med; 41(8):e9) and to observe changes in this grade over time. Tendon disorders are characterized by thickened, heterogeneous rotator cuff tendons with increased signal intensity for all pulse MRI sequences, although not as bright as fluid on typical T2-weighted images. Since tendinitis and partial-thickness tendon injuries are common in sports activities and middle age, another grading system, namely the Bauer score, can also be used for the evaluation of supraspinatus partial tears and tendinosis (Bauer et al (2014) J.Orthopaedic Surg.Res 9:128). These images can also be used to measure the thickness of the rotator cuff tendon and to evaluate the presence of subacromial bursitis within the rotator cuff region. In some embodiments, when a population of tendon disorders is treated according to the disclosed method, at least 40%, at least 50%, at least 60%, at least 70% or at least 90% of the patients will show little progression to tendon rupture (partial / complete) as measured by the MRI Bauer score. In a preferred embodiment, when a population of tendon disorders is treated according to the disclosed method, at least 50% of the patients will show little progression to tendon rupture (partial / complete) as measured by the MRI Bauer score. In some embodiments, when a population of tendon disorders is treated according to the disclosed method, at least 40%, at least 50%, at least 60%, at least 70% or at least 90% of the patients will show at least one grade improvement (i.e., reduced injury) in the tendon structure as measured by the MRI Sein score. In some embodiments, when a population of tendon disorders is treated according to the disclosed method, at least 50% of the patients will show at least one grade improvement (i.e., reduced injury) in the tendon structure as measured by the MRI Sein score.

[0124] Improvement of the subacromial bursa can be evaluated by the method of Hodgson et al (2012) Br.J.Radiology; 85:1482-1487.

[0125] Improvement in Achilles tendon pain and function can be evaluated using the Victorian Institute of Sport Assessment - Achilles (VISA - A).

[0126] Improvement in patellar tendon pain and function can be evaluated using the Victorian Institute of Sport Assessment - Patella (VISA - P).

[0127] Improvement in upper trapezius tendon pain and function can be evaluated using the Patient - Rated Tennis Elbow Evaluation (PRTEE).

[0128] Other MRI measurements, such as ultra - short echo time (UTE) pulse sequences and contrast mechanisms based on T2* relaxation rate (Juras et al (2013) Eur Radiol 23:2814 - 2822) and / or magnetization transfer ratio (MTR) (Syha et al (2011) Fortschr Rontgenstra;183:1043 - 1050) - based MRI techniques can also be considered as markers of tendon "quality / integrity".

[0129] Due to their elastic properties, tendons in the body can withstand large muscle forces with minimal deformation and loss of force transmission by allowing energy absorption and release during movement. In tendon disorders, changes in tendon morphology and composition can lead to changes in their mechanical properties. Shear wave elastography (SWE) is a non - invasive ultrasound - based imaging technique that can evaluate the elastic properties of soft tissues, including tendons (Chen et al (2013) J Ultrasound Med;32:449 - 455). The stiffness of the rotator cuff tendon can be measured by SWE.

[0130] The Visual Analog Scale (VAS) is a means of measuring a characteristic or tendency that is considered to span the entire range of a continuum of values. For example, the amount of pain a patient feels spans the entire range of a continuum from no pain to the maximum amount of pain imaginable. From the patient's perspective, this range appears continuous, as would be indicated by the categorical classifications of none, mild, moderate, and severe ± the patient's pain does not experience a discontinuous jump. The VAS pain scale is generally used as an outcome measure to characterize pain intensity in clinical research. This is typically presented as a 100 mm horizontal line, on which the patient's pain intensity is represented by a point between the two poles of "no pain at all" and "the worst pain imaginable" (etc.). The responder is asked to place a line perpendicular to the VAS line at the point that best represents the responder's pain at the current time. This tool is scored in millimeters (the score is often recorded in tenths of a centimeter using a 10-point scale). Generally, a score of less than 40 millimeters (or 4 if recorded in centimeters) is considered desirable for chronic pain management.

[0131] In some embodiments, the patient experiences at least a 5%, at least a 10%, at least a 15%, at least a 20%, at least a 25%, at least a 30%, at least a 35%, at least a 40%, at least a 45%, at least a 50%, at least a 55%, at least a 60%, at least a 65%, at least a 70%, at least a 75%, at least an 80%, at least an 85%, at least a 90%, at least a 95% or 100% reduction in pain, reduction in inflammation, improvement in tendon regeneration and / or repair, and / or improvement in movement of the affected tendon 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months (preferably 1, 2, or 3 months) after treatment according to the claimed method. In preferred embodiments, the patient experiences at least a 20% reduction in pain, reduction in inflammation, improvement in tendon regeneration and / or repair, and / or improvement in movement after treatment according to the claimed method.

[0132] In some embodiments, the patient experiences an improvement of 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% in the VAS score, WORC score, QuickDASH score, ASES score and / or EQ5D-5L score 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months (preferably 1, 2 or 3 months) after treatment according to the claimed method. In a preferred embodiment, the patient experiences at least a 20% reduction in pain as determined by the VAS score after treatment according to the claimed method. In a preferred embodiment, after treatment according to the claimed method, the patient experiences at least a 20% improvement in shoulder-related quality of life (QoL) as determined by the WORC score, QuickDASH score or ASES score. In a preferred embodiment, the patient experiences at least a 20% overall improvement as determined by the PGA score after treatment according to the claimed method.

[0133] IL-17 antagonists, such as 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 antibodies or antigen-binding fragments thereof), can be used as pharmaceutical compositions when combined with a pharmaceutically acceptable carrier. Such compositions can contain, in addition to the IL-17 antagonist, carriers, various diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials. The properties of the carrier depend on the route of administration. The pharmaceutical compositions for use in the disclosed methods can also contain additional therapeutic agents for the treatment of the specific disorder targeted. For example, the pharmaceutical composition can also include an anti-inflammatory agent. Inclusion of such additional factors and / or agents in the pharmaceutical composition can result in a synergistic effect with the IL-17 binding molecule or minimize the side effects caused by 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).

[0134] The pharmaceutical compositions for use in the disclosed methods can be manufactured in known ways. In one embodiment, the pharmaceutical composition is provided in lyophilized form. For immediate administration, this is dissolved in a suitable aqueous carrier, such as sterile water for injection or sterile buffered saline. When it is desirable to constitute a larger volume of solution for administration by infusion rather than bolus injection, it may be convenient to incorporate human serum albumin or the patient's own heparinized blood into the saline during formulation. The presence of an excess amount of such physiologically inert proteins prevents loss of the antibody due to adsorption to the walls of the containers and tubes used with the infusion solution. When albumin is used, a suitable concentration is 0.5 to 4.5% by weight of the saline solution. Other formulations include liquid or lyophilized formulations.

[0135] Antibodies, such as antibodies against IL-17, are typically formulated in an aqueous form that is immediately injectable or as a lyophilized product for reconstitution with a suitable diluent prior to administration. In some embodiments of the disclosed methods and uses, an IL-17 antagonist, such as an IL-17 antibody, such as secukinumab, is formulated as an immediately available liquid pharmaceutical composition. Suitable lyophilized formulations can be reconstituted in a small volume of liquid (e.g., 2 ml or less) to enable subcutaneous administration and can provide a solution with low levels of antibody aggregation. The use of antibodies as active pharmaceutical ingredients is currently widespread, including products such as HERCEPTIN™ (trastuzumab), RITUXAN™ (rituximab), SYNAGIS™ (palivizumab). Techniques for the purification of antibodies to pharmaceutical grade are well 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, dermal, or subcutaneous injection, the IL-17 antagonist will be in the form of a pyrogen-free parenterally acceptable solution. Pharmaceutical compositions for intravenous, dermal, or subcutaneous injection can contain, in addition to the IL-17 antagonist, 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.

[0136] In preferred embodiments of the disclosed methods, uses, kits, etc., the IL-17 binding molecule (e.g., an IL-17 antibody or antigen-binding fragment thereof) or the IL-17 receptor binding molecule (e.g., an IL-17 antibody or antigen-binding fragment thereof) is secukinumab provided in a stable liquid pharmaceutical formulation comprising from about 25 mg / mL to about 150 mg / mL secukinumab, from about 10 mM to about 30 mM histidine (pH 5.8), from about 200 mM to about 225 mM trehalose, about 0.02% polysorbate 80, and from about 2.5 mM to about 20 mM methionine, and this liquid formulation is not reconstituted from a lyophilized product. A preferred pharmaceutical product for use in the disclosed methods, uses, kits, etc. is provided in a prefilled syringe or autoinjector (i.e., having a 1 mL or 2 mL formulation) and comprises a stable liquid formulation of 150 mg / ml secukinumab, 200 mM trehalose, 0.02% polysorbate 80, and 5 mM L-methionine in 20 mM histidine buffer (pH 5.8).

[0137] Appropriate dosages can vary, for example, depending on the particular 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 recipient, the mode of administration, and the nature and severity of the condition being treated, as well as the nature of any prior treatments the patient has received. Ultimately, the responsible healthcare provider determines the amount of the IL-17 antagonist to administer to each individual patient. In some embodiments, the responsible 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 is then dose-adjusted downward until signs of recurrence occur. Larger doses of the IL-17 antagonist can be administered until an optimal therapeutic effect is obtained for the patient, and this dosage generally is not increased further.

[0138] In practicing some of the methods of treatment or use of the present disclosure, a therapeutically effective amount of an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof), is administered to a patient, such as a mammal (e.g., a human). It is understood that the disclosed methods provide treatment of tendinopathy patients using an IL-17 antagonist (e.g., secukinumab), but this does not exclude the possibility that such IL-17 antagonist therapy will necessarily be monotherapy if the patient is ultimately treated with an IL-17 antagonist. Indeed, if a patient is selected for treatment with an IL-17 antagonist, the IL-17 antagonist (e.g., secukinumab) can be administered alone or in combination with other agents and therapies (e.g., other standard therapeutic therapies for tendinopathy, such as steroids, NSAIDs, acetaminophen, physical therapy, etc.) in accordance with the methods of the present disclosure. Additional therapies for use in combination with the disclosed IL-17 antagonists (e.g., secukinumab) for treating tendinopathy include rest, ice, massage therapy, extracorporeal shock wave therapy (ESWT), ultrasound, laser therapy, stretching exercises, LIPUS, electrotherapy, taping, sclerosing agent injection, glycerol trinitrate, and other forms of physical and physiotherapy. Tendinopathy medications for use in combination with the disclosed IL-17 antagonists (e.g., secukinumab) for treating tendinopathy include steroids (e.g., corticosteroids, glucocorticoids, methylprednisolone, betamethasone) (oral, IV or IM), autologous blood, platelet-rich plasma (PRP), protein-depleted hemodialysate, aprotinin, polysulfated glycosaminoglycans, acetaminophen, NSAIDs (salicylate esters [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 (fenamic acid) [e.g., meclofenamic acid], selective COX-2 inhibitors [e.g., celecoxib], sulfonanilides [e.g., nimesulide] and others [clonixin, licofelone, h-harpagide]).Additional tendon disorder drugs for use in combination with the disclosed IL-17 antagonists (e.g., secukinumab) for treating tendon disorders include somatropin, hyaluronic acid, insulin-like growth factor I, autologous conditioned plasma, lidocaine, tetracaine patch, ethoxysclerol, polidocanol, SM04755, Celestone, ketorolac, autologous mesenchymal stem cells, sodium thiosulfate, Depo-Medrol, RCT-01, ketamine, MRX-7EAT, ketoprofen, TNF-α inhibitors (infliximab, adalimumab, certolizumab pegol, golimumab, etanercept), IL-1 inhibitors (anakinra, rilonacept, canakinumab), IL-23 inhibitors (ustekinumab, guselkumab), IL-17 inhibitors (ixekizumab, brodalumab), alibadol, gerol, triamcinolone acetonide, xylocaine, doxycycline, ketorolac, etoricoxib, oxycodone, bupivacaine, hydrocodone, and codeine.

[0139] When co-administered with one or more additional tendon disorder drugs, the IL-17 antagonist can be administered simultaneously or sequentially with the other agent. When administered sequentially, the attending physician determines the appropriate order for administering the IL-17 antagonist in combination with the other agent and the appropriate dosage for co-delivery. The IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody or an antigen-binding fragment thereof), is preferably administered parenterally, e.g., intravenously (e.g., into the antecubital or other peripheral vein), intramuscularly, or subcutaneously.

[0140] The duration of therapy using the pharmaceutical compositions of the present disclosure will vary depending on the severity of the disease and condition being treated and the individual response of each individual patient. The healthcare provider determines the appropriate duration of therapy and the timing of administration of this therapy using the pharmaceutical compositions of the present disclosure. As used herein, the expression "total treatment period" refers to the total amount of time a patient is treated with an IL-17 antagonist, including, where applicable, an induction period (e.g., initial weekly dosing). Thus, for example, if a patient is administered an IL-17 antagonist weekly during weeks 0, 1, 2, 3, and 4 and then every 4 weeks over a total treatment period of 2 months, that patient will receive administration during weeks 0, 1, 2, 3, 4, and 8. Similarly, for example, if a patient is administered an IL-17 antagonist weekly during weeks 0, 1, 2, 3, and 4 and then every 4 weeks over a total treatment period of 3 months, that patient will receive administration during weeks 0, 1, 2, 3, 4, 8, and 12.

[0141] Preferred total treatment periods are 1 to 3 months, 3 to 6 months, 6 to 9 months, or 9 to 12 months. In some embodiments, the patient is treated over 3 months or less, e.g., 1, 2, or 3 months. In other embodiments, the patient is treated over up to 12 months, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. The most preferred total treatment period is 1, 2, or 3 months.

[0142] A preferred SC treatment regimen (including both an induction regimen and a maintenance regimen) using secukinumab that can be used to treat patients with tendon disorders is provided in PCT applications PCT / US2011 / 064307 and PCT / IB2014 / 063902, the entire contents of which are incorporated herein by reference where applicable.

[0143] In some embodiments, a patient can be administered a single S.C. dose 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), in an amount of about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg).

[0144] In some embodiments, 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), is administered S.C. to a patient at about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) once a week during weeks 0, 1, 2, 3, and 4.

[0145] In a preferred embodiment, 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), is administered S.C. to a patient at a fixed dose of about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) once a week during weeks 0, 1, 2, 3, and 4, and then, every 4 weeks (monthly), at about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg). In this regimen, a patient is administered S.C. an IL-17 antagonist (e.g., secukinumab) at about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) at weeks 0, 1, 2, 3, 4, 8, and other time points.

[0146] In other embodiments, 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 subcutaneously (SC) to a patient at a fixed dose of about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) every four weeks (monthly). In this regimen, the patient is administered SC with an IL-17 antagonist (e.g., secukinumab) at about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) at weeks 0, 1, 4, 8, 12, and other intervals. Ideally, a patient, such as a patient having a rotator cuff tendon disorder or an Achilles tendon disorder (preferably a rotator cuff tendon disorder), is administered an IL-17 antagonist (e.g., secukinumab) monthly (every four weeks) (at weeks 0, 4, 8, and 12) for a total of four administrations.

[0147] In other embodiments, 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), is administered to a patient twice a month (every two weeks, every other week), once a month, four times a year (every three months), twice a year (every six months), or once a year.

[0148] A preferred S.C. dosage (e.g., a fixed dosage) is from about 150 mg to about 300 mg, preferably about 150 mg or about 300 mg. However, it will be understood that for certain patients, e.g., those who exhibit 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, e.g., secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody or an antigen-binding fragment thereof), a dosage escalation may be required (e.g., during induction and / or maintenance). Thus, the S.C. dosage of an IL-17 antagonist, e.g., secukinumab, may be greater than from about 150 mg to about 300 mg, e.g., 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 will also be understood that for certain patients, e.g., those who exhibit an adverse event or adverse reaction to treatment with an IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab), a dosage reduction may be required (e.g., during induction and / or maintenance). Thus, the dosage of an IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) may be less than from about 150 mg to about 300 mg (S.C.), e.g., 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, an IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody or an antigen-binding fragment thereof), can be administered to a patient at an initial dosage of 150 mg (S.C. delivery), which can then be escalated to about 300 mg as needed, as determined by a physician.In some embodiments, 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 a patient at an initial dose of 300 mg (SC delivery), which can then be titrated up to about 450 mg as needed, as determined by the physician.

[0149] The timing of dosing is generally measured from the day of the first administration of the drug (also known as the "baseline"). However, healthcare providers often use different nomenclatures to clarify the dosing schedule as shown in Table 2.

[0150] [Table 2]

[0151] In particular, the 0th week may be considered the 1st week by some healthcare providers, while the 0th day may be considered the 1st day by some healthcare providers. Thus, to ensure different physicians refer to the same dosing schedule, for example, doses given during the 3rd week / approximate 21st day, 3rd week / approximate 22nd day, 4th week / approximate 21st day, 4th week / approximate 22nd day may be referred to. To maintain consistency, the first week of dosing is considered the 0th week herein, while the first day of dosing is considered the 1st day. However, this nomenclature is used solely for consistency and should not be construed as limiting, i.e., it will be understood by those skilled in the art that weekly dosing, regardless of whether a physician refers to a particular week as the "1st week" or the "2nd week", is defined by the weekly dose of the IL-17 antibody. In one dosing regimen, the antibody is administered at weeks 0, 4, 8, 12, and other intervals, monthly. In one dosing regimen, the antibody is administered at weeks 0, 1, 2, 3, 4, 8, 12, and other intervals. There are providers who may refer to this regimen as weekly for 5 weeks and then, starting in the 8th week, monthly (or every 4 weeks), while there are also providers who may refer to this regimen as weekly for 4 weeks and then, starting in the 4th week, monthly (or every 4 weeks). It will be understood by those skilled in the art that administering injections at weeks 0, 1, 2, and 3 followed by monthly (every 4 weeks) dosing starting in the 4th week to a patient is equivalent to: 1) administering injections at weeks 0, 1, 2, 3, and 4 followed by monthly dosing starting in the 8th week to the patient, 2) administering injections at weeks 0, 1, 2, 3, and 4 followed by dosing every 4 weeks to the patient, and 3) administering injections at weeks 0, 1, 2, 3, and 4 followed by monthly administration to the patient.

[0152] Disclosed herein is a method for treating a patient having a tendon disorder, the method 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 an 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, and the IL-17 antibody or an antigen-binding fragment thereof has a K D for human IL-17 of about 100-200 pM and the IL-17 antibody or an antigen-binding fragment thereof has an in vivo half-life of about 4 weeks.

[0153] Further disclosed herein is a therapeutically effective amount of an IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) for use in treating a patient having a tendon disorder, wherein the IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., 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, and the IL-17 antibody or an antigen-binding fragment thereof has a K D for human IL-17 of about 100-200 pM and the IL-17 antibody or an antigen-binding fragment thereof has an in vivo half-life of about 4 weeks.

[0154] 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 having a tendon disorder, 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, and the IL-17 antibody or an antigen-binding fragment thereof has a K D for human IL-17 of about 100 - 200 pM and the IL-17 antibody or an antigen-binding fragment thereof has an in vivo half-life of about 4 weeks.

[0155] 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 having a tendon disorder, wherein the medicament is formulated to form a container, and each container has an amount of the IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) sufficient to enable subcutaneous delivery of at least about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) of the IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) per unit dose. Further, 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, and the IL-17 antibody or an antigen-binding fragment thereof has a KD and the IL-17 antibody or antigen-binding fragment thereof has an in vivo half-life of about 4 weeks.

[0156] As used herein, the expression "a container having an amount of an IL-17 antagonist sufficient to enable delivery of [the specified dose]" is used to mean that a given container (e.g., a vial, pen, syringe) has a volume of an IL-17 antagonist (e.g., as part of a pharmaceutical composition) disposed therein that can be used to provide the desired dose. By way of example, if the desired dose is 300 mg, a clinician can use 2 ml from a container containing an IL-17 antibody formulation having a concentration of 150 mg / ml, 1 ml from a container containing an IL-17 antibody formulation having a concentration of 300 mg / ml, 0.5 ml from a container containing an IL-17 antibody formulation having a concentration of 600 mg / ml, etc. In each such case, these containers have an amount of an IL-17 antagonist sufficient to enable delivery of the desired 300 mg dose. In one embodiment, the container has a 1 ml formulation containing 150 mg / ml secukinumab dispensed therein. In another embodiment, the container has a 2 ml formulation containing 150 mg / ml secukinumab dispensed therein. Preferred formulations are liquid pharmaceutical compositions containing from about 25 mg / mL to about 150 mg / mL secukinumab, from about 10 mM to about 30 mM histidine (pH 5.8), from about 200 mM to about 225 mM trehalose, about 0.02% polysorbate 80 and from about 2.5 mM to about 20 mM methionine.

[0157] 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 having a tendon disorder, the medicament being formulated in a dosage that enables 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 a patient, and further, 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, and the IL-17 antibody or an antigen-binding fragment thereof has a K D for human IL-17 of about 100 to 200 pM and the IL-17 antibody or an antigen-binding fragment thereof has an in vivo half-life of about 4 weeks.

[0158] As used herein, the expression "formulated in a dosage amount to enable delivery of [designated dosage] via [route of administration]" is used to mean that a given pharmaceutical composition can be used to provide a desired dosage of an IL-17 antagonist, such as an IL-17 antibody, such as secukinumab, via a designated route of administration (e.g., SC or IV). As an example, if the desired subcutaneous dosage is 300 mg, a clinician can use a 2 ml IL-17 antibody formulation having a concentration of 150 mg / ml, a 1 ml IL-17 antibody formulation having a concentration of 300 mg / ml, a 0.5 ml IL-17 antibody formulation having a concentration of 600 mg / ml, etc. In each of these cases, these IL-17 antibody formulations are at a concentration high enough to enable subcutaneous delivery of the IL-17 antibody. Subcutaneous delivery typically requires delivery of a volume of ≦2 ml. In one embodiment, a patient is administered a single 2 ml SC injection of a formulation containing 150 mg / ml secukinumab. In another embodiment, a patient is administered two 1 ml SC injections of a formulation containing 150 mg / ml secukinumab.

[0159] Disclosed herein are methods, uses, pharmaceutical compositions and kits for inducing tendon tissue regeneration or promoting tendon repair in a patient having a tendon disorder, comprising subcutaneously administering to a patient in need thereof from about 150 mg to about 300 mg of an IL-17 antibody or antigen-binding fragment thereof. Here, the IL-17 antibody or antigen-binding fragment thereof binds to an epitope of a human 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, and the IL-17 antibody or antigen-binding fragment thereof has a K D of from about 100 to 200 pM for human IL-17 and the IL-17 antibody or antigen-binding fragment thereof has a half-life in vivo of about 4 weeks.

[0160] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient is administered the IL-17 antibody or an antigen-binding fragment thereof only once.

[0161] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient is administered the IL-17 antibody or an antigen-binding fragment thereof weekly.

[0162] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient is administered the IL-17 antibody or an antigen-binding fragment thereof during weeks 0, 1, 2, 3, and 4.

[0163] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient is administered the IL-17 antibody or an antigen-binding fragment thereof every four weeks.

[0164] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient is administered the IL-17 antibody or an antigen-binding fragment thereof over a total treatment period of at least two months.

[0165] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient is administered the IL-17 antibody or an antigen-binding fragment thereof over a total treatment period of at least four months.

[0166] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient is administered the IL-17 antibody or an antigen-binding fragment thereof weekly during weeks 0, 1, 2, 3, and 4 and then every four weeks.

[0167] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient is administered the IL-17 antibody or an antigen-binding fragment thereof during weeks 0, 1, 2, 3, 4, 8, and 12.

[0168] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient is administered an IL-17 antibody or an antigen-binding fragment thereof weekly during weeks 0, 1, 2, 3, and 4 over a total treatment period of at least 3 months, and then every 4 weeks thereafter.

[0169] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, prior to treatment with an IL-17 antibody or an antigen-binding fragment thereof, the patient did not respond, had an inadequate response, or was intolerant to previous tendon disorder treatments selected from the group consisting of local steroid injection into the affected tendon, treatment with an NSAID, treatment with acetaminophen, physical therapy, and combinations thereof.

[0170] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient has an overuse tendon disorder.

[0171] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient has a subacute tendon disorder.

[0172] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, treatment with an IL-17 antibody or an antigen-binding fragment thereof reduces progression to a chronic tendon disorder.

[0173] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient has a chronic tendon disorder.

[0174] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient has an active tendon disorder.

[0175] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient has a partially torn tendon.

[0176] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, treatment with an IL-17 antibody or an antigen-binding fragment thereof reduces progression to a completely torn tendon.

[0177] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient has plantar fasciitis, Achilles tendon disorder, patellar tendon disorder, rotator cuff tendon disorder, jumper's knee, lateral epicondylitis, medial epicondylitis, supraspinatus syndrome, or any combination thereof.

[0178] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, after treatment with an IL-17 antibody or an antigen-binding fragment thereof, the patient experiences at least a 20% reduction in pain, at least a 20% reduction in inflammation, at least a 20% improvement in tendon regeneration and / or repair, and / or at least a 20% improvement in the movement of the affected tendon.

[0179] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, after treatment with an IL-17 antibody or an antigen-binding fragment thereof, the patient experiences at least a 20% reduction in pain as determined by the VAS score.

[0180] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient has a rotator cuff tendon disorder, and after treatment with an IL-17 antibody or an antigen-binding fragment thereof, the patient experiences at least a 20% improvement in shoulder-related quality of life (QoL) as determined by the WORC score, QuickDASH score, or ASES score.

[0181] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, after treatment with an IL-17 antibody or an antigen-binding fragment thereof, the patient experiences at least a 20% overall improvement as determined by the PGA score.

[0182] In some embodiments, the disclosed methods, uses, pharmaceutical compositions, and kits further comprise administering to the patient a steroid, an NSAID, or acetaminophen.

[0183] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, after treatment with an IL-17 antibody or an antigen-binding fragment thereof, the patient has a reduced need for physical therapy, or the patient has reduced symptoms of tendon disorder, thereby improving the effectiveness of physical therapy.

[0184] In some embodiments of the disclosed uses, methods, pharmaceutical compositions, and kits, the IL-17 antibody or an antigen-binding fragment thereof comprises: i) an immunoglobulin heavy chain variable domain (V H ) comprising the amino acid sequence set forth as SEQ ID NO: 8, ii) an immunoglobulin light chain variable domain (V L ) comprising the amino acid sequence set forth as SEQ ID NO: 10, iii) an immunoglobulin V H domain comprising the amino acid sequence set forth as SEQ ID NO: 8 and an immunoglobulin V L domain comprising the amino acid sequence set forth as SEQ ID NO: 10, iv) an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, v) an immunoglobulin V L domain comprising the hypervariable regions set forth as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, vi) an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13, vii) an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 and an immunoglobulin V L domain comprising the hypervariable regions set forth as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, viii) an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13 and an immunoglobulin V LDomain, ix) an immunoglobulin light chain comprising the amino acid sequence described as SEQ ID NO: 14, x) an immunoglobulin heavy chain comprising the amino acid sequence described as SEQ ID NO: 15, or xi) an immunoglobulin light chain comprising the amino acid sequence described as SEQ ID NO: 14 and an immunoglobulin heavy chain comprising the amino acid sequence described as 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.

[0185] Also disclosed herein are a method, use, pharmaceutical composition, and kit for treating a patient having an active overuse tendinopathy, comprising administering to the patient by subcutaneous injection approximately 300 mg of secukinumab at weeks 0, 1, 2, 3, and 4 and then every 4 weeks for a total treatment period of at least 3 months.

[0186] Also disclosed herein are a method, use, pharmaceutical composition, and kit for treating a patient having an active overuse tendinopathy, comprising administering to the patient by subcutaneous injection approximately 150 mg of secukinumab at weeks 0, 1, 2, 3, and 4 and then every 4 weeks for a total treatment period of at least 3 months.

[0187] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, prior to treatment with secukinumab, the patient was resistant to previous tendinopathy treatment selected from the group consisting of local steroid injection into the affected tendon, treatment with NSAIDs, treatment with acetaminophen, physical therapy, and combinations thereof.

[0188] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient has received physical therapy treatment, the patient is ineligible 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 previous tendinopathy treatment selected from the group consisting of local steroid injection into the affected tendon, treatment with NSAIDs, treatment with acetaminophen, and combinations thereof.

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

[0190] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, prior to treatment with secukinumab, the patient had a suboptimal response to previous rotator cuff tendon disorder surgery.

[0191] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient has a rotator cuff tendon disorder, has been treated using standard treatment for the tendon disorder, and is ineligible for surgery.

[0192] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, when a population of patients having a rotator cuff tendon disorder is treated with secukinumab, at least 40%, preferably at least 60%, of the patients reach MCID on the WORC score.

[0193] Kit The present disclosure also encompasses kits for treating patients with tendon disorders. 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 (described above) comprising a therapeutically effective amount of an IL-17 antagonist. Further, such kits may include means for administering the IL-17 antagonist (e.g., an autoinjector, syringe and vial, prefilled syringe, prefilled pen) and instructions for use. These kits can contain, for example, an additional therapeutic agent (described above) for delivery in combination with an encapsulated IL-17 antagonist, such as an IL-17 binding molecule, such as an IL-17 antibody, such as secukinumab, for treating tendon disorders. Such kits may also include instructions for administration of an IL-17 antagonist (e.g., an IL-17 antibody, such as secukinumab) for treating patients with tendon disorders. Such instructions can provide dosage (e.g., about 150 mg to about 300 mg, such as 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 (every 4 weeks after weeks 0, 1, 2, 3, and 4), and total treatment period (e.g., 1, 2, 3, 4, 6, 8, 12 months, (preferably 3 to 12 months, such as 3 months)) for use in combination with an encapsulated IL-17 antagonist, such as an IL-17 binding molecule, such as an IL-17 antibody, such as secukinumab.

[0194] The term "means for administration" is used to denote any available means for systemic administration of a drug to a patient, including, but not limited to, prefilled syringes, vials and syringes, pen injectors, autoinjectors, intravenous drip bags, pumps, etc. Using such means, a patient can self-administer the drug (i.e., administer the drug without the assistance of a physician), or a physician can administer the drug. In some embodiments, a total dose of 300 mg is delivered in a total volume of 2 ml with an IL-17 antibody at 150 mg / ml, such as secukinumab, dispensed into a single PFS or autoinjector. In some embodiments, a total dose of 300 mg is delivered in a total volume of 2 ml dispensed into two PFSs or autoinjectors, each containing a volume of 1 ml with an IL-17 antibody at 150 mg / ml, such as secukinumab.

[0195] Disclosed herein is a kit for use in treating a patient having a tendon disorder comprising an IL-17 antagonist (e.g., an IL-17 binding molecule, e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab). In some embodiments, the kit further comprises means for administering the IL-17 antagonist to the patient. In some embodiments, the kit further comprises instructions for administration of the IL-17 antagonist, the instructions indicating that the IL-17 antagonist (e.g., an IL-17 binding molecule, e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) should be 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, e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) should be 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., an IL-17 binding molecule, e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) should be administered to the patient every 4 weeks (monthly) over a total treatment period 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., an IL-17 binding molecule, e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) should be administered to the patient weekly during weeks 0, 1, 2, 3, and 4, and then every 4 weeks (monthly) over a total treatment period of at least 3 months, e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months (preferably 2 or 3 months). In some embodiments, the instructions provide for a dose escalation (e.g., 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 determined by the physician and as needed.

[0196] General In preferred embodiments of the disclosed methods, treatments, pharmaceuticals, 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 an IgG 1 isotype human antibody. In a preferred embodiment of the disclosed method, the antibody or an antigen-binding fragment thereof is secukinumab.

Example

[0197] Example 1 - IgG in tendon disorders 1 Tissue exposure and effects of an anti-IL-17 monoclonal antibody In an in vivo rat disease model, tendon disorder of the rotator cuff tendon was induced by unilateral surgical partial tenectomy of the supraspinatus tendon along the coronal plane. IgG 1 An anti-IL-17 monoclonal antibody (CJM112) (15 mg / kg) or vehicle was administered subcutaneously or intravenously, respectively, one week or one day prior to surgical introduction of the tendon disorder, followed by three weekly subcutaneous or intravenous dosing for 3 weeks. Antibody exposure to the rotator cuff tendon tissue and its pharmacological effects on tendon disorder inflammation and gait ataxia were evaluated 4 weeks after surgical introduction of the tendon disorder and 1 week after the last dosing of the antibody. The final trough exposure levels of the antibody to the rotator cuff tendon tissue, skeletal muscle and skin were evaluated using enzyme-linked immunosorbent assay (ELISA) after tissue homogenization and protein extraction. The effect of the antibody on tendon disorder inflammation was evaluated by magnetic resonance imaging (MRI) (10.1136 / bjsm.2006.034421) during survival, and the effect on gait ataxia was evaluated by quantification of footprint illumination in animals moving non-forcibly across a catwalk (10.1007 / s11916-014-0456-x).

[0198] After repeated dosing, the trough exposure levels of the IL-17 antibody in the rotator cuff tendon were similar after subcutaneous and intravenous administration routes (500 ng / mg (total protein), n = 5). The trough exposure levels of the antibody to tendon tissue were similar to those in skeletal muscle and lower in the skin (2,500 ng / mg (total protein), n = 5).

[0199] The introduction of tendon injury 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 increase in the MRI T2 tendinopathy inflammatory signal (p < 0.01, Student's t-test, n = 4). The introduction of tendon injury induced gait ataxia and significantly increased the forefoot-to-hindfoot ratio of the footprint contact ground surface from 1 before the introduction of tendon injury to 1.5 after the introduction of tendon injury (p < 0.05, ANOVA Tukey's post hoc test, n = 8). The antibody reversed gait ataxia (p < 0.05, ANOVA Tukey's post hoc test, n = 8).

[0200] The results of this in vivo study strongly suggest that the antagonist IL-17 antibody has potential for treating tendon injury.

[0201] Example 2 - Ex vivo and in vitro examples of tendon bundle inflammation induced by IL17 In an ex vivo rat tail tendon bundle model, which is a model of load-induced tendon degeneration, RNASeq analysis revealed the characteristics of intrinsic tendon bundle inflammation. The unloaded bundles showed >10-fold upregulation of several 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 bundles, indicating that this tissue is sensitive to IL-17. Computational analysis of signaling pathways from an internal database revealed five pathway hits specific to IL-17 or a TH17 cell-specific signature. Addition of recombinant IL-17A (1.67 nM) to unloaded tendon bundles induced a further increase in the expression of cytokines, chemokines, and MMPs (IL-6, CXCL-1, PTGS-2, MMP-3). Concomitantly and consistent with tendon degeneration, the tendon marker genes scleraxis and tenomodulin were dramatically downregulated. Furthermore, after 8 days of culture, the elastic modulus of unloaded tendon bundles decreased compared to fresh tissue controls (ANOVA; p = 0.0001), and IL-17A treatment induced a tendency for further decrease (Dunnett's post hoc test; p = 0.0774), suggesting that inflammatory cytokines contribute to the loss of biomechanical ability (Figure 1).

[0202] In vitro assays in rat tendon cells demonstrated that IL-17A induces a dose-dependent increase in IL-6 and CXCL-1 mRNA expression (Figure 2). Furthermore, the murine anti-IL-17A antibody BZN035 at 33 nM was able to completely block the induction of IL-6 and CXCL-1 expression induced by IL-17A in rat tendon cells (Figure 3).

[0203] Example 3 - A randomized, double-blind, placebo-controlled, parallel-group, 24-week Phase II study to investigate the efficacy, safety, and tolerability of AIN457 in patients with active overuse tendon disorders resistant to oral NSAID / acetaminophen, physical therapy, or corticosteroid injection "Enthesitis" is a term used to describe inflammation at the tendon, ligament or joint capsule attachment sites. This applies to diseases associated with spondyloarthritis (SpA), including AS and PsA. Enthesitis can be inflammatory or mechanically induced, and the two can have common features (McGonagle D and Benjamin M (2009) Reports on Rheumatic Diseases Series 6.4: 1-6).

[0204] Neutralization of IL-17 has shown efficacy in inflammatory enthesitis in PsA and AS, as seen in studies with secukinumab. In study CAIN457F2312, enthesitis was evaluated in a subset of patients who had disease activity at baseline. In this patient population, secukinumab significantly increased the proportion of patients in whom enthesitis resolved, compared with placebo (CAIN457F2312). Overall, the proportion of patients in whom enthesitis did not resolve at week 24 was 67.6%, 57.8%, 51.8%, 59.6% and 78.5% for the secukinumab 75mg, 150mg, 300mg, secukinumab (pooled) and placebo groups, respectively. At week 24, these differences from placebo were also greater for the 150mg and 300mg dose groups compared with placebo (p = 0.0108 and p = 0.0025, respectively), whereas 75mg was similar to placebo (p = 0.1678).

[0205] Combined with the effects of IL-17 antagonism on enthesitis in PsA and AS patients, and considering the in vitro, ex vivo and in vivo tendon disorder treatment evidence shown in Examples 1 and 2, the inventors believe that inactivation of IL-17 reduces tendon inflammation and, perhaps more importantly, reduces non-repair and degeneration of the tendon matrix. Thus, secukinumab is being tested as a disease-modifying therapy for active overuse tendon disorders to induce tendon cell regeneration and promote tendon repair.

[0206] The objective of this Phase II study is to determine the efficacy of secukinumab in treating patients with a diagnosis of overuse, non-systemic inflammatory rotator cuff (subscapularis, infraspinatus, teres minor, and supraspinatus) tendon disorders, and to confirm the safety and tolerability profile of secukinumab at a dose of 300 mg (s.c.) given as an injection on Day 1 (Week 0) and weekly (Weeks 1, 2, 3, and 4) up to Week 4 (including Week 4), and then with additional injections at Weeks 8 and 12. The efficacy of secukinumab is evaluated at the end of Week 14 based on validated patient-reported outcomes (PROs) including improvement in signs and symptoms, physical function, quality of life, and range of motion (ROM). Changes in tendon structure reflecting tendon regeneration and repair are investigated by MRI and shear wave elastography. Patients are followed without treatment from Week 12 to Week 24 to investigate long-term safety. The details of this study are provided below.

[0207]

Table 3

[0208]

Table 4

[0209]

Table 5

[0210]

Table 6

[0211]

Table 7

[0212] Results Patient Allocation and Baseline Characteristics A total of 353 patients were screened, 98 patients were enrolled, 97 were randomized, and 96 patients (49 in the secukinumab group and 47 in the placebo group) received at least one dose. A total of 90 patients out of all the patients (N = 96; 100%) who received treatment in this study completed the treatment phase, and 88 patients completed the study including the follow-up phase (Figure 5).

[0213] Demographic variables were generally comparable between the two groups. Patients in the secukinumab group were approximately 5 years younger and more male than the placebo group (Table R1).

[0214]

Table 8

[0215]

Table 9

[0216] Clinical efficacy Main pain and function outcomes (primary and secondary endpoints): WORC and pain scores In the full study population, treatment with secukinumab and placebo in combination with standard of care (SoC) resulted in a clinically meaningful improvement in the total WORC score (primary endpoint at week 14), WORC subdomains, and pain scores (secondary endpoints), but there were no statistically significant differences between the groups at week 14 and over time (Figure 6).

[0217] Patient-reported outcomes: ASES, QuickDASH, EQ-5D scores The secukinumab group showed a numerical improvement in the ASES score compared to placebo. However, the difference was not statistically significant. Both groups showed an improvement in the QuickDASH score over time, but there was no statistically significant difference between the groups. For both the secukinumab group and the placebo group, there was a consistent improvement in the EQ-5D-5L index score at all time points. However, the difference at day 15 was significantly better (p = 0.05) than placebo only (Figure 7).

[0218] Comprehensive disease assessment: PGA, PhGA Both the secukinumab group and the placebo group showed improvement in PGA. Patients treated with secukinumab had a smaller mean PGA score and greater improvement compared to the placebo group at all visits except the 15th day, but there was no significant difference between the groups. Both the secukinumab group and the placebo group showed time - dependent improvement with a decrease in disease activity reflected by the decrease in mean PhGA score, but there was no statistically significant difference between the groups (Figure 7).

[0219] Imaging: MRI, Sein and Bauer scores The table of changes in the MRI Sein score showed no change for the secukinumab group at week 14 compared to baseline. In the placebo group, 1 patient had a change in the Sein score from 2 at baseline to 1 at week 14. For the Bauer MRI score, 1 patient in the placebo group showed a worsening change from a score of 1 to a score of 2 at week 14.

[0220] Physical function assessment: range of motion Active and passive range of motion (ROM) improved in both treatment groups for all parameters evaluated: abduction, adduction, extension, flexion, and internal and external rotation at week 14 (day 99). No clear differences and specific patterns in active and passive ROM were observed between the secukinumab group and the placebo group (Figure 8).

[0221] Post - hoc analysis Since many patients (n = 77, 87.5%) had mild disease with a WORC score above 60 (maximum 100), and / or a Sein tendon disorder score of 1 at baseline, and / or a Bauer score of 0, according to current literature 1 a hypothesis was made that these patients would have improved with standard physical therapy. Pre - clinical bridging studies 10、12It suggests that targeting the IL-17A pathway by shining light on the high tissue signal of IL-17A in patients with early tendon disorders accompanied by inflammatory infiltration may be most beneficial in the early disease. Furthermore, noting that 37 (42%) patients had symptoms of tendon disorders lasting more than 6 months, corresponding to more advanced disease, based on these findings, subsequently, to represent the typical cases of early moderate to severe disease, a subgroup of patients (n = 37, 42%) with disease duration ≤ 6 months, WORC score ≤ 40, Sein score ≥ 2 or Bauer score ≥ 1 was analyzed (Figure 9).

[0222] Both the secukinumab-treated subgroup and the placebo-treated subgroup had an improvement in WORC score over time, and the secukinumab group showed a clinically significant and nominally statistically significant improvement compared to placebo at all time points (Table R2, Figure 9).

[0223]

Table 10

[0224] Regarding the WORC subdomains of physical symptoms, work, sports, lifestyle and emotional scores, the improvement in the secukinumab group was nominally statistically significantly different from placebo at all time points except for lifestyle at days 85 and 99 and emotion at days 85, 99 and 169 (Figure 10).

[0225] The difference in pain score (VAS) was clinically significant at all time points compared to placebo and was statistically significantly different from placebo from day 57 to day 127 (Table R2, Figure 10).

[0226] Similar results were seen for the ASES score, and the difference from placebo was statistically significant at all time points except days 15, 99, and 169 (p = 0.07). For QuickDASH, secukinumab showed numerical improvement over placebo at all time points, but there was no statistically significant difference. The secukinumab group showed improvement in the EQ-5D-5L index compared to placebo, which was significant at all time points except days 99 and 169, with p-values of 0.06 and 0.07, respectively (Figure 11).

[0227] In the post hoc subgroups, active and passive ROM improved in both groups, but the secukinumab group showed a clinically meaningful and statistically significant improvement compared to placebo (Figure 12). To better understand the treatment effect in the defined subacute moderate to severe subpopulation, the effects of secukinumab on various clinical signs in response to placebo were also investigated, showing a clear trend towards improvement during secukinumab treatment in various subpopulations.

[0228] Safety Secukinumab generally showed good tolerance over 12 weeks. The excellent safety profile of secukinumab is consistent with previous secukinumab studies. No serious AEs were present in this study (Table R3).

[0229]

Table 11

[0230] There were no significant differences in AEs between all groups, and they were all mild or moderate in severity. No clinically significant changes between groups were reported in hematology, clinical chemistry, urine analysis, or vital signs. Anti-drug antibodies developing under treatment were not observed in any patient.

[0231] Discussion This is the first study to examine the effect of an IL-17A blocker in a cohort of patients with active RC tendon disorders. There was a significant improvement in symptoms and function in both groups in addition to SoC treatment (NSAIDs, physical therapy), and there was no clear additional benefit of secukinumab treatment compared to placebo in the entire study population. Secukinumab, which has demonstrated a favorable safety profile, showed good tolerance, and the AEs observed were consistent with the safety profile seen with secukinumab in other indications. The current results demonstrate that patients have clinically meaningful improvements with SoC treatment 16 , which makes it difficult to find a treatment effect compared to the SoC group. Furthermore, some patients with RC tendon disorders had a long-term history (>6 months) with potential tissue degeneration when anti-inflammatory treatment could be functionally excessive. Based on this study, it was concluded that the widespread use of secukinumab in RC tendon disorders cannot be justified.

[0232] This study provided an opportunity to more deeply explore the relationship between cytokine effector pathology and the clinical picture within and around human tendons. Considering the nature of the tendon biopsy material presented within the Human Atlas project 17 and which will thereby be broken down to the molecular level, this has utility for future translation of histopathological description and rational therapeutic intervention. The immunobiology of enthesitis 18 is potentially similar to tendon disorders because both entheses and tendons are sites of high mechanical stress. Some IL-17A inhibitors have shown efficacy in treating multiple aspects of spondyloarthritis, including psoriasis, enthesitis, synovitis, osteitis, new bone formation, and pain, which indicates the importance of IL-17A in the tissue-wide disease pathophysiology 19 . Some findings suggest a plausible biological profile demonstrated by IL-17A in preclinical and bridging studies of tendon tissue. Therefore, the hypothesis was formulated that IL-17A inhibition could show a beneficial therapeutic effect in RC tendon disorders. Increased IL-17 mRNA and protein expression levels have been previously described in early human tendon disorder biopsy material 20 ​10 Interestingly, IL-17A-high expressing tendon resident immune cells were most dominant early on in late stage human tendon disorder biopsy materials. 10 In contrast, the functional IL-17A blocker significantly improved tendon structure and function in a supraspinatus tendon disorder rodent model, i.e., a model of early disease by definition. 12 For this reason, as a post hoc analysis, a cohort of patients meeting early disease criteria was examined.

[0233] Therefore, an exploratory post hoc analysis was performed on 37 (42%) patients with moderate to severe disease defined as disease duration ≤6 months and WORC score ≤40, Sein score ≥2 or Bauer score ≥1. In this subgroup of RC tendon disorder patients, secukinumab provided a nominally significant but clearly clinically meaningful sustained improvement in WORC score beyond the minimal clinically important difference from baseline for the 48 at week 14 and 56 in the treatment group at the end of the study. 21 This subanalysis supports the data obtained from preclinical studies and thus provides interesting bridging insights. RC tendon disorder patients with early (<6 months) moderate to severe tendon disorders may have a more inflammatory phenotype and be more likely to respond to IL-17A inhibition.

[0234] There remains a large gap in the development of new drugs and agents that can improve tendon disorders in patients who are non-responders to exercise regimens. Due to the multiple anatomical sites and different phenotypes of tendon disorders, translation of findings from preclinical studies remains difficult as demonstrated in this trial. Interpretation of clinical trials in individuals who are not athletes is rarely done and thus it is difficult to determine whether certain treatment strategies are beneficial in different subgroups of patients. Applying patient stratification to post hoc analysis has shown significant improvement in various clinically meaningful outcomes.

[0235] The current research limitations that affect the ability to meet the predefined primary and secondary assessment items include the heterogeneous and broad disease spectrum of mild to severe diseases and the long disease duration up to 12 months in the inclusion. Furthermore, rigorous physical therapy treatment 22 is applied, optimal NSAID treatment is given, and improvement in the placebo group is brought about. Furthermore, this study was underpowered to detect significant changes in MRI imaging in a short treatment period in a large number of patients with mild diseases.

[0236] In conclusion, the inactivation of IL-17A with secukinumab is not beneficial in all patients with mild to severe RC tendon disorders, but appears to improve pain, function, and quality of life in patients with moderate to severe diseases over a shorter period. Larger prospective studies in this subpopulation are needed to confirm the results obtained from this Phase 2 study.

[0237] Example 4 - A randomized, parallel-group, 24-week, double-blind, placebo-controlled, multi-center Phase 3 study to evaluate the efficacy and safety of secukinumab compared to placebo in adult participants with rotator cuff tendon disorders Study population The target population will consist of adult men and women aged 18 to 65 years with unilateral non-acute moderate to severe RCTs with or without partial tears, resistant to conventional SoC. To participate, participants must: · Be resistant to SoC treatment, defined as 2 months of NSAIDs (or discontinued in case of intolerance) and physical therapy (PT). Symptoms should be present for at least 6 weeks but not more than 6 months. · Have a pain score of 5 or more on the NRS for 3 days out of 7 days at and before baseline (which corresponds to moderate to severe levels of pain) (scale of 0 - 10, where 10 indicates the worst possible pain). Participants must also have no night pain in the affected shoulder on at least 4 days out of 7 days in the week before baseline. · Have a WORC total percentage score of 40 or less at baseline (where 100 points is the percentage with no symptoms). Since the WORC total score has been reported to be confirmed and widely referenced in RCT literature, it is appropriate to use a cut-off on the WORC total score to define the target population. This allows for the identification of appropriate RCT participants from a broad overall perspective, taking into account the status of the participants and the impact of the RCT on the participants' quality of life (QoL) (Kirkley et al., 2003a; Ekeberg et al., 2008; de Witte et al., 2012). Further justification for the WORC total cut-off of 40 percentage points to identify moderate to severe disease is provided in Section 4.4. · Have a partial tear of 50% or less by MRI or ultrasound.

[0238] Objectives and evaluation items The proposed primary and key secondary efficacy evaluation items for the Phase 3 study are shown in Table 2-1. The primary evaluation item is the proportion of participants who achieve an improvement of at least 40 percentage points from baseline in the WORC physical symptoms domain at Week 14. The clinical benefit of secukinumab will be supported by secondary evaluation items that assess daily pain intensity and functional impact specific to the shoulder, sleep disturbances caused by shoulder pain, and overall sleep quality.

[0239]

Table 12

[0240]

Table 13

[0241] NRS, Numerical Rating Scale; PSQI, Pittsburgh Sleep Quality Index; WORC, Western Ontario Rotator Cuff Index.

[0242]

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Claims

Claim 1 A method for inducing tendon tissue regeneration or promoting tendon repair in patients with moderate to severe tendon disorders, comprising subcutaneously administering to a patient in need thereof from 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, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 on one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain, and the IL-17 antibody or the antigen-binding fragment thereof has a K Ｄ for human IL-17 of about 100 to 200 pM, and the IL-17 antibody or the antigen-binding fragment thereof has a half-life in vivo of about 4 weeks. Claim 2 The method according to claim 1, wherein the patient is administered the IL-17 antibody or antigen-binding fragment thereof only once. Claim 3 The method according to claim 1, wherein the patient is administered the IL-17 antibody or antigen-binding fragment thereof weekly. Claim 4 The method according to claim 3, wherein the patient is administered the IL-17 antibody or antigen-binding fragment thereof during weeks 0, 1, 2, 3 and 4. Claim 5 The method according to claim 1, wherein the patient is administered the IL-17 antibody or antigen-binding fragment thereof every four weeks. Claim 6 The method according to claim 5, wherein the patient is administered the IL-17 antibody or antigen-binding fragment thereof over a total treatment period of at least two months. Claim 7 The method according to claim 5, wherein the patient is administered the IL-17 antibody or antigen-binding fragment thereof every four weeks over a total treatment period of four months. Claim 8 The method according to claim 3, wherein the patient is administered the IL-17 antibody or antigen-binding fragment thereof weekly during weeks 0, 1, 2, 3 and 4 and then every four weeks. Claim 9 The method according to claim 8, wherein the patient is administered the IL-17 antibody or antigen-binding fragment thereof during weeks 0, 1, 2, 3, 4, 8 and 12. Claim 10 The method according to claim 8, wherein the patient is administered the IL-17 antibody or antigen-binding fragment thereof weekly during weeks 0, 1, 2, 3 and 4 over a total treatment period of at least three months and then every four weeks thereafter. Claim 11 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 previous tendon disorder treatments selected from the group consisting of local steroid injection into the affected tendon, treatment with NSAIDs, treatment with acetaminophen, physical therapy and combinations thereof, or the patient was resistant or intolerant to, for example, two months of treatment with NSAIDs and / or physical therapy. The method according to any one of claims 1 to 10. Claim 12 The method according to any one of claims 1 to 11, wherein the patient has symptoms of tendon disorder for more than six weeks. Claim 13 The method according to any one of claims 1 to 12, wherein the patient has subacute tendon disorder and / or the treatment with the IL-17 antibody or its antigen-binding fragment is initiated when the patient has symptoms of tendon disorder for 6 months or less.

14. The method according to claim 13, wherein the treatment with the IL-17 antibody or its antigen-binding fragment reduces the progression to chronic tendon disorder.

15. The method according to any one of claims 1 to 14, wherein the patient has active tendon disorder.

16. The method according to any one of claims 1 to 15, wherein the patient has a partially torn tendon.

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

18. The method according to claim 16 or 17, wherein the treatment with the IL-17 antibody or its antigen-binding fragment reduces the progression to a completely torn tendon.

19. The method according to any one of claims 1 to 18, wherein the patient has plantar fasciitis, Achilles tendon disorder, patellar tendon disorder, rotator cuff tendon disorder, jumper's knee, lateral epicondylitis, medial epicondylitis, supraspinatus syndrome or any combination thereof.

20. The method according to any one of claims 1 to 19, wherein the patient has rotator cuff tendon disorder, has been treated using standard treatment for tendon disorder and is ineligible for surgery.

21. The patient has rotator cuff tendon disorder, and the method includes determining that the patient has night pain in the affected shoulder on at least 4 days out of 7 days before the start of the treatment with the IL-17 antibody or its antigen-binding fragment, or The method according to any one of claims 1 to 20, wherein the patient has night pain in the affected shoulder on at least 4 days out of 7 days before the start of the treatment with the IL-17 antibody or its antigen-binding fragment.

22. The patient has rotator cuff tendon disorder, and the patient has a total WORC percentage score ≤ 40 before the start of the treatment with the IL-17 antibody or its antigen-binding fragment, or The method according to any one of claims 1 to 21, wherein the method includes determining that the patient has a total WORC percentage score ≤ 40 before the start of the treatment with the IL-17 antibody or its antigen-binding fragment.

23. The patient has rotator cuff tendon disorder, and The patient has an NRS pain score ≥ 5 for 3 days out of 7 days prior to the start of said treatment with said IL-17 antibody or antigen-binding fragment thereof, or The method according to any one of claims 1 to 22, comprising determining that the patient has an NRS pain score ≥ 5 for 3 days out of 7 days prior to the start of said treatment with said IL-17 antibody or antigen-binding fragment thereof.

24. After treatment with said IL-17 antibody or antigen-binding fragment thereof, the patient experiences at least a 20% reduction in pain, at least a 20% reduction in inflammation, at least a 20% improvement in tendon regeneration and / or repair, and / or at least a 20% improvement in the movement of the affected tendon. The method according to any one of claims 1 to 23.

25. After treatment with said IL-17 antibody or antigen-binding fragment thereof, the patient experiences at least a 20% reduction in pain as determined by the VAS score. The method according to any one of claims 1 to 24.

26. The patient has a rotator cuff tendon disorder, and after treatment with said 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 the WORC score, QuickDASH score, or ASES score. The method according to any one of claims 1 to 25.

27. After treatment with said IL-17 antibody or antigen-binding fragment thereof, the patient experiences at least a 20% overall improvement as determined by the PGA score. The method according to any one of claims 1 to 26.

28. The method according to any one of claims 1 to 27, further comprising administering a steroid, NSAID, or acetaminophen to the patient.

29. After treatment with said IL-17 antibody or antigen-binding fragment thereof, the patient has a reduced need for physical therapy, or the patient has reduced symptoms of tendon disorder, thereby improving the effectiveness of physical therapy. The method according to any one of claims 1 to 28.

30. Said IL-17 antibody or antigen-binding fragment thereof is i) An immunoglobulin heavy chain variable domain (V Ｈ ) containing the amino acid sequence described as SEQ ID NO: 8, ii) An immunoglobulin light chain variable domain (V Ｌ ) containing the amino acid sequence described as SEQ ID NO: 10 iii) An immunoglobulin V domain comprising the amino acid sequence described as SEQ ID NO: 8 and an immunoglobulin V domain comprising the amino acid sequence described as SEQ ID NO: 10 Ｈ domain and Ｌ domain iv) Immunoglobulin V domain containing the highly variable regions described as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 Ｈ domain v) Immunoglobulin V domain containing the highly variable regions described as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 Ｌ domain vi) An immunoglobulin V domain comprising highly variable regions described as SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13 Ｈ domain vii) Immunoglobulin V domains containing the highly variable regions described as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 Ｈ domains and immunoglobulin V domains containing the highly variable regions described as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 Ｌ domains, viii) Immunoglobulin V domains containing the highly variable regions described as SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13, and immunoglobulin V domains containing the highly variable regions described as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 Ｈ domains, Ｌ and ix) an immunoglobulin light chain comprising the amino acid sequence described as SEQ ID NO: 14, x) an immunoglobulin heavy chain comprising the amino acid sequence described as SEQ ID NO: 15, or An immunoglobulin light chain comprising the amino acid sequence described as SEQ ID NO: 14 and an immunoglobulin heavy chain comprising the amino acid sequence described as SEQ ID NO: 15 The method according to any one of claims 1 to 29, comprising

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

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

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

34. Prior to treatment with secukinumab, the patient was resistant to tendinopathy treatment selected from the group consisting of local steroid injection into the affected tendon, treatment with NSAIDs, treatment with acetaminophen, physical therapy, and combinations thereof, or the patient was resistant or intolerant to, for example, 2 months of treatment with NSAIDs and / or physical therapy. The method according to claim 32 or 33.

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

36. The method according to any one of claims 32 to 35, wherein the patient has rotator cuff tendinopathy.

37. The patient has rotator cuff tendinopathy, has been treated using standard treatment for tendinopathy, and is ineligible for surgery, or the patient is resistant or intolerant to, for example, 2 months of treatment with NSAIDs and / or physical therapy. The method according to any one of claims 32 to 35.

38. When a population of patients having rotator cuff tendinopathy is treated with secukinumab, at least 40%, preferably at least 60%, of the patients will reach MCID on the WORC score. The method according to claim 36 or 37.

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

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

41. The method according to claim 39 or 40, wherein the patient has night pain in the affected shoulder on at least 4 days out of 7 days prior to the start of the treatment with secukinumab, a total WORC percentage score ≦ 40 and / or an NRS pain score ≧ 5 over 3 days out of 7 days prior to the start of the treatment with secukinumab.

Images