A method of treating rheumatoid arthritis using IL-17 antagonists.

Abstract

To provide novel regimens for treating inflammatory arthritis, e.g., rheumatoid arthritis (RA) patients, e.g., a high risk RA patient with a therapeutically effective amount of IL-17 antagonist or IL-17 receptor binding molecule.SOLUTION: Disclosed is a method for treating a rheumatoid arthritis (RA) patient with a therapeutically effective amount of IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody or antigen binding fragment thereof, e.g., secukinumab) or IL-17 receptor binding molecule (e.g., IL-17 antibody or antigen binding fragment thereof).SELECTED DRAWING: None

Description

[Technical Field]

[0001] This disclosure is incorporated herein in whole by reference in 2010. This claim asserts priority from U.S. Provisional Patent Application No. 61 / 410,533, filed on November 5. Let's assume that.

[0002] This disclosure provides a therapeutically effective amount of IL-17-binding molecules, for example, AIN457 antibody ("Sec") Using IL-17 antibodies such as "kinumab" to treat rheumatoid arthritis Regarding a new regimen for this purpose. [Background technology]

[0003] Rheumatoid arthritis (RA) is a chronic inflammatory systemic autoimmune disease of unknown etiology. Characterized by symmetrical synovitis resulting in cartilage damage and joint destruction, and many extraarticular conditions This condition may be accompanied by rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA). Considering the presence of autoantibodies such as RA, rheumatoid arthritis (RA) is considered an autoimmune disease. Rheumatoid arthritis (RA) is a progressive disease characterized by a decline in functional status, serious pathological conditions, and premature death in long-term RA. It is acknowledged. The disease can occur at any age, with the highest incidence occurring between the ages of 40 and 60. It is in the 20s. The goal of long-term RA treatment is disease remission.

[0004] A heterogeneous collection of drugs classified by use and convention, for disease treatment. Disease-modifying antirheumatic drugs (DMARDs) are the first-line treatment for patients with rheumatoid arthritis (RA). RD reduces joint swelling and pain, decreases acute phase markers, and slows the progression of joint injury. Used to restrict and improve joint function. DMARDs, in most cases, methotrexate. Lexate (MTX) is typically used after diagnosis of the disease (i.e., early RA), and for long-term RA. It is prescribed before the onset of erosive diseases and deformities observed in [the patient]. MTX therapy is used for pain and gliding. It is initiated when dysentery persists (especially when function is impaired) and when disease control is achieved. Additional DMARDs (with or without steroids) may be added for this purpose. Unfortunately, only about two-thirds of patients respond to DMARDs, and DMARDs are not long-term. It only partially controls the affected RA disease. Radiographic progression is in remission or remission. Even in 5-20% of RA patients treated with DMARDs, the clinical improvement is still sustained, achieving a level close to that of sustained improvement. DMARDs have many side effects that limit their long-term use (e.g., liver damage, It also presents with bone marrow suppression and severe lung infection.

[0005] Due to insufficient response and risks associated with long-term DMARD treatment, biologics are the second-line treatment for rheumatoid arthritis (RA). It was introduced as a therapeutic drug. Generally, anti-TNF drugs (Cimzia®, Enbre l(registered trademark), Humira(registered trademark), Remicade(registered trademark), Simp oni(registered trademark) is a patient who has a history of DMARD failure or an insufficient response to DMARDs. TNF inhibitors are the first biologics used in patients, and they are used to actively treat long-term rheumatoid arthritis. It is often used in combination with MTX (or other DMARDs) for this purpose. Unfortunately, long-term illness 30-40% of patients A do not respond to TNF-α antagonists, and initially, the majority of patients do not respond. Many do not achieve complete remission or lose their response over time. Short- and long-term tolerability and safety, and most notably, the effects of TNF-alpha antagonism. This can lead to reactivation of serious infections (e.g., tuberculosis), hepatotoxicity, increased cardiovascular disease, and demyelinating symptoms. Concerns were also raised regarding the induction (or worsening) of the condition and an increased incidence of malignant tumors (M. Khraish). i (2009) J. Rheumatol Suppl, vol. 82, pp. 25-32, Salliot et al. (2009) Ann. Rheum. Dis., 68 (Volume, pp. 25-32). However, TNF inhibitors are not used unless they become ineffective or adverse events occur. Typically, treatment is continued, and at that point, the clinician may administer a different TNF inhibitor or a different life-sustaining medication with a different mechanism of action. Physical formulations (e.g., Kineret® [IL-1R antagonist], MabT) hera (registered trademark) [CD20 Antagonist], Orencia (registered trademark) [CT LA4 fusion protein] or Actemra® [IL-6 receptor antagonist] It may switch to (T) (Scott et al. (2010) The Lancet, vol. 376, pp. 1095-1108).

[0006] Considering the aforementioned problems with current RA therapy, developing new treatments for RA patients is necessary. It is necessary to do so. [Overview of the project] [Problems that the invention aims to solve]

[0007] Secukinumab, a new biologic currently in clinical development for rheumatoid arthritis (RA), contains interleukin-17 This is a high-affinity, fully human monoclonal anti-human antibody that inhibits A activity. RA Proof of Concept (P In the oC) trial, patients with active RA who were receiving a stable dose of MTX were given Cukinumab administered as a single dose at 1 mg / kg, 3 mg / kg, and 10 mg / kg, followed by two more doses (2 (Administered intravenously with a 1-day interval) (Hueber et al. (2010) Sci. Transl. Med., Vol. 2 (No. 52), 52- (Page 72). Treatment with secukinumab has shown clinical improvement in RA in many patients compared to placebo. This resulted in a rapid improvement in symptoms. These data suggest that neutralization of IL-17A is effective in treating active RA. It provides evidence that it may be effective in RA patients with [specific condition]. However, Patients who respond to biological treatment change, and for patients who show resistance to it, medication is used. Since it is desirable to avoid supplying the substance, the inventors have developed a method to counteract the antagonistic effect of IL-17. We explore ways to treat RA by first identifying patients who are most likely to show a favorable response. The inventors identified IL-17 antagonists as "high-risk RA patients." We identified a subgroup of RA patients who showed improvement in their potential response to the treatment.

[0008] Therefore, one objective of this disclosure is to provide a therapeutically effective amount of IL-17 antagonist, for example For example, an IL-17 binding molecule (for example, an IL-17 antibody or its antigen-binding fragment, for example) , secukinumab) or IL-17 receptor-binding molecules (e.g., IL-17 antibody or so To provide a method for identifying and treating "high-risk RA patients" using antigen-binding fragments. That is the case.

[0009] Another purpose of this disclosure is to determine whether a patient is a high-risk RA patient, RA patients are ill with IL-17 antagonists, for example, IL-17 binding molecules (e.g., IL- 17 antibody or its antigen-binding fragment (e.g., secukinumab) or IL-17 receptor binding Potential response to treatment with sex molecules (e.g., IL-17 antibody or its antigen-binding fragment). The objective is to provide a method for determining sex.

[0010] Another purpose of this disclosure is to provide therapeutically effective doses of IL-17 antagonists, e.g., IL-17 Binding molecules (e.g., IL-17 antibody or its antigen-binding fragment, e.g., secukinumab) ) or IL-17 receptor-binding molecules (e.g., IL-17 antibody or its antigen-binding fragment) ) can be used, for example, as part of the treatment regimen during the introduction and maintenance regimens. By delivering IL-7 antagonists such as AS, R The objective is to provide a method for treating A and PsA. [Means for solving the problem]

[0011] Therefore, what is disclosed herein is how to increase the therapeutically effective amount of IL-17 antagonist This is a method of treating rheumatoid arthritis (RA), which includes a step of administering it to patients at risk of RA. .

[0012] Also disclosed herein is a) treatment based on the fact that the patient is a high-risk RA patient. The steps include: a) selecting patients for the purpose of, and b) administering a therapeutically effective dose of IL-17 antagonist. A method for treating rheumatoid arthritis (RA), comprising the step of administering a drug to a patient.

[0013] This specification discloses a) samples from patients i. rheumatoid factor (RF), anti-citrulline Phosphated protein antibody (ACPA), or RF and ACPA, and ii. C-reactive tan Regarding protein (CRP), erythrocyte sedimentation rate (ESR), or both CRP and ESR, The steps to be performed, and a) after the patient has RF+, ACPA+, or RF+ and ACPA The result is positive, and the patient has high levels of CRP, high ESR, or high levels of both CRP and high ESR. The procedure includes the step of administering an IL-17 antagonist to a patient if the patient has the condition. This is a method for treating rheumatoid arthritis (RA).

[0014] Disclosed herein are a) RF+, ACPA+, or both RF+ and ACPA+ a) high levels of CRP, high ESR, or both high levels of CRP and high ESR Under the condition that patients are selected for treatment purposes based on having the ability to administer a therapeutically effective dose, A step of administering an IL-17 antagonist to a patient for rheumatoid arthritis (RA) This is a method of treatment. In some embodiments, the step of administration is a) IL-1 7) The step of administering an antagonist to the patient during the introduction regimen, and b) thereafter IL-1 The procedure includes the step of administering an antagonist to the patient during the maintenance regimen.

[0015] Disclosed herein is a) an IL-17 antagonist administered at a dose of approximately 10 mg / kg The steps are: administering the drug to high-risk RA patients three times (delivering each of the three doses every other week) and b) Subsequently, administer an IL-17 antagonist at a dose of approximately 75 mg to 150 mg via a third intravenous injection. A step of administering the drug to the patient monthly, starting one month after dose delivery, for rheumatoid arthritis ( This is a method of treating rheumatoid arthritis (RA).

[0016] Disclosed herein is a)i. a patient who has RF+, ACPA+, or RF+ and ACP Both A+ and ii. the patient has high levels of CRP, high ESR, or high CR Step 1: Select patients with RA based on the criterion of having both P and high ESR. b) Administer the IL-17 antagonist to the patient three times at a dose of approximately 10 mg / kg. The first dose is delivered in week zero, the second dose in week two, and the third dose in week four. (To reach) step, and c) then, starting in the 8th week, twice a month, once a month, every two months or 3 Every month, the patient is administered an IL-17 antagonist at a dose of approximately 75 mg to 150 mg. This is a treatment regimen for rheumatoid arthritis (RA), including TEP.

[0017] Disclosed herein are a) rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA), or RF and ACPA, and b) C-reactive protein (CRP), red blood Samples from patients are assayed for either the estrogen saturation rate (ESR) or both CRP and ESR. The procedure includes the step of the patient being RF+, ACPA+, or RF+ and ACPA+, and the patient When a person has high levels of CRP, high ESR, or high levels of both CRP and high ESR, Patients may respond to RA treatment with IL-17 antagonists, RA patients This is a method for determining the likelihood of responding to treatment with an IL-17 antagonist.

[0018] This specification discloses the administration of IL-17 antagonists to high-risk RA patients. IL-17 antagonists, characterized by [specific features], are used to treat rheumatoid arthritis (RA). This specification discloses treatment based on the fact that the patient is a high-risk RA patient. This method is characterized by administering an IL-17 antagonist to patients selected for the purpose of treatment. It is an IL-17 antagonist used to treat rheumatoid arthritis (RA).

[0019] Disclosed herein is an IL-17 antagonist used to treat high-risk RA patients. It is a rheumatoid factor. In some embodiments, high-risk RA patients a) rheumatoid factor ( RF+), serologically positive for anti-citrullinated protein antibody (ACPA+), or R The test is both F+ and ACPA+, and also b) has high levels of C-reactive protein (CRP). They have a high erythrocyte sedimentation rate (ESR) or both high CRP and high ESR. In one embodiment, when measured by hsCRP, a high level of CRP is 10 mg It is 28 mm / hour or more. In some embodiments, the high ESR is 28 mm / hour or more.

[0020] Disclosed herein are a) RF+, ACPA+, or both RF+ and ACPA+ a) high levels of CRP, high ESR, or both high levels of CRP and high ESR Under the condition that patients are selected for treatment purposes based on having the ability to do so, IL-17 A treatment for rheumatoid arthritis (RA) characterized by administering an antagonist to the patient. It is an IL-17 antagonist to be used.

[0021] This specification discloses an IL-17 antagonist at a dose of approximately 10 mg / kg The drug is administered to high-risk RA patients three times (each dose delivered every other week), and then b) thereafter Starting one month after the delivery of the third intravenous dose, a monthly dose of approximately 75 mg to 150 mg. IL- 17. He is an antagonist.

[0022] This specification discloses a) samples from patients i. rheumatoid factor (RF), anti-citrulline Phosphated protein antibody (ACPA), or RF and ACPA, and ii. C-reactive tan Regarding protein (CRP), erythrocyte sedimentation rate (ESR), or both CRP and ESR, b) The patient is RF+, ACPA+, or RF+ and ACPA+, and the patient In cases of high CRP, high ESR, or high CRP and high ESR, IL -17 Treatment of rheumatoid arthritis (RA) characterized by administering an antagonist to the patient. This is the IL-17 antagonist used for that purpose.

[0023] This specification discloses the administration of IL-17 antagonists to high-risk RA patients. IL-17 antagonist for the manufacture of drugs to treat RA, characterized by the following It is for use.

[0024] This specification discloses the use of an IL-17 antagonist during and after the introduction regimen. A drug for treating rheumatoid arthritis, characterized by being administered to high-risk rheumatoid arthritis patients during their ongoing treatment regimen. This involves the use of IL-17 antagonists in the manufacture of the agent.

[0025] Disclosed herein are IL-17 antagonists for administration to high-risk RA patients. This is a pharmaceutical composition for treating rheumatoid arthritis (RA), containing it as an active ingredient.

[0026] This specification discloses high-risk RAs during the introduction regimen and subsequent maintenance regimens. A drug containing an IL-17 antagonist as the active ingredient, to be administered to patients to treat rheumatoid arthritis (RA). It is a pharmaceutical composition.

[0027] Disclosed herein are a) the step of selecting high-risk RA patients, and b) 0, 2 and In the fourth week, the patient is administered an IL-17 antagonist at approximately 10 mg / kg. c) Then, starting in the 8th week, take an IL-17 antagonist once a month, approximately 75 mg to approximately 15 mg. This is a treatment regimen for treating rheumatoid arthritis (RA), which includes the step of administering 0 mg to the patient.

[0028] This specification discloses a) an IL-17 binding molecule in an introduction regimen that requires it When administered to patients, the mean peak plasma concentration of IL-17-binding molecules was approximately 360 μg / ml. C max a) a) a step that brings about IL-17 binding in the patient during the maintenance regimen After administering the molecule, i) the average concentration of IL-17-binding molecules was approximately 8 μg / ml to 30 μg / ml. Steady state trough level and / or ii) approximately 331 mg / day / L to approximately 1323 mg / day / L A step that brings forth the mean AUC-tau at steady state in patients with RA or high risk. This is a method for treating rheumatoid arthritis (RA) patients.

[0029] This specification discloses a) administering an IL-17 binding molecule to a patient during an introduction regimen. The average peak plasma concentration of IL-17-binding molecules was approximately 360 μg / ml (C max ) brings b) Subsequently, during the maintenance regimen, administer to the patient at approximately 8 μg / ml to 30 μg / ii) the mean steady-state trough level of IL-17-binding molecules in ml and / or approximately 331 mg *D / L ~ approximately 1323 mg* provides the mean AUC tau at a steady state of D / L. A characteristic feature is the IL-17 binding molecule used to treat RA patients or high-risk RA patients. That is the case.

[0030] This specification discloses a) an IL-17 binding molecule in an introduction regimen that requires it When administered to patients, the mean peak plasma concentration of IL-17-binding molecules was approximately 401 μg / ml. C max a) a) a step that brings about IL-17 binding in the patient during the maintenance regimen By administering the molecule, i) approximately 9.4 μg / ml to approximately 31 μg / ml of IL-17-binding molecules Average steady-state trough level and / or ii) approximately 314 mg / day / L to approximately 1256 mg / day High-risk RA patients, including a step that yields the mean AUC tau at steady state / L This is a method of treating it.

[0031] This specification discloses a) administering an IL-17 binding molecule to a patient during an introduction regimen. The average peak plasma concentration of IL-17-binding molecules was approximately 401 μg / ml (C max ) brings b) Subsequently, administer to the patient during the maintenance regimen, i) approximately 9.4 μg / ml to approximately 31 μg ii) the mean steady-state trough level of IL-17-binding molecules in g / ml and / or approximately 314 mg* / day / L yields a steady-state mean AUCtau of approximately 1256 mg* / day / L. It is an IL-17 binding molecule used to treat psoriasis, characterized by the following properties.

[0032] In some embodiments, the maintenance regimen ranges from approximately 9.4 μg / ml to approximately 17.3 μg This yields an average steady-state trough level of IL-17-binding molecules per ml. Several implementations In terms of morphology, maintenance is achieved with approximately 9.4 μg / ml or approximately 17.3 μg / ml of IL-17 binding. This results in an average steady-state trough level for the sex molecule. In some embodiments, the introduced resistance The regimen includes bi-weekly intravenous administration of an IL-17-binding molecule. In some embodiments, The maintenance regimen includes monthly subcutaneous administration of an IL-17-binding molecule.

[0033] Disclosed herein are (a) ILs used in the treatment of rheumatoid arthritis (RA) in patients. -17 A pharmaceutical composition comprising an antagonist, and a) a method of administering the pharmaceutical composition to a patient. The patient may receive i) RF+, ACPA+, or RF+ and ACPA + Both and ii) high levels of CRP, high ESR, or high levels of CRP and high This kit is characterized by having both ESR and SR.

[0034] Disclosed herein are a) RF+, ACPA+, or both RF+ and ACPA+ a) high levels of CRP, high ESR, or both high levels of CRP and high ESR Under the condition that patients are selected for treatment purposes based on having the ability to treat RA, It is an IL-17 antagonist used in the preparation of drugs for this purpose.

[0035] Disclosed herein are a) RF+, ACPA+, or both RF+ and ACPA+ a) high levels of CRP, high ESR, or both high levels of CRP and high ESR IL- for the manufacture of drugs for the treatment of RA in patients characterized by having the following characteristics 17 Antagonists, and the drug contains a container, with each container containing at least approximately A sufficient amount to enable the delivery of 75 mg to approximately 150 mg of IL-17 antagonists. It is prescribed to contain an IL-17 antagonist.

[0036] Disclosed herein are a) RF+, ACPA+, or both RF+ and ACPA+ a) high levels of CRP, high ESR, or both high levels of CRP and high ESR IL- for the manufacture of drugs for the treatment of RA in patients characterized by having the following characteristics 17 Antagonists, and the drug contains a container, with each container containing at least approximately It has enough IL-17 antagonist to enable delivery of 10 mg / kg. It is prescribed for sea urchin.

[0037] Disclosed herein are a) RF+, ACPA+, or both RF+ and ACPA+ a) high levels of CRP, high ESR, or both high levels of CRP and high ESR IL- for the manufacture of drugs for the treatment of RA in patients characterized by having the following characteristics It is an antagonist, and the drug can be delivered intravenously at a unit dose of approximately 10 mg / kg. It is prescribed in a dose that is effective.

[0038] Disclosed herein are a) RF+, ACPA+, or both RF+ and ACPA+ a) high levels of CRP, high ESR, or both high levels of CRP and high ESR IL- for the manufacture of drugs for the treatment of RA in patients characterized by having the following characteristics It is an antagonist, and the drug contains approximately 75 mg to 150 mg of IL- per unit dose. It is prescribed in doses that allow for subcutaneous delivery of the 17 antagonist.

[0039] Disclosed herein is i. a patient who is RF+, ACPA+, or RF+ and ACPA+ Both of the above, and ii. the patient has high levels of CRP, high ESR, or high levels of CRP and For the treatment of RA, including a step to determine whether both high ESR and high ESR are present. This is an in vitro trial method for selecting patients. Several of the disclosed in vitro trial methods are... In that embodiment, the patient undergoes the following regimen, namely, a) IL-17 antagonist The drug is administered to the patient three times at a dose of approximately 10 mg / kg, with the first dose given in week zero. The first dose is delivered, the second dose is delivered in the second week, and the third dose is delivered in the fourth week, and a) the Then, starting in the 8th week, twice a month, once a month, every two or three months, IL-17 Antah Improved therapeutic response compared to administering gonists to patients at doses of approximately 75 mg to 150 mg To have a response.

[0040] This specification discloses a) a sample from a patient and i) rheumatoid factor (RF), anti-citrulline Phosphated protein antibody (ACPA), or RF and ACPA, and ii) C-reactive tan Regarding protein (CRP), erythrocyte sedimentation rate (ESR), or both CRP and ESR, b) the steps to be performed and b) the steps to be materialized into information in a form that can communicate the results of step a). This is a method for creating a communicable form of information about patients with rheumatoid arthritis (RA), including a link.

[0041] In this specification, IL-17 antagonists, for example, IL-17 binding molecules (e.g.) If so, an IL-17 antibody or its antigen-binding fragment, for example, secukinumab, or IL-17 Approximately 10 mg of receptor-binding molecules (e.g., IL-17 antibody or its antigen-binding fragment) The induction dose is 3 times at a dose of 150 mg / kg (e.g., IV, induction dose). For example, several times (e.g., 1, 2, 3, 4, or 5 times) with the introductory dose of sc, rheumatoid arthritis (RA), selected from the group consisting of spondyloarthritis, ankylosing spondylitis (spondyloarthritis), and psoriatic arthritis. A treatment for inflammatory arthritis, comprising the step of administering to a patient with selected inflammatory arthritis. Methods are also provided. In some embodiments, the introductory dose is delivered every other week, and then, for example Then, starting one month after delivery of the final introductory dose, an IL-17 antagonist (for example, Secukinumab) is administered in doses of approximately 75 mg to 300 mg (for example, approximately 75 mg to 150 mg, for example) Then, once a month, a maintenance dose of approximately 75 mg or approximately 150 mg (for example, SC maintenance dose) is administered to the patient. Administer to the person(s).

[0042] In this specification, RA patients (e.g., high-risk RA patients) or baseline CRP levels The steps include selecting patients with elevated Bell's score and performing I every other week (e.g., weeks 0, 2, and 4). L-17 antagonists, for example, IL-17 binding molecules (for example, IL-17 antibodies or or its antigen-binding fragment, for example, secukinumab or an IL-17 receptor-binding molecule (for example) Then, administer IL-17 antibody or its antigen-binding fragment) to the patient at approximately 10 mg / kg. For example, via the IV pathway) step, and then once a month (for example, starting in the 8th week) , IL-17 antagonist approximately 75mg to 300mg (for example, approximately 75mg to 15mg Administer to the patient at doses of 0 mg, for example, approximately 75 mg or approximately 150 mg (e.g., via sc). It also provides methods for treating RA, including steps (depending on the route).

[0043] In some embodiments of the disclosed methods, kits, uses, pharmaceutical compositions, and regimens High-risk RA patients: a) Rheumatoid factor (RF+), anti-citrullinated protein antibodies ( For ACPA+, the serological reaction is positive, or both RF+ and ACPA+, and b) High levels of C-reactive protein (CRP), high erythrocyte sedimentation rate (ESR), or high levels It has both CRP and high ESR.

[0044] In some embodiments of the disclosed methods, kits, uses, pharmaceutical compositions, and regimens IL-17 antagonists are IL-17 binding molecules or IL-17 receptor binding molecules. In some embodiments, IL-17 binding molecules or IL-17 receptor binding molecules are used. The sex molecules are a) secukinumab, b) Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128 , an IL-17 antibody that binds to an epitope of IL-17 containing His129, c) Tyr4 3, an IL-17 antibody that binds to an epitope of IL-17 containing Tyr44, Arg46, Ala79, Asp80 , d) an IL-17 antibody that binds to an epitope of an IL-17 homodimer having two mature IL-17 protein chains (the epitope is Leu u74, Tyr85, His86, Met87, Asn88, Val124, Thr12 5, Pro126, Ile127, Val128, His129 on one chain and Tyr4 3, Tyr44, Arg46, Ala79, Asp80 on the other chain), e) an IL-17 antibody that binds to an epitope of an IL-17 homodimer having two mature IL- 17 protein chains (the epitope is Leu74, Tyr85, His86, Met87, [[ID=第十六条]] an IL-17 antibody that binds to an epitope of an IL-17 homodimer having two mature IL-17 protein chains (the epitope is Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128 , His129 on one chain and Tyr43, Tyr44, Arg46, Ala79, As p80 on the other chain, and the IL-17 binding molecule has a K D of about 100 - 200 pM and the IL-17 binding molecule has an in vivo half-life of about 4 weeks), and f) i) an immunoglobulin heavy chain variable domain (V ) containing the amino acid sequence shown as SEQ ID NO: 8, ii) an immunoglobulin light chain variable domain (V H ) containing the amino acid sequence shown as SEQ ID NO: 1 0, iii L ), an immunoglobulin V domain containing the amino acid sequence shown as SEQ ID NO: 8 and an immunoglobulin V H domain containing the amino acid sequence shown as SEQ ID NO: 10, iv) SEQ ID NO: an immunoglobulin V L domain containing the amino acid sequence shown as SEQ ID NO: 8 and an immunoglobulin V 1. Immunoglobulin V containing the hypervariable region shown as SEQ ID NO: 2 and SEQ ID NO: 3 H Dome In, v) Immunotherapy including the hypervariable region shown as SEQ ID NOs: 4, 5, and 6 Globulin V L Domain, vi) shown as Sequence ID 11, Sequence ID 12 and Sequence ID 13 Immunoglobulin V containing the hypervariable region H Domain, vii) Sequence ID 1, Sequence ID 2 and immunoglobulin V including the hypervariable region shown as SEQ ID NO: 3 H Domain and sequence Immunoglobulin V containing the hypervariable region, indicated as number 4, SEQ ID NO: 5, and SEQ ID NO: 6. L The domain, and viiii) shown as Sequence ID No. 11, Sequence ID No. 12 and Sequence ID No. 13 Immunoglobulin V containing a hypervariable region H Domain and sequence numbers 4, 5 and sequence Immunoglobulin V containing the hypervariable region indicated as number 6 L Select from a group of domains These are IL-17-binding molecules (for example, IL-17 antibodies).

[0045] In preferred embodiments of the disclosed methods, kits, uses, pharmaceutical compositions and regimens, The IL-17 binding molecule is a human antibody. Disclosed methods, kits, uses, pharmaceutical compositions and In a more preferred embodiment of the regimen, the IL-17 binding molecule is secukinumab. be. [Brief explanation of the drawing]

[0046] [Figure 1] This diagram shows the test design for the CAIN457F2201 test. [Figure 2A]This figure shows the ACR20 response using the length-of-care follow-up (LOCF) method for each treatment method up to week 16 in the CAIN457F2201 trial in the largest analysis group (FAS). [Figure 2B] This figure shows the ACR20 response (LOCF) by treatment method up to week 16 in high-risk RA patients. [Figure 2C] This figure shows the time progression of ACR20 responses up to week 52 in responders (R) and non-responders (NR) in FAS. [Figure 3A] This figure shows the ACR50 response (LOCF) by treatment method up to week 16 in the largest analysis group (FAS) of the CAIN457F2201 trial. [Figure 3B] This figure shows the time progression of ACR50 responses up to week 52 in responders (R) and non-responders (NR) in FAS. [Figure 4A] This figure shows the ACR70 response (LOCF) by treatment method up to week 16 in the largest analysis group (FAS) of the CAIN457F2201 trial. [Figure 4B] This figure shows the time progression of ACR70 responses up to week 52 in responders (R) and non-responders (NR) in FAS. [Figure 5A] This figure shows the change from baseline (LOCF) of DAS28-CRP by treatment method up to week 16 in the CAIN457F2201 FAS trial. [Figure 5B] This figure shows the time progression of DAS28-CRP response up to week 52, separated into responders (R) and non-responders (NR) in the FAS study. [Figure 6A] This figure shows the change from baseline (LOCF) in HAQ(C) scores by treatment method up to week 16 in the CAIN457F2201 FAS trial. [Figure 6B] This figure shows the time progression of HAQ(C) responses up to week 52 in responders (R) and non-responders (NR) in the FAS. [Figure 7]This figure shows the ACR20 / 50 / 70 responses at week 52, separated into responders (R) and non-responders (NR) in the FAS. [Figure 8A] This figure shows the ACR 20 / 50 / 70% response rate at week 16 in high-risk and non-high-risk RA patients. [Figure 8B] This figure shows the DAS28-CRP response at week 16 in high-risk and non-high-risk RA patients. [Figure 9] This figure shows the ACR20 response rate and CRP baseline levels by dose group in the CAIN457F2201 trial. The columns, from left to right, represent all patients, patients with a CRP baseline of over 10 mg / L, over 20 mg / L, and over 30 mg / L, respectively. [Figure 10] This figure shows a simulation of the pharmacokinetics (PK) of secukinumab in patients with rheumatoid arthritis. The solid line shows the PK without an induction strategy (single dose of 300 mg sc at week 0), the dotted line shows the PK with a subcutaneous induction strategy (300 mg sc at weeks 0, 1, 2, 3, and 4), and the dashed line shows the PK with an intravenous induction strategy (10 mg / kg iv at weeks 0, 2, and 4). Each of the three options is followed by a maintenance dose of 300 mg sc every four weeks. [Figure 11] This figure shows the ASAS20 response rate (%). [Modes for carrying out the invention]

[0047] The 1987 American College of Rheumatology (ACR) RA classification criteria are for patients with long-term rheumatoid arthritis. These criteria distinguish individuals with and without other confirmed rheumatic diagnoses. It was not useful in identifying patients with early-stage rheumatoid arthritis who could benefit from the treatment. 201 In 0 years, ACR is associated with the earlier stages of disease related to persistent and / or erosive disease. A new classification system focusing on the characteristics of A (hereafter referred to as the "2010 ACR / EULAR standard") ) established (Aletaha et al. (2010) Ann. Rheum. Dis., Vol. 69, pp. 1580-1588). 2010 A The CR / EULAR classification system focuses on six criteria, the first two of which are... The standard specifies who should be tested for RA, but the remaining four criteria determine the score. It is something to be marked (Table 1). A score of 6 or higher indicates a clear RA.

[0048] [Table 1]

[0049] R for IL-17 binding molecules, e.g., IL-17 antibody therapy such as secukinumab In exploring indicators that may precede a patient's response, the inventors identified four 2010 AC We analyzed two R / EULAR scoring criteria and found that these criteria are related to IL-17 binding molecules. For example, we determined whether it affected the response to treatment with secukinumab, etc. 1. The inventors analyzed the patient's serological test results and found that the patient was RF+ and / or ACPA+. They determined whether or not it was present. Secondly, the inventors analyzed the presence of acute-phase reactive substances and the patient It has high levels of C-reactive protein (CRP) and / or high erythrocyte sedimentation rate (ESR). They determined whether to do so or not. In that process, the inventors determined 1) RF+ or ACPA+( Patients who are (or both) and 2) have high levels of CRP or ESR (or both) Good treatment with IL-17 binding molecules, such as IL-17 antibodies like secukinumab. We found that such patients (referred to as "high risk") are more likely to have a reaction. A patient referred to as a "RA patient" is a patient who exhibits the most prominent characteristics of RA (for example, Yildirim (See et al. (2004) Annals Clin. Lab. Sci, Vol. 34, p. 423). Therefore, the disclosure herein This involves administering a therapeutically effective amount of IL-17-binding molecules to high-risk RA patients. This includes methods for treating rheumatoid arthritis (RA).

[0050] The inventors also found that an increase in baseline CRP levels (e.g., >10 mg / L) is also a symptom of septic encephalopathy. Further confirmation was made that this is related to responsiveness to kinumab. Therefore, as disclosed herein This is because a therapeutically effective amount of IL-17 binding molecules is required to raise baseline CRP levels (for example). (greater than approximately 10 mg / L, greater than approximately 20 mg / L, greater than approximately 30 mg / L) A method for treating rheumatoid arthritis (RA), which includes a step of administering to RA patients who exhibit the following symptoms. .

[0051] The inventors believe that a treatment regimen useful for treating high-risk RA patients is not high-risk. Patients with rheumatoid arthritis and other inflammatory arthritis, such as ankylosing spondylitis (AS) or psoriatic arthritis. Further discoveries were made that it is even more useful in treating patients with PsA (PsA). Therefore, this specification discloses the therapeutically effective amount of IL-17-binding molecule for inflammatory arthritis. A step comprising administering to a patient having inflammatory arthritis (e.g., RA, AS, PsA) This is a regimen of administration and treatment to address [the condition].

[0052] The term "comprising" is the same as "including" and "consisting of". "Includes X, for example, a composition "comprising X" is even if it consists solely of X. It may contain either or other things (for example, X + Y).

[0053] The term "approximately" in relation to the number x means + / - 10% unless otherwise specified in the context. The term "approximately" refers to pharmacokinetic (PK) parameters (e.g., AUC, C). max , t max When used in relation to trough levels, etc., a person skilled in the art can determine if it is biologically equivalent to the reference treatment. This indicates the assumed treatment method (e.g., dosage and / or administration regimen). Therefore, a standard method for demonstrating bioequivalence is two treatments (i.e., a reference treatment). A predetermined PK parameter (e.g., AUC, C) between the experimental treatment and the experimental treatment method. max The ratio of the ratio The surrounding 90% confidence interval (CI) (the lower limit of this CI is greater than 0.8, and the upper limit of this CI is greater than 1) To statistically prove that the value is between 0.8 and 1.25 (i.e., less than 0.25). Therefore, for example, comparing the PK profiles of a reference treatment and an investigational treatment. During the experiment, a 10 μg / ml reference C was used. max If obtainable, a person skilled in the art can biologically determine the experimental treatment method. If considered equivalent, the test treatment is considered to be "approximately 10 μg / ml". As used in pharmacokinetic terminology, for example, t max t 1 / 2 , AUC, AUC (0-tau) (AUC until the end of the prescribed administration period, hereafter referred to as "AUC tau"), C max Those techniques It has meaning that is accepted in the field of technology.

[0054] The term "administer" in relation to compounds, for example, IL-17 binding molecules or anti-rheumatic drugs. The term is used to refer to the delivery of the compound via any route.

[0055] The terms "active rheumatoid arthritis" or "active RA" refer to visible signs and symptoms (for example) It is used to refer to rheumatoid arthritis (RA) accompanied by swelling, difficulty bending, etc.

[0056] The term "assay" means to detect, identify, screen, or measure It is used to refer to the act of doing something, and that act can be carried out by any conventional means. For example, the sample is used in an ELISA to detect whether a marker is present in the sample. By using assays, Northern blotting, imaging, etc., the presence of specific markers can be detected. It can be used for assays.

[0057] The word "substantially" does not exclude "completely." For example, "substantially does not include Y." The composition may not contain Y at all. Where necessary, the word “substantially” may be used. This may be excluded from the definitions in this disclosure.

[0058] As used herein, "mg / kg" refers to the amount of the drug administered to a patient in 1 kg of body weight. This refers to the amount of drug in milligrams (mg) per dose.

[0059] "IL-17 Antagonist" is used in this specification to describe the function of IL-17, Antagonizing expression and / or signaling (e.g., reducing, inhibiting, lowering, blocking) It is possible to stop or delay the binding of IL-17 to the IL-17 receptor (for example, the binding of IL-17 to the IL-17 receptor). It refers to a molecule (by blocking it). An unspecified example of an IL-17 antagonist is: Examples include IL-17 binding molecules and IL-17 receptor binding molecules. Disclosed methods, registration In some embodiments of the men, kits, processes, uses, and compositions, IL-17 Antah Use a gonist.

[0060] "IL-17 binding molecules" are molecules that bind to IL-17 alone or in association with other molecules. This refers to molecules that can bind to the IL-17 antigen. The binding reaction is independent of specificity. However, refer to a negative control test using the same isotype antibody, for example, an anti-CD25 antibody. For example, a binding assay to measure the inhibition of IL-17 binding to its receptor, competition Standard methods such as assays or bioassays (qualitative assays) or any type This can be demonstrated by binding assays. Non-limiting examples of IL-17 binding molecules include , small molecules, IL-17 receptor decoys, and anti- Body and chimeras, CDR grafts or human antibodies or their fragments, e.g., F(ab')2 These include Fab fragments, as well as single-chain or single-domain antibodies. Preferably, IL-17 antibodies. The compound molecule antagonizes the function, expression, and / or signaling of IL-17 (e.g., reduces it). (to do, inhibit, reduce, delay). Disclosed methods, regimens, kits, processes, In some embodiments of use and composition, IL-17 binding molecules are used.

[0061] An "IL-17 receptor-binding molecule" is a molecule that binds to the human IL-17 receptor, either alone or in association with other molecules. This refers to molecules that can bind to a substance. Binding reactions are independent of specificity, but... Refer to a negative control test using a diisotype antibody, for example, an anti-CD25 antibody, for example, I Binding assay for measuring inhibition of L-17 receptor binding to IL-17, competitive assay (i) Standard methods such as bioassays (qualitative assays) or any type of binding This can be demonstrated by assays. Non-limiting examples of IL-17 receptor-binding molecules include , small molecules, IL-17 decoy, and IL-1 produced by B cells or hybridomas 7. Antibodies and chimeric forms of receptors, CDR grafts, or human antibodies or fragments thereof, for example These include F(ab')2 and Fab fragments, as well as single-chain or single-domain antibodies. Furthermore, IL-17 receptor-binding molecules affect the function, expression, and / or signaling of IL-17. To counteract (e.g., reduce, inhibit, decrease, delay). Disclosed method, In some embodiments of regimens, kits, processes, uses, and compositions, IL-17 Use a solution-binding molecule.

[0062] The term "antibody" as used herein refers to the entire antibody and its antigen-binding portion or Includes single chains. Naturally occurring "antibodies" are a small number of molecules linked together by disulfide bonds. It is a glycoprotein containing at least two heavy (H) chains and two light (L) chains. Each heavy chain is heavy Chain variable region (V in this specification) H It consists of a heavy chain constant region (abbreviated as ) and a heavy chain constant region. The heavy chain constant region consists of three domains CH1, CH2, and CH3. It consists of a light chain variable region (abbreviated as VL in this specification) and a light chain constant region. The light chain constant region consists of one domain CL. H and V L The area is, It is scattered by more conservative areas called framework areas (FRs). It can be further subdivided into a highly variable region called the complementarity determination region (CDR). . Each V H and V L It consists of three C atoms arranged from the amino terminus to the carboxyl terminus in the following order. It consists of DR and four FRs: FR1, CDR1, FR2, CDR2, FR3 , CDR3, FR4. Variable regions of the heavy and light chains contain binding domains that interact with the antigen. The constant region of antibodies is located in various cells of the immune system (e.g., effector cells) and classical complement. It can mediate the binding of immunoglobulins to host tissues or factors containing the first component (C1q) of the system. In some embodiments of the disclosed methods, regimens, kits, processes, uses, and compositions Then, an antibody against IL-17 or the IL-17 receptor is used.

[0063] The term "antigen-binding site" of an antibody, as used herein, refers to the antigen (e.g., I This refers to a fragment of an antibody that retains the ability to specifically bind to L-17. It has been shown that this function can be achieved by fragments of full-length antibodies. The antibody's "antigen-binding site" Examples of combined fragments included in a term include V L , V H , a monovalent valent CL and CH1 domain The Fab fragment is a fragment, and the two are connected by disulfide bridges in the hinge region. The F(ab)2 fragment is a divalent fragment containing the Fab fragment, V H and consists of CH1 domain Fd fragment, V of one arm of the antibody L and V H Fv fragments consisting of domains, V H From the domain dAb fragment (Ward et al., 1989 Nature Vol. 341, pp. 544-546) and isolated complementarity-determining region (C Examples include DR). Specific examples of antigen-binding sites include SEQ ID NOs: 1-6 and 11-13 (Table). 4) The CDR of secukinumab, preferably the heavy chain CDR3, etc. , two domains V of the Fv fragment L and V H These are encoded by separate genes, but V Land V H A single protein chain (single-chain Fv) is a monovalent molecule formed by a pair of regions. (scFv) is publicly known, for example, Bird et al., 1988 Science Vol. 242, pp. 423-426, and (See Huston et al., 1988 Proc. Natl. Acad. Sci. Vol. 85, pp. 5879-5883) Such a synthetic linker can be used to link them by recombination. Single-chain antibodies shall also be included in the term "antibody." Single-chain antibodies and antigen-binding sites are defined by those skilled in the art. This can be obtained using known prior art. Disclosed methods, regimens, kits, processes, uses and In some embodiments of the composition, IL-17 (e.g., secukinumab) or IL- A single-chain antibody or the antigen-binding portion of an antibody is used against receptor 17.

[0064] The term "pharmaceutically acceptable" refers to the biological activity of the active ingredient(s)(s). This refers to non-toxic substances that do not interfere with the effectiveness of the substance.

[0065] "Isolated antibody" is, as used herein, an isolated antibody that has different antigen specificity from other antibodies. This refers to antibodies that do not contain IL (for example, isolated antibodies that specifically bind to IL-17 are IL (Substantially contains no antibodies that specifically bind to antigens other than -17). Isolated antibodies can be used with other cells. It does not have to substantially contain substances and / or chemical substances. However, it does not have to be specifically IL-17. "Binding" isolated antibodies may cross-react with other antigens, such as IL-17 molecules from other species. In some embodiments of the disclosed methods, regimens, kits, processes, uses, and compositions Therefore, the IL-17 antagonist is an isolated antibody.

[0066] The terms "monoclonal antibody" or "monoclonal antibody composition" are defined herein as follows: As used, it refers to a formulation of an antibody molecule with a single molecular composition. Monoclonal antibody composition The disclosed methods and regimens exhibit single-binding specificity and affinity for specific epitopes. In some embodiments of the kit, process, use, and composition, IL-17 antagonist Sto is a monoclonal antibody.

[0067] The term "human antibody" is used as it is used herein in the Framework and CDR. The antibody shall contain a variable region in which both regions are derived from human sequences. If the antibody contains a constant region, the constant region is also considered by Knappik et al. (2000 J Mol Biol Vol. 296, 57-86) Human sequences as described on page (page), for example, human germline sequences or human germline sequences Consensus framework obtained from sequence variants or human framework sequence analysis Derived from antibodies containing the sequence. "Human antibodies" are produced by humans, human tissues, or human cells. It is not necessary. The human antibodies of this disclosure contain amino acid residues not encoded by human sequences. This may include (for example, by random or site-directed mutagenesis in vitro or (Mutations introduced in vivo by somatic mutation). However, the term "human antibody" is used... The term, as used herein, refers to CDs derived from the germline of other mammalian species such as mice. This does not include antibodies in which the R sequence is grafted onto a human framework sequence. In some embodiments of the methods, regimens, kits, processes, uses, and compositions, IL- 17. Antagonists are human antibodies.

[0068] The term "IL-17" refers to IL-17A, which was previously known as CTLA8. Furthermore, wild-type IL-17A and IL-17A in various species (e.g., humans, mice, and monkeys) This disclosure includes polymorphic variants and functional equivalents of IL-17A. The equivalent is preferably at least one equivalent to wild-type IL-17A (e.g., human IL-17A). Approximately 65%, 75%, 85%, 95%, 96%, 97%, 98%, or even 99% of the total distribution It possesses serial identity and substantially retains the ability to induce IL-6 production by human dermal fibroblasts. I have it.

[0069] "K D The term "K" is d and K a The ratio to (i.e., K d / K a ) obtained from, molar concentration (M) refers to the dissociation constant. K of the antibody D The value is sufficient in this field. It can be determined using established methods. The K of the antibody D The method for measuring is shown in the table. Biosensors that use surface plasmon resonance or the Biacore® system -By using the system. In some embodiments of the present invention, IL-17 Tagonists, for example, IL-17 binding molecules (e.g., IL-17 antibodies or their antigens) A binding fragment (e.g., secukinumab) or an IL-17 receptor-binding molecule (e.g., IL-1 7. Antibodies or their antigen-binding fragments) contain approximately 100-250 pM K D And human IL-17 Combine.

[0070] As used herein, the term "affinity" refers to the relationship between an antibody and a single antigen site. Refers to the strength of the interaction with an antigen. Within each antigenic site, the variable regions of the "arms" of the antibody interact with the antigen at multiple sites via weak non-covalent forces. The greater the interaction, the stronger the parental affinity. For example, standard assays for evaluating the binding affinity of antibodies against various species of IL -17, such as ELISA, Western blot, and RIA, are known in the art and are available. The antibody kinetics (e.g., binding affinity) can also be evaluated by standard assays known in the art such as Biacore analysis . Assays for evaluating the effect of antibodies on the functional characteristics of IL-17 (e.g., receptor binding, preventing or ameliorating osteolysis) will be described in more detail in the Examples .

[0071] As used herein, the terms "subject" and "patient" include humans or non-human animals. The term "non-human animal" includes all vertebrates, e.g., mammals such as non-human primates, sheep, dogs, cats, horses, cows, chickens, as well as amphibians, reptiles, etc., and non-mammals.

[0072] An antibody that "inhibits" one or more of the IL-17 functional characteristics (e.g biochemical, immunochemical, cellular, physiological, or other biological activities or the like) measured by methods known in the art and described herein is understood to be related to a statistically significant decrease in a particular activity compared to that observed when the antibody is absent (or when a control antibody of irrelevant specificity is present). An antibody that inhibits IL-17 activity causes a statistically significant decrease in a measurement parameter, e.g at least 10%, at least 50%, 80%, or 90%, and in certain embodiments, the antibodies of the present disclosure inhibit 95%, 9 of the IL-17 functional activity. ​ It can inhibit 8% or 99% or more.

[0073] The term "derivative" refers to IL-17 antagonists, for example, this one, unless otherwise specified. Disclosure of IL-17-binding molecules (e.g., IL-17 antibodies or their antigen-binding fragments) For example, secukinumab) or an IL-17 receptor-binding molecule (for example, an IL-17 antibody or (or its antigen-binding fragment), for example, amino acid sequence variants and covalent modifications of the specified sequence Used for definition. "Functional derivative" refers to the disclosed IL-17 antagonist. For example, IL-17 binding molecules (e.g., IL-17 antibodies or their antigen-binding fragments, e.g.) For example, secukinumab) or an IL-17 receptor-binding molecule (for example, an IL-17 antibody or It contains molecules that have the same qualitative biological activity as its antigen-binding fragment. Functional derivatives are This includes fragments and peptide analogs of IL-17 antagonists disclosed herein. This includes a polypeptide according to the present disclosure, for example, a region within the sequence of a specified sequence. The functional derivatives of the disclosed IL-17 antagonist are preferably those disclosed herein. V of L-17 binding molecules H and / or V L Array (for example, V in Table 4) H and / or V L (array) and At least approximately 65%, 75%, 85%, 95%, 96%, 97%, 98% or more V has 99% overall sequence identity. H and / or V L Domains including or disclosed herein At least approximately 65% ​​of IL-17 antagonists (e.g., secukinumab) have a CDR. All sequences are identical at 75%, 85%, 95%, 96%, 97%, 98%, or even 99%. Contains a CDR with a specific property (a difference of 1, 2, or 3 amino acids from the CDR shown in Table 4), and human IL -17 binding, or, for example, IL-6 production in IL-17-inducible human dermal fibroblasts It essentially possesses the ability to inhibit life.

[0074] "Inhibiting IL-6" as used herein refers to primary human dermal fibroblasts or IL-17 antagonists (e.g., secukinumab) reduce the production of IL-6. This refers to the ability to produce IL-6. IL-6 production in primary human (skin) fibroblasts is dependent on IL-17. (Hwang SY et al., (2004) Arthritis Res Ther, Vol. 6, R120-128). In short, human skin Skin fibroblasts contain human IL-17 with various concentrations of IL-17-binding molecules or Fc moieties. Stimulated by recombinant IL-17 in the presence of the receptor. Chimeric anti-CD25 antibody Simul ect® (basiliximab) can be conveniently used as a negative control. After 16 hours of stimulation, the supernatant is collected and assayed for IL-6 by ELISA. IL-17 antagonists, for example, IL-17 binding molecules disclosed herein (e.g., , IL-17 antibody or its antigen-binding fragment (e.g., secukinumab) or IL-17 receptor Electrolyte-binding molecules (e.g., IL-17 antibodies or their antigen-binding fragments) are as described above. When tested, that is, when induced by hu-IL-17 in human dermal fibroblasts When the inhibitory activity on IL-6 production was measured, it was approximately 50 nM or less (for example, approximately 0 Inhibition of IL-6 production (from 0.01 to approximately 50 nM) (in the presence of 1 nM human IL-17) IC related to 50 Generally, it has the following: Disclosed methods, regimens, kits, processes, uses and combinations. In some embodiments of the composition, an IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof) and its functional derivatives have an IC for inhibition of IL-6 production 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. 50

[0075] The term "covalent modification" includes modification of a polypeptide according to the present disclosure by an organic proteinaceous or non-proteinaceous derivatizing agent, e.g., of a specified sequence, or a fragment thereof, fusion to a heterologous polypeptide sequence, and post-translational modification. For example, a covalently modified polypeptide of a specified sequence still has the ability to bind to human IL-17 or, e.g., inhibit the production of IL-6 in IL-17-induced human skin fibroblasts by crosslinking. Covalent modification is traditionally introduced by reacting a target amino acid residue with an organic derivatizing agent capable of reacting with a selected side or terminal residue, or by utilizing the mechanism of post-translational modification that functions in a selected recombinant host cell. Certain post-translational modifications are the result of the action of a recombinant host cell on an expressed polypeptide. Glutaminyl and asparaginyl residues are often deamidated to the corresponding glutamyl and aspartyl residues by post-translational modification. Alternatively, these residues are deamidated under weakly acidic conditions. Other post-translational modifications include hydroxylation of proline and lysine, and hydroxylation of serine, tyrosine or threonine by reacting the target amino acid residue with an organic derivatizing agent capable of reacting with a selected side or terminal residue, or by utilizing the mechanism of post-translational modification that functions in a selected recombinant host cell. Certain post-translational modifications are the result of the action of a recombinant host cell on an expressed polypeptide. Glutaminyl and asparaginyl residues are often deamidated to the corresponding glutamyl and aspartyl residues by post-translational modification. Alternatively, these residues are deamidated under weakly acidic conditions. Other post-translational modifications are the result of the action of a recombinant host cell on an expressed polypeptide. Glutaminyl and asparaginyl residues are often deamidated to the corresponding glutamyl and aspartyl residues by post-translational modification. Alternatively, these residues are deamidated under weakly acidic conditions. Other post-translational modifications include hydroxylation of proline and lysine, hydroxylation of serine, tyrosine or threonine, and so on. and so on.Phosphorylation of the hydroxyl group of the residue, α-amine of the side chains of lysine, arginine and histidine Examples include methylation of the 'n' group. For example, TE Creighton, Proteins: Structure and Molec See *Urular Properties*, WH Freeman & Co., San Francisco, pp. 79–86 (1983). Covalent modifications, for example, involve the modification of a specified sequence as well as immunoadhesins and heterologous signal sequences. This disclosure provides fusion molecules including polypeptides, such as N-terminal fusions, resulting from the present disclosure of these amino acid sequence variants. These include protein, etc.

[0076] The phrase "substantially identical" refers to the related amino acid or nucleotide sequence (e.g., C DR (singular or plural), V H or V L Is the domain the same as a specific reference sequence? Or it means having a minute difference (for example, due to conservative amino acid substitution). Minor difference This involves slight amino acid changes, such as one or two substitutions, in the five-amino acid sequence of a specified region. Includes. In the case of antibodies, the substituted antibody has the same specificity and at least the same affinity for the same substance. It also has 50%. Substantially the same as the sequences disclosed herein (e.g., at least about 85%). The sequence identity of % is also part of this application. In some embodiments, the sequence identity This is approximately 90% or greater, for example, 90%, 91%, 92%, 93%, 94%, It may be 95%, 96%, 97%, 98%, 99%, or higher.

[0077] The "identity" of natural polypeptides and their functional derivatives is, in this specification, To align the array and achieve the maximum percentage of identity, gaps are introduced where necessary. After input, without considering conservative substitutions as part of sequence identity, the corresponding natural polypeptide Defined as the percentage of amino acid residues in a candidate sequence that is identical to the residue of [the specified residue]. N or C-terminal extension Neither lengthening nor insertion shall be interpreted as reducing identity. Alignment method and computer program The program is well known. The percentage of identity is determined by a standard sorting algorithm, e.g., Al Basic Lo described by tshul et al. ((1990) J. Mol. Biol., Vol. 215, pp. 403-410) Cal Alignment Search Tool (BLAST), Needleman et al. Algorithm ((1970) J. Mol. Biol., Vol. 48, pp. 444-453) or Meyers et al.'s algorithm This can be determined by ((1988) Comput. Appl. Biosci., Vol. 4, pp. 11-17). One set of P Lameter has a gap penalty of 12, a gap extension penalty of 4, and a frame shift penalty. Even with a Blosum 62 scoring matrix that has a cap penalty of 5, Good. The percentage of identity between two amino acid or nucleotide sequences is PAM120. AL using a weighted residue table, 12 gap length penalties, and 4 gap penalties The IGN program (version 2.0) incorporates the work of E. Meyers and W. Miller. It can also be determined using rugolism ((1989) CABIOS, Vol. 4, pp. 11-17).

[0078] "Amino acids (singular or plural)" refers to all naturally occurring L-α-amino acids. It also contains, for example, D-amino acids. Amino acids are identified by well-known one- or three-letter designations. It will be done.

[0079] The term "amino acid sequence variant" refers to those amino acids compared to the sequence described herein. This refers to molecules with slight differences in sequence. For example, the polypeptide according to this disclosure with a specified sequence Amino acid sequence variants bind to human IL-17, or, for example, IL-17-inducible hemoglobin. It still retains the ability to inhibit IL-6 production by cutaneous fibroblasts. The substitution mutant, At least one amino acid residue is removed, for example, the polypeptide of the specified sequence according to this disclosure It has different amino acids inserted at the same position in the cydose. These substitutions may be single, involving the substitution of only one amino acid within the molecule, or These may be multiple molecules in which two or more amino acids are substituted within the same molecule. The variant is, for example, at a specific position in the polypeptide of the specified sequence according to this disclosure. It has one or more amino acids inserted directly adjacent to an amino acid. Directly adjacent to an acid means bonded to an α-carboxyl group or an α-amino functional group of an amino acid. The deletion mutant is removed, for example, from the polypeptide of the specified sequence according to this disclosure. It is a molecule that has one or more amino acids. Typically, deletion mutants have a specific region of the molecule. It has one or two missing amino acids in the region.

[0080] As used herein, “therapeutic effective dose” means the amount used to treat a disorder or recurrent disorder. To treat, prevent, prevent the onset of, heal, delay the onset of, reduce the severity of To improve at least one of its symptoms, or to treat if such treatment is not given. The target (human patients) is a subject whose purpose is to extend the survival period beyond the expected survival period. IL-17 antagonists that are effective with single or repeated administration to (etc.), for example, IL -17 binding molecules (e.g., IL-17 antibody or its antigen-binding fragment, e.g., secchus keratin) Numab) or IL-17 receptor-binding molecules (e.g., IL-17 antibody or its antigen-binding molecule) This refers to the amount of the combined fragment. It also refers to the amount of the individual active ingredient administered alone (e.g., IL-17 antagonist). For example, IL-17 binding molecules (for example, IL-17 antibodies or their antigen-binding fragments) For example, secukinumab) or IL-17 receptor-binding molecules (for example, IL-17 antibody) When applied to (or its antigen-binding fragment), this term applies only to this component. When applied to a drug, this term refers to whether the drug was administered consecutively or simultaneously as a combination drug. It remains the same; it refers to the total amount of active ingredients that produce a therapeutic effect.

[0081] The terms "treatment" or "to treat" include preventive treatment or therapy and risk of morbidity. Patients who have or are suspected of having the disease, and patients who are diagnosed with the disease or have a medical condition. This refers to both curative or disease-modifying therapies, including treatment of patients who have undergone treatment, and includes suppression of clinical relapse. To prevent, treat, delay the onset of, or reduce the severity of a disorder or recurrent disorder. To improve one or more of these symptoms, or if such treatment is not available. To extend the lifespan of the subject beyond the expected lifespan, treatment is necessary to address medical impairments. This can be done for subjects who have or are likely to eventually suffer from a disability.

[0082] As used herein, the term "inflammatory arthritis" refers to a condition related to the immune system and inflammation. This refers to various conditions affecting the joints, including autoimmune disorders such as rheumatoid arthritis. (Not limited to specific conditions.) Examples include seronegative spinal cord conditions such as AS, Reiter's syndrome, PsA, and enterovascular arthritis. Arthritis and other arthritis such as RA, juvenile rheumatoid arthritis and systemic rheumatoid arthritis, crystals Arthritis (gout, pseudogout, apatite gout), polymyalgia rheumatica, amyloid arthritis Pigmented villonodular synovitis, synovial osteochondromatosis, hemophilic arthritis, and reactive synovitis are among the conditions that can be treated. In some embodiments of the disclosed methods, regimens, uses, kits, and pharmaceutical compositions... The patient has inflammatory arthritis.

[0083] As used herein, the terms "ankylosing spondylitis," "AS," and "spondyloarthritis" are used. The term refers to the final fusion of the vertebrae, the joints that may include the sacroiliac bones within the pelvis and the spine. This refers to inflammatory arthritis characterized by chronic inflammation that can lead to [unspecified condition]. (Revised version of AS) Using the New York criteria or the ASAS axial SPA criteria (2009), patients are classified as having AS. It can be diagnosed as such. In several embodiments, the patient has AS.

[0084] As used herein, the terms “psoriatic arthritis” and “PsA” refer to skin conditions. It refers to inflammatory arthritis often accompanied by psoriasis. Various criteria exist, e.g., Moll and Wri ght criteria, revised ESSG criteria, McGonagle criteria, classification criteria for psoriatic arthritis (C Using ASPAR criteria, etc., it is possible to diagnose a patient as having PsA. In some embodiments of the methods, regimens, uses, kits, and pharmaceutical compositions, the patient It has PsA.

[0085] As used herein, “rheumatoid arthritis” or “RA” refers to a disease affecting many tissues and organs. It can affect other joints, but primarily refers to chronic systemic inflammatory arthritis that attacks the synovial joints. 20 Using the 10-year ACR / EULAR criteria, a patient can be diagnosed with rheumatoid arthritis (RA). In some embodiments of the disclosed methods, regimens, uses, kits, and pharmaceutical compositions, The patient has rheumatoid arthritis (RA).

[0086] As used herein, the phrase "2010 ACR / EULAR standards" means Aletaha et al. (2010) Ann. Rheum. Dis., Vol. 69, pp. 1580-1588, where RA's 2010 This refers to the American College of Rheumatology / European League for Rheumatism classification criteria. Patients with rheumatoid arthritis The criteria used for classification are shown in Table 1.

[0087] As used herein, "C-reactive protein" and "CRP" are used in relation to inflammation. Serum C-reactive protein, a plasma protein commonly used as an indicator of acute phase reactions, is a plasma protein. It means protein. The level of CRP in plasma is any concentration, e.g., mg / dl, n It can be expressed in mol / L. The level of CRP can be measured by various well-known methods, such as radiation immunity. diffusion method, electrical immunoassay, immunoturbidimetry, ELISA, turbidimetry, fluorescence polarization immunoassay and It can be measured by laser turbidimetric analysis. CRP testing is performed using the standard CRP test or This is a high-sensitivity CRP (hs-CRP) test (i.e., a laser turbidimetric analysis method used to analyze the CRP in a sample). A highly sensitive test (which can measure low levels of CRP) can be used. Kits for detecting levels are available from various companies, such as Calbiotech, Inc. , Cayman Chemical, Roche Diagnostics Corp. ration, Abazyme, DADE Behring, Abnova Corpo ration, Aniara Corporation, Bio-Quant Inc. Purchase from Siemens Healthcare Diagnostics, etc. It is possible.

[0088] As used herein, “high levels of CRP” is defined in the 2010 ACR / EULA. As defined in the R criteria (Aletaha et al. (2010) Ann. Rheum. Dis., Vol. 69, pp. 1580-88) This means that the CRP level is above normal. According to the 2010 ACR / EULAR criteria. Normal / abnormal CRP levels are based on local laboratory standards. Each local laboratory uses the standard for normal levels. To calculate high CRP levels, we use the cutoff value for abnormal (high) CRP levels based on our laboratory's rules. Yes. Doctors generally order a CRP test performed by a local laboratory, and the local laboratory will determine if the CRP level is normal. Calculating P using the rules used by each laboratory, normal or abnormal (low or high) C Report RP. Therefore, unless otherwise indicated by the context, consider it a normal CRP value. Since the results vary between laboratories and assays, as used herein, "high level" The term "CRP" does not mean a specific numerical value. In some embodiments of this disclosure, And, "high levels of CRP" are those exceeding approximately 10 mg / L (for example, 10 mg / L), approximately If the concentration exceeds 20 mg / L (for example, 20 mg / L) or exceeds approximately 30 mg / L (for example, (30 mg / L). When evaluating CRP levels at baseline, "baseline This is called "in-CRP". High levels of CRP at baseline are referred to as "baseline C This can be called "elevated RP" or "high baseline CRP." Disclosed method, regime In some embodiments of the use, kits, and pharmaceutical compositions, the patient receives high-baseline treatment. Having CRP (or hsCRP) or high levels of CRP (or hsCRP) The term "hsCRP" refers to the rate at which CRP levels in the blood are measured by a high-sensitivity CRP test. It means bell.

[0089] As used herein, "erythrocyte sedimentation rate," "ESR," "sedimentation rate," and " "Sedrate" refers to the rate at which red blood cells settle in a patient sample (e.g., a plasma sample). It has a taste. ESR reflects the viscosity of plasma and the presence of acute-phase proteins, and is usually "mm Reported in units of " / hour". ESR measures the distance red blood cells settle over time in a tube. It is determined by [method]. Typical ESR test methods include the Westergren method and zeta precipitation. The descending rate (ZSR) method and the Wintrobe method are used (all by reference). Incorporated herein as Moseley and Bull (1982) Clin. Lab. Haematol., Vol. 4, Pages 169-78, Miller et al. (1983) Br Med J (Clin Res Ed), Vol. 286 (No. 6361), p. 266, Wetteland P et al. (1996) J. Intern. Med., Vol. 240 (No. 3), pp. 125-310. For measuring ESR Commercially available kits include, for example, those from ARKRAY USA and BD Diagnostic Systems. Available from tems and Polymedco Inc. ESR equipment is available, for example, in the United States. This can be found in National Patent No. 6974701, Steelex Scientif ic, Nicesound Electronics Co., Globe Scien tific Inc., Alifax, Analysis Instrument AB, Streck Laboratories, PolyMed Co, Inc., and Qua It is offered by various companies, including ntimetrix.

[0090] As used herein, "high ESR" refers to the 2010 ACR / EULAR standard ( As defined by Aletaha et al. (2010) Ann. Rheum. Dis., Vol. 69, pp. 1580-88, normal E This means it exceeds SR. According to the 2010 ACR / EULAR standards, it is normal / abnormal. ESR is based on local laboratory standards. Each local laboratory calculates the normal maximum ESR. To do this, we use the cutoff value for abnormal (high) ESR according to the rules of this laboratory. The physician, Generally, ESR testing is ordered to be performed by a local laboratory, and the local laboratory calculates the normal ESR. Therefore, normal or high ESR will be reported using the rules used by the laboratory. Unless otherwise indicated, what is considered a normal ESR value varies between laboratories and assays. Therefore, as used herein, "high ESR" does not mean indicating a specific numerical value. In some embodiments of the disclosed methods, regimens, uses, kits, and pharmaceutical compositions... Therefore, the patient has a high ESR.

[0091] As used herein, “rheumatoid factor” or “RF” is often found in RA patients. This refers to an autoantibody against the Fc portion of an existing IgG antibody. This is how it's used in this specification. "RF" refers to any RF isotype, such as IgG, IgE, IgM, and IgA. This includes. RF is a variety of well-known techniques that can be used to determine the presence or absence of a particular antibody, for example. The assay can be performed using methods such as ELISA assay, agglutination test, and turbidimetry test. RF levels are measured in various ways by the laboratory, for example, IU / ml, units / ml and titer. How much should the patient's blood sample be diluted using a dilution test before RF is no longer detectable? It measures whether it is possible, for example, a titer of 1:80 is greater than a titer of 1:20. Many detectable RFs may be reported. RF kits are, for example, IBL-Ame Commercially available from rica (Immuno-Biological Laboratories) It is being done.

[0092] Patients who are serologically positive for RF are referred to as "RF+" in this specification. If a sample obtained from a patient contains RF, this sample is classified as "RF+". This involves calculating the normal maximum RF based on the normal RF level cutoff according to our laboratory rules. Use values. Proposed by Aletaha et al. (2010) Ann. Rheum. Dis., Vol. 69, pp. 1580-1588. Thus, the patient's RF+ was determined based on the upper limit of normal [ULN] for each laboratory test and assay. If a value greater than ULN is measured in each laboratory test and assay, the patient is considered to be in a state of ill health. It is RF+. Therefore, unless otherwise indicated by the context, ULN is for laboratory and adult Because it varies between services, as used in this specification, "RF+" indicates a specific value. This does not mean that. As a non-limiting example, during the test, laboratory X was within the normal range of RF in the blood. The range is shown as 14-60 units / mL. During the test, laboratory Y was within the normal range of RF in the blood. This is shown as 40 IU / ml or less. During the test, Laboratory Z considered the normal range of RF in the blood to be 1 :20~1:80 titer is shown. Therefore, if laboratory X is greater than 60 units / ml, R If an F level is reported, and laboratory Y reports an RF value greater than 40 IU / ml, Alternatively, if Laboratory Z reports an RF titer greater than 1:80, the patient will be classified as RF+. In some embodiments of the methods, regimens, uses, kits, and pharmaceutical compositions described, patients The user is RF+.

[0093] The term "serologically positive" refers to the presence of a specific substance (e.g., RF) in a patient's serum. Used to point.

[0094] As used herein, "anti-citrullinated protein antibody", "ACPA", Anti-cyclic citrullinated peptide antibodies and anti-CCPs are found in the joints of RA patients. This refers to autoantibodies that bind to citrullinated amino acid residues on proteins. The ionized peptide is used in in vitro tests to confirm the presence of ACPA in the patient's blood (for example) For example, ACPA is used in ELISA assays, and as a result, ACPA is also known as an "anti-CCP" antibody. It is called. ACPA levels are a variety of well-known indicators that can be used to determine the presence or absence of specific antibodies. The assay can be performed using techniques such as agglutination and ELISA assays. PA kits are commercially available, for example, Axis-Shield Diagnosti DIASTAT® anti-CCP testing provided by cs, Ltd. (UK) and AxSYM Ant provided by Abbot Diagnostics (Germany) This is the i-CCP (registered trademark) kit.

[0095] In this specification, patients who test positive for ACPA are referred to as "ACPA+". Similarly, if a sample obtained from a patient has ACPA, the sample is "ACPA+". Each local laboratory calculates the normal maximum ACPA according to the rules of that laboratory. Use the cutoff value for CPA levels. Aletaha et al. (2010) Ann. Rheum. Dis., vol. 69, 1580. -As suggested on page 1588, the patient should be within the normal upper limit of each laboratory test and assay [ Based on ULN, it is considered ACPA+ and is greater than the ULN of each laboratory test and assay. If a high value is measured, the patient is ACPA+. Therefore, unless otherwise indicated in the context, Unless otherwise specified, ULN will vary between laboratories and assays, as used herein. "ACPA+" does not mean that a specific numerical value is indicated. As a non-limiting example, during the test... Laboratory A set the reference range for ACPA in blood to less than 20 EU (arbitrary ELISA units) As shown below, during the test, Laboratory B set the reference range for ACPA in blood to less than 5 U / ml. Therefore, if laboratory A reports an ACPA value greater than 20 EU or laboratory If B reports an ACPA value greater than 5 U / ml, the patient will be classified as ACPA+. Disclosure In some embodiments of the methods, regimens, uses, kits, and pharmaceutical compositions described, patients This is ACPA+.

[0096] Selected normal / abnormal and reference ranges for ACPA, ESR, RF, and CRP are, for example, Fischbach and Dunning (2009) "A Man" is incorporated herein by reference in its entirety. 'ual of Laboratory and Diagnostic Tests' (8th edition) Wolters Kluwer / Lippincott Willia It can be found in ms and Williams.

[0097] As used herein, the term "high-risk RA patients" refers to a) RF+, AC Both PA+ or RF+ and ACPA+, and a) high levels of CRP (or hsC). To define patients with RP, high ESR, or both high levels of CRP and high ESR Used for several embodiments of the disclosed methods, regimens, uses, kits, and pharmaceutical compositions. In this case, the patient is a high-risk RA patient. In some embodiments, the patient is small At least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 small joints The lesion is shown. In some embodiments, the patient has at least one, two, three, or four , showing lesions in 5, 6, 7, 8, 9, or 10 major joints. Several embodiments In this case, the patient showed lesions in more than 10 joints, and at least one of the joints was a microarticular. Yes. In some embodiments, the patient has symptoms that last for at least 6 weeks. ru.

[0098] "Joint lesions" can be confirmed by imaging evidence of synovitis, any swelling or examination This refers to joints that are tender to examination. The categories of joint distribution are classified according to the location and number of affected joints. The highest category is determined by the pattern of joint lesions. "Major joints" include the shoulder. , refers to the elbow, hip, knee and ankle. "Minor joints" include the metacarpophalangeal joints and proximal interphalangeal joints. This refers to the 2nd to 5th metatarsophalangeal joints, the interphalangeal joints, and the radiocarpal joint. Disclosed methods, regimens, In some embodiments of the use, kit, and composition, the patient has 28 tender joint capsules. Six or more swollen joints and six or more of the 28 swollen joints and hsCR exceeding 10 mg / L It has P.

[0099] "Duration of symptoms" is the duration of symptoms in the clinically affected joint at the time of evaluation, regardless of the treatment status. This refers to patient self-reports of the duration of signs or symptoms of synovitis (e.g., pain, swelling, tenderness). ru.

[0100] As used herein, “selecting high-risk RA patients for therapeutic purposes” and "Patients are selected for treatment purposes based on the fact that they are high-risk RA patients" and "Selected for therapeutic purposes" means that a specific RA patient is considered to be at high risk of RA. Criteria (i.e., the patient is RF+, ACPA+, or both RF+ and ACPA+, and The patient has high levels of CRP, high ESR, or both high levels of CRP and high ESR. This refers to being selected from a larger group or from RA patients based on the criteria met. To use for that purpose.

[0101] As used herein, the phrase "previously treated for RA" means anti- This term is used to refer to patients who have previously received rheumatoid arthritis (RA) treatment with rheumatoid drugs, for example, if the patient previously Patients who have failed, responded poorly to, or are intolerant of RA therapy, anti-rheumatic drugs, or treatment regimens. Such patients are MTX, DMARDs and / or TNF alpha antagonists. This includes patients who have previously received treatment with biological agents such as Streptococcus. Disclosed methods, regimens, and uses. In some embodiments of the kit and pharmaceutical composition, the patient has previously been treated for RA. I received medical treatment.

[0102] As used in this specification, the phrase "not having received prior treatment for RA" This term is used to refer to patients who have not previously received RA treatment with anti-rheumatic drugs. Yes, that is, the patient is "treatment-naive". Disclosed methods, regimens, uses, kits And in some embodiments of the pharmaceutical composition, the patient has previously received treatment for RA. It wasn't there.

[0103] As used herein, “failures” with previous RA therapy mean (1) (1) Patients who do not have a clinical benefit (lack of primary efficacy), (2) Measurable and meaningful response Although it has the characteristic of having a better response, for example, low disease activity of RA or remission of RA (3) Patients in whom this was not achieved (also called "insufficient response"), after an initial good response , patients whose condition worsens (secondary reduction in efficacy) and (4) patients who have a good response but due to side effects This refers to patients who discontinue treatment (also called "intolerance"). This is also known as an insufficient TNF response (TNF-IR). Patients who show intolerance to TNF will be considered TNF failures. Patients showing an insufficient response to lexate (MTX-IR) or intolerance to MTX This will be considered an unsuccessful case. DMARD insufficient response (DMARD-IR) or DM Patients who show intolerance to ARDs will be considered DMARD failure cases. In some embodiments of the methods, regimens, uses, kits, and pharmaceutical compositions described, patients These are cases of TNF failure, MTX failure, or DMARD failure.

[0104] A "treatment regimen" refers to a pattern of treatment for a disease, for example, the treatment regimen used during the treatment of rheumatoid arthritis (RA). This refers to the pattern of treatment. The treatment regimen may include an induction regimen and a maintenance regimen. Table 2 shows examples of treatment regimens for RA, but all of them are for high-risk RA patients. We do not provide treatment to the person.

[0105] [Table 2]

[0106] The terms "introduction regimen" or "introduction period" refer to treatment regimens used in the initial treatment of a disease. Refers to a regimen (or part of a treatment regimen). In some embodiments, the disclosed method , use, kits, processes and regimens (e.g., inflammatory arthritis, e.g., high-risk RA) The method of treating RA (rheumatoid arthritis) like the patient's involves using an induction regimen. A typical induction regimen is... The goal is to deliver a high level of medication to the patient during the initial period of the treatment regimen. The introductory regimen involves administering a higher dose of the drug than the one used in the maintenance regimen (in part or (As a whole) is used when a physician administers the drug more frequently than when administering it during a maintenance regimen. It may be, or both. Any of the disclosed methods, uses, kits, processes and regimens In that embodiment, the introductory dose is a single, high-dose infusion (e.g., about 30 mg / kg) It can be delivered during the introductory regimen. Alternatively, the introductory dose can be administered in several doses (e.g., two doses). It can be delivered as three injections (for example, approximately 10 mg / kg). Alternatively, The dosage is administered by subcutaneous injection several times (for example, 1, 2, 3, 4, 5, 6 times or more). For example, it can be delivered as approximately 75-300 mg. Drug delivery during the introduction regimen. These drugs are administered via the subcutaneous (sc) pathway, for example, approximately 75 mg to approximately 300 mg via the sc (For example, approximately 75 mg sc, approximately 150 mg sc, approximately 300 mg sc) Delivery of doses, or via intravenous (iv) route, for example, approximately 1 mg / kg to approximately 3 0 mg / kg, iv (for example, approximately 1 mg / kg, approximately 3 mg / kg, approximately 10 mg / kg) Delivery of a dose of approximately 30 mg / kg or any other route of administration (e.g., intramuscular, im ) may be the process of some of the disclosed methods, compositions, kits, uses and regimens. In one embodiment, an IL-17 antagonist (e.g., secukinumab) is introduced into the regimen. It is delivered by IV administration during at least a portion of the period. In some embodiments The introductory regimen is approximately 1 mg / kg to 30 mg / kg, and approximately 1 mg / kg to 10 mg / A dose of IL-17 antagonist (e.g., secchu) in kg, preferably about 10 mg / kg. The procedure includes the step of administering numab. In a further embodiment, the induction dose is once a week, weekly It is delivered twice, every other week or once a month, preferably every other week. In a further embodiment, the introduction Dimen is preferred to be given 1 to 10 doses of an IL-17 antagonist (e.g., secukinumab). Alternatively, three doses of an IL-17 antagonist (e.g., secukinumab) may be used.

[0107] IL-17 antagonists, for example, IL-17 binding molecules (e.g., secukinumab) Which IL-17 antibody) or IL-17 receptor-binding molecule (e.g., IL-17 receptor antibody) The introductory regimen for the delivery of ) uses PK information (see Table 10) rather than a specific dose. It can also be designed. Disclosed uses, regimens and methods (e.g., inflammatory arthritis) For example, regarding methods for treating RA in high-risk RA patients, those skilled in the art can introduce During the regimen, the average C content ranged from approximately 360 μg / mL to approximately 401 μg / mL. max To bring about IL-17 antagonists, for example, IL-17 binding molecules (e.g., secukinumab) Which IL-17 antibody) or IL-17 receptor-binding molecule (e.g., IL-17 receptor antibody) ) can be delivered. Alternatively, a person skilled in the art can deliver up to approximately 30 for a person with an average weight of 90 kg. With an inter-patient variability of %~40% [+ or -], the average C was approximately 401 μg / mL. max It will bring During the urchin introduction regimen, an IL-17 antagonist, for example, an IL-17 binding molecule (for example) (For example, IL-17 antibodies such as secukinumab) or IL-17 receptor-binding molecules (e.g., I It can deliver L-17 receptor antibodies. Alternatively, a person skilled in the art can deliver a human weighing an average of 75 kg. Regarding the average C of approximately 360 μg / mL max IL-17 during the introduction regimen to bring about Antagonists, for example, IL-17 binding molecules (e.g., IL-17 such as secukinumab) 7) delivers an antibody or an IL-17 receptor-binding molecule (e.g., an IL-17 receptor antibody). It is possible. Alternatively, a person skilled in the art could study a person weighing an average of 75 kg over a period of 10 weeks. During the induction regimen, IL-17 was administered to achieve trough levels exceeding 80 μg / mL. Tagonists, for example, IL-17 binding molecules (e.g., IL-17 inhibitors such as secukinumab) To deliver the body or an IL-17 receptor-binding molecule (e.g., an IL-17 receptor antibody). This is possible. In some embodiments, for a person with an average weight of 90 kg, up to approximately 30%~4 With 0% inter-patient variability [+ or -], the mean C was approximately 401 μg / mL. max Leading to During the initiation regimen, an IL-17 antagonist will be delivered intravenously at weeks 0, 2, and 4. In several embodiments, an average C of approximately 360 μg / mL was observed in a person with an average weight of 75 kg. ma x To achieve this, an IL-17 antagonist was administered during the introduction regimen at weeks 0, 2, and 4. In another embodiment, for a person with an average weight of 75 kg, over a period of 10 weeks. During the induction regimen, IL- 17. The antagonist is delivered intravenously at weeks 0, 2, and 4.

[0108] The terms "maintenance regimen" or "maintenance period" refer to, for example, a long period of time (several months or several years). Used to maintain patients in remission during treatment for the disease. It means a treatment regimen (or part of a treatment regimen). In some embodiments, The methods, uses, and regimens shown (e.g., inflammatory arthritis, e.g., in patients with high-risk RA) The method of treating RA involves using a maintenance regimen. A maintenance regimen is a series of therapies (for example) (For example, administering the drug regularly, for example, once a week, once a month, once a year, etc.) or intermittent therapy (for example) Intermittent treatment, intermittent therapy, treatment upon recurrence, or predetermined criteria [e.g., pain, disease] Treatment after achieving [symptoms, etc.] can be used. IL-17 antagonists during maintenance regimens Nist, for example, an IL-17 binding molecule (e.g., an IL-17 antibody or its antigen binding) Fragments, e.g., secukinumab) or IL-17 receptor-binding molecules (e.g., IL-17 inhibitors) The delivery of the body or its antigen-binding fragments is via the subcutaneous route, for example, approximately 75 mg to approximately 300mg, sc (for example, approximately 75mg, sc, approximately 150mg, sc, approximately 3 Delivery of a dose of 00 mg (sc), or via an intravenous route, for example, approximately 1 mg / kJ g ~ approximately 30 mg / kg, iv (for example, approximately 1 mg / kg, approximately 3 mg / kg, approximately 10 mg / kg) Delivery of doses (g / kg, approximately 30 mg / kg) or any other route of administration (e.g., intramuscular, It may go through im). Some implementations of the disclosed methods, uses and regimens In this state, an IL-17 antagonist (e.g., secukinumab) is used during the maintenance regimen. c. Delivered by administration. In some embodiments, the maintenance regimen is approximately 75 mg ~300 mg, approximately 75 mg to approximately 150 mg, preferably approximately 75 mg or approximately 150 mg The procedure includes the step of administering a dose of an IL-17 antagonist (e.g., secukinumab). In some embodiments, the maintenance regimen involves administering an IL-17 antagonist once a month (e.g., For example, the procedure includes the step of administering a dose of secukinumab.

[0109] IL-17 antagonists, for example, IL-17 binding molecules (e.g., secukinumab) Which IL-17 antibody) or IL-17 receptor-binding molecule (e.g., IL-17 receptor antibody) The maintenance regimen for the delivery of ) is based on PK information (see Table 9), rather than a specific dose. It can also be designed. Disclosed uses, regimens and methods (e.g., inflammatory arthritis, For example, for methods of treating RA in high-risk RA patients, a person skilled in the art would know the average 75 For individuals weighing approximately 71-79 kg, there is a maximum inter-patient variability of about 30% [+ or -]. So, approximately 9.4 μg / mL to approximately 31 μg / mL (for example, approximately 9.4 μg / mL, approximately 17.3 μg / mL) Maintain a stable resistance to achieve an average steady-state trough level of approximately 31 μg / mL (μg / mL). The men contains an IL-17 antagonist, for example, an IL-17 binding molecule (e.g., seckin). IL-17 antibodies such as Mab or IL-17 receptor-binding molecules (e.g., IL-17 receptor Somatic antibodies can be delivered. Alternatively, a person skilled in the art can deliver approximately 8 for a person with an average weight of 75 kg. 0.0 μg / mL to approximately 30.0 μg / mL (for example, approximately 8.0 μg / mL, approximately 17 μg / mL) During the maintenance regimen, to achieve an average steady-state trough level of L (approximately 30 μg / mL) IL-17 antagonists, for example, IL-17 binding molecules (e.g., secukinumab, etc.) IL-17 antibody) or IL-17 receptor-binding molecule (e.g., IL-17 receptor antibody) It can deliver the most for a person with an average weight of 70 kg. With approximately 30% inter-patient variation [+ or -], the range is approximately 9.4 μg / mL to approximately 31 μg / mL (for example) For example, the average steady state of approximately 9.4 μg / mL, approximately 17.3 μg / mL, and approximately 31 μg / mL. Administer an IL-17 antagonist once a month during the maintenance regimen to achieve a rough level. In other embodiments, the concentration for a person with an average weight of 75 kg is approximately 8.0 μg / mL to approximately 30. 0 μg / mL (for example, approximately 8.0 μg / mL, approximately 17 μg / mL, approximately 30 μg / mL) IL-17 antagonist once a month during the maintenance regimen to achieve an average steady-state trough level. To deliver Nist. Alternatively, a person skilled in the art can deliver approximately 314 mg / day / L to approximately 1323 mg / day / L. (For example, approximately 314 mg / day / L to approximately 1256 mg / day / L, for example, approximately 331 mg / day Maintaining a steady state to obtain an average AUCtau of approximately 1323 mg / L (approximately 1323 mg / L) The regimen includes an IL-17 antagonist, for example, an IL-17 binding molecule (e.g., septembryonic acid). IL-17 antibodies such as cukinumab or IL-17 receptor-binding molecules (e.g., IL-1 It can deliver receptor antibodies (7).

[0110] The timing of administration is generally the same day as the first dose of secukinumab (also known as "baseline"). It is measured from (knowledge). However, different healthcare providers have different methods, as shown in Table 3 below. The nomenclature used is...

[0111] [Table 3]

[0112] In particular, week 0 is sometimes called week 1 in some nomenclature, while day 0 is sometimes called week 1 in some nomenclature. In the nomenclature, it is sometimes called day 1. Therefore, different doctors may use the same dosage schedule. It mentions a timeline, for example, week 3 / day 21, week 3 / day 22, week 4 / day 21 The dosage to be administered on day 4, week 4 / day 22 may be specified. To maintain consistency... In this specification, the first week of administration will be referred to as week 0, while the first week of administration Let us refer to the first day as Day 1. Therefore, as an example, if administered once a week during the introductory regimen... The four induction doses of secukinumab are: Week 0 (e.g., around day 1), Week 1 (e.g., around day 8), and Week 1 (e.g., around day 8). It is supplied in the first week, the second week (for example, around day 15), and the third week (for example, around day 22). Yes, that's possible. The introductory dose is given every two weeks (i.e., every other week), for example, week 0, week 2, week 4 It can be administered in weeks, etc. The induction dose is given every three weeks, for example, week 0, week 3, It can be administered in the 6th week, for example. The induction dose is daily for one week, for example, 1 to 7 days. It can be administered to the eyes. However, this nomenclature is used only for clarity. It should be noted that this should not be interpreted as restrictive.

[0113] As used herein, the term “means of administration” means a pre-filled syringe, a bicycle This includes aluminum and syringes, pen-type syringes, automatic infusion devices, intravenous drip infusion devices and bags, pumps, etc. to illustrate, and not limited to, available devices for systemic administration of biological agents. Yes, such items allow patients to self-administer drugs (i.e., for themselves). Drugs may be administered, or a physician may administer drugs.

[0114] Various aspects of this disclosure are described in further detail in the following subsections. All patents, patents Requests, references, and other publications are incorporated herein by reference as a whole. .

[0115] IL-17 Antagonist Various disclosed pharmaceutical compositions, regimens, processes, uses, methods and kits are related to IL-17 Antagonists, for example, IL-17 binding molecules (for example, IL-17 antibodies or similar) Antigen-binding fragments (e.g., secukinumab) or IL-17 receptor-binding molecules (e.g., IL -17 Antibodies or their antigen-binding fragments are used.

[0116] In one embodiment, an IL-17 antagonist, for example, an IL-17 binding molecule, is used. (For example, IL-17 antibody or its antigen-binding fragment, e.g., secukinumab) is supercapable. At least one immunoglobulin heavy chain containing variant regions CDR1, CDR2, and CDR3 in order. Variable domain (V H ) includes, and the CDR1 is amino acid sequence number 1 (NYW- The CDR2 has the amino acid sequence number 2 (AINQDG- SEKYYVGSVKG) is present, and the CDR3 has an amino acid sequence Sequence ID 3 (DYYDILTDYYIHYWYFD- It has L).

[0117] In one embodiment, an IL-17 antagonist, for example, an IL-17 binding molecule, is used. (For example, IL-17 antibody or its antigen-binding fragment, e.g., secukinumab) is supercapable. At least one immunoglobulin containing variant regions CDR1', CDR2', and CDR3' in order Light chain variable domain (V L ) includes, and the CDR1' is amino acid sequence number 4 (R- The CDR2' has ASQSVSSSYLA, and the CDR2' is an amino acid compound The sequence number 5 (GASSRAT) is present, and the CDR3' is an amino acid sequence. It has sequence number 6 (QQYGSSPCT).

[0118] In one embodiment, an IL-17 antagonist, for example, an IL-17 binding molecule, is used. (For example, IL-17 antibody or its antigen-binding fragment, e.g., secukinumab) is supercapable. At least one immunoglobulin containing variant regions CDR1-x, CDR2-x, and CDR3-x in order Robulin heavy chain variable domain (V H ) includes, and the CDR1-x is an amino acid sequence number. It has 11(GFTFSNYWMN), and the CDR2-x is amino The acid sequence sequence number 12 (AINQDGSEKYY) is present, and the CD R3-x is the amino acid sequence number 13 (CVRDYYDILTD It has -YYIHYWYFDLWG).

[0119] In one embodiment, an IL-17 antagonist, for example, an IL-17 binding molecule, is used. (For example, IL-17 antibodies or their antigen-binding fragments, e.g., secukinumab) are few in number. At least one immunoglobulin V H domain and at least one immunoglobulin V L Domaine It includes a) immunoglobulin V H The domains are i) hypervariable regions CDR1, CDR2 and CDR3 (The CDR1 has amino acid sequence number 1, and the CDR2 has amino acid (i) Having sequence sequence number 2, and the CDR3 having amino acid sequence sequence number 3) or (ii) Ultravariable regions CDR1-x, CDR2-x and CDR3-x (where CDR1-x is amino The CDR2-x has amino acid sequence sequence number 11, and the CDR2-x has amino acid sequence sequence number 12, The CDR3-x contains (the amino acid sequence number 13), and b) immunoglobulin V L The domains are the hypervariable regions CDR1', CDR2', and CDR3' (where CDR1' is, The CDR2' has amino acid sequence SEQ ID NO: 4, and the CDR2' has amino acid sequence SEQ ID NO: 5, The CDR3' contains the amino acid sequence number 6.

[0120] In one embodiment, an IL-17 antagonist, for example, an IL-17 binding molecule, is used. (For example, IL-17 antibodies or their antigen-binding fragments, e.g., secukinumab) are few in number. At least one immunoglobulin V H domain and at least one immunoglobulin V L Domaine It contains a) at least one immunoglobulin V H The domain is the hypervariable region CDR1. It contains CDR2 and CDR3 in order, and CDR1 has amino acid sequence number 1, CDR2 has amino acid sequence number 2, and CDR3 has amino acid sequence number 2. 3 has, b) at least one immunoglobulin V L The domain is the hypervariable region CDR1' It contains CDR2' and CDR3' in order, and CDR1' is the amino acid sequence SEQ ID NO: 4 The CDR2' has amino acid sequence SEQ ID NO: 5, and the CDR3' has amino acid It has sequence number 6.

[0121] In one embodiment, an IL-17 antagonist, for example, an IL-17 binding molecule, is used. (For example, IL-17 antibodies or their antigen-binding fragments, e.g., secukinumab) are few in number. At least one immunoglobulin V H domain and at least one immunoglobulin V L Domaine It contains a) at least one immunoglobulin V H The domain is the hypervariable region CDR1- x, CDR2-x, and CDR3-x are included in that order, and the CDR1-x is an amino acid sequence sequence The CDR2-x has the number 11, and the CDR3 has the amino acid sequence number 12. -x has amino acid sequence number 13, and b) at least one immunoglobulin V L Do The main includes the ultra-variable regions CDR1', CDR2', and CDR3' in order, and the CDR1 ' has amino acid sequence number 4, and the CDR2' has amino acid sequence number 5. Furthermore, the CDR3' has amino acid sequence number 6.

[0122] In one embodiment, an IL-17 antagonist, for example, an IL-17 binding molecule, is used. (For example, IL-17 antibody or its antigen-binding fragment, e.g., secukinumab) is as follows: Includes: a) Immunoglobulin heavy chain variable dominant containing the amino acid sequence shown as Sequence ID No. 8 In (V Ha) Immunoglobulin light chain containing the amino acid sequence shown as SEQ ID NO: 10 Variable domain (V L ), c) Immunoglobulin containing the amino acid sequence shown as Sequence ID No. 8 V H Immunoglobulin V containing the domain and the amino acid sequence shown as SEQ ID NO: 10 L Do Main, d) Immune including hypervariable region shown as Sequence ID 1, Sequence ID 2 and Sequence ID 3 Epidemic globulin V H Domain, e) shown as Sequence ID No. 4, Sequence ID No. 5 and Sequence ID No. 6 Immunoglobulin V including the hypervariable region L Domain, f) Sequence ID 11, Sequence ID 12 and distribution Immunoglobulin V containing the hypervariable region shown as column number 13 H Domain, g) Sequence ID 1. Immunoglobulin V containing the hypervariable region shown as SEQ ID NO: 2 and SEQ ID NO: 3 H Dome Immunity including the hypervariable region shown as SEQ ID NOs. 4, SEQ ID NOs. 5, and SEQ ID NOs. 6. Globulin V L Domain, or as sequence numbers 11, 12 and 13 Immunoglobulin V including the indicated hypervariable region H Domain and Sequence ID No. 4, Sequence ID No. 5 and Immunoglobulin V containing the hypervariable region shown as SEQ ID NO: 6 L domain

[0123] For easy reference, based on Kabat's definition, it was determined by X-ray analysis, Ch Ultraviolet development of secukinumab monoclonal antibodies using the approach of othia and collaborators The amino acid sequence of the variable region is shown in Table 4 below.

[0124] [Table 4]

[0125] In a preferred embodiment, both the heavy and light chain variable domains are of human origin, e.g. For example, SEQ ID NO: 10 (= variable domain of the light chain, i.e., amino acids 1-1 of SEQ ID NO: 10) 09) and SEQ ID NO: 8 (= variable domain of the heavy chain, i.e., amino acids 1-1 of SEQ ID NO: 8) This is the secukinumab antibody shown in 27). A constant region domain is also preferred, for example, “Sequences of Proteins of Immunological Interest”, Kabat EA et al., US Department of Health and Human Services, Public Health Service, National Institute of Heal Contains appropriate human constant region domains as described in th.

[0126] In some embodiments, an IL-17 antagonist, for example, an IL-17 binding agent, is used. The molecule (for example, IL-17 antibody or its antigen-binding fragment, e.g., secukinumab) Includes the variable light domain of Sequence ID No. 10. In other embodiments, IL-17 antagonist For example, IL-17 binding molecules (for example, IL-17 antibodies or their antigen-binding fragments) For example, secukinumab contains the variable weight domain of SEQ ID NO: 8. In other embodiments, Therefore, IL-17 antagonists, for example, IL-17 binding molecules (for example, IL-17 inhibitors) The body or its antigen-binding fragment, for example, secukinumab, is a variable light domain of SEQ ID NO: 10. It includes the variable weight domain of sequence number 8. In some embodiments, IL-17A Intagonists, for example, IL-17 binding molecules (for example, IL-17 antibodies or their anti- The original binding fragment (e.g., secukinumab) contains three CDRs of SEQ ID NO: 10. Other implementations Morphologically, IL-17 antagonists, for example, IL-17 binding molecules (e.g., I L-17 antibody or its antigen-binding fragment (e.g., secukinumab) is one of the three components of Sequence ID No. 8. Includes a CD-R of IL-17. In other embodiments, an IL-17 antagonist, for example, IL-1 7. Binding molecules (e.g., IL-17 antibody or its antigen-binding fragment, e.g., secchus numbing) (B) includes three CDRs with sequence number 10 and three CDRs with sequence number 8. The CDRs for Sequence IDs 8 and 10, which conform to both ia and Kabat definitions, are shown in Table 4. It can be released.

[0127] In some embodiments, an IL-17 antagonist, for example, an IL-17 binding agent, is used. The molecule (for example, IL-17 antibody or its antigen-binding fragment, e.g., secukinumab) It contains the light domain of Sequence ID No. 15. In other embodiments, an IL-17 antagonist, For example, IL-17 binding molecules (e.g., IL-17 antibodies or their antigen-binding fragments, e.g.) For example, secukinumab contains the heavy domain of SEQ ID NO: 17. In other embodiments, I L-17 antagonists, for example, IL-17 binding molecules (for example, IL-17 antibodies or The antigen-binding fragment, for example, secukinumab, is the light domain and sequence of Sequence ID No. 15. Includes a heavy domain number 17. In some embodiments, the IL-17 antagonist For example, IL-17 binding molecules (for example, IL-17 antibodies or their antigen-binding fragments) For example, secukinumab contains three CDRs of SEQ ID NO: 15. In other embodiments, , IL-17 antagonists, for example, IL-17 binding molecules (e.g., IL-17 antibodies) Alternatively, the antigen-binding fragment (e.g., secukinumab) is the three CDRs of SEQ ID NO: 17 Includes. In other embodiments, IL-17 antagonists, for example, IL-17 binding compounds. The child (for example, IL-17 antibody or its antigen-binding fragment, for example, secukinumab) Includes three CDRs with column number 15 and three CDRs with sequence number 17. Chothia and The CDRs for Sequence IDs 15 and 17, which conform to both Kabat definitions, can be found in Table 4. It is possible.

[0128] The hypervariable domain is preferably of human origin, but of any kind of framework domain It can be linked to a specific domain. Appropriate framework domains are described above by Kabat EA et al. It is being done. A preferred heavy chain framework is the human heavy chain framework, for example, secchus. This is the heavy chain framework of the numab antibody. It is, in order, for example, FR1 (SEQ ID NO: 8) Amino acids 1-30), FR2 (amino acids 36-49 of SEQ ID NO: 8), FR3 (SEQ ID NO: 8 From amino acids 67-98 and FR4 (amino acids 117-127 of SEQ ID NO: 8) Taking into account the confirmed hypervariable region of secukinumab by X-ray analysis, other preferred heavy chains The framework is, in order, FR1-x (amino acids 1-25 of sequence number 8), FR2-x ( Amino acids 36-49 of SEQ ID NO: 8, FR3-x (amino acids 61-95 of SEQ ID NO: 8) and It consists of the FR4 region (amino acids 119-127 of SEQ ID NO: 8). Similarly, the light chain frame The work is, in order, FR1' (amino acids 1-23 of SEQ ID NO: 10), FR2' (SEQ ID NO: 10) FR3' (amino acids 36-50 of sequence number 10) and FR4 It consists of the region (amino acids 99-109 of SEQ ID NO: 10).

[0129] In one embodiment, an IL-17 antagonist, for example, an IL-17 binding molecule, is used. (For example, IL-17 antibodies or their antigen-binding fragments, e.g., secukinumab) are few in number. a) Variable domains including hypervariable regions CDR1, CDR2, and CDR3 in order, and An immunoglobulin heavy chain or fragment thereof containing the constant portion of the heavy chain or a fragment thereof (the CDR1 is, The CDR2 has amino acid sequence sequence number 1, and the CDR2 has amino acid sequence sequence number 2, CDR3 has the amino acid sequence number 3), and b) the hypervariable region CDR1' , variable domains including CDR2' and CDR3', and constant parts or fragments thereof of human light chains The immunoglobulin light chain or fragment thereof contains (the CDR1' has amino acid sequence number 4) Furthermore, CDR2' has amino acid sequence SEQ ID NO: 5, and CDR3' has amino acid sequence SEQ ID NO: 5 Selected from human IL-17 antibodies (containing sequence number 6).

[0130] In one embodiment, an IL-17 antagonist, for example, an IL-17 binding molecule, is used. (For example, IL-17 antibody or its antigen-binding fragment, e.g., secukinumab) is a) The first domain includes, in order, hypervariable regions CDR1, CDR2, and CDR3 (the CDR1 is , has amino acid sequence sequence number 1, and the CDR2 has amino acid sequence sequence number 2, (Note CDR3 has amino acid sequence number 3), and b) hypervariable region CDR1', The second domain includes CDR2' and CDR3' (the CDR1' is an amino acid sequence sequence) It has number 4, the CDR2' has amino acid sequence number 5, and the CDR3' has, (having amino acid sequence number 6), and c) the N-terminus of the first domain and the second domain selected from single-chain binding molecules comprising an antigen-binding site that binds to the C-terminus of In or the C-terminus of the first domain and the N-terminus of the second domain and comprises a peptide linker.

[0131] Alternatively, an IL-17 antagonist, for example, an IL-17 binding molecule (e.g., an IL- 17 antibody or an antigen-binding fragment thereof, such as secukinumab) may in turn comprise at least one antigen-binding site comprising at least one immunoglobulin heavy chain variable domain (V <0'000090> i i i i i H H i i i i i i

[0132] ​Similarly, 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 turn, a) has complementarity-determining regions C DR1-x (SEQ ID NO: 11), CDR2-x (SEQ ID NO: 12), and CDR3-x (SEQ ID NO NO: 13) or b) has at least one antigen-binding i site that includes complementarity-determining regions CDR1 i -x, CDR2 i -x, and CDR3 -x and includes at least one immunoglobulin heavy chain variable domain (V H ), wherein the complementarity-determining region CDR1 -x differs from the complementarity-determining region of CDR1-x by 3, preferably 2, more preferably 1 amino acid as shown in SEQ ID NO: 11, the complementarity-determining region CDR2 i -x differs from the complementarity-determining region of CDR2-x by 3 , preferably 2, more preferably 1 amino acid as shown in SEQ ID NO: 12, the complementarity-determining region CDR3 -x differs from the complementarity-determining region of CDR3-x by 3, preferably 2, more preferably i 1 amino acid as shown in SEQ ID NO: 13, and the IL-17 binding molecule inhibits the activity of 1 nM (= 30 ng / ml) human IL-17 by 50% at a concentration of about 50 nM or less, about 20 nM or less, about 10 nM or less, about 5 nM or less, about 2 nM or less, or more preferably about 1 nM or less of the molecule, and the inhibitory activity is measured based on the production of IL-6 induced by hu-IL-17 in human skin fibroblasts. i Similarly, 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 turn, a) has complementarity-determining regions C DR1-x (SEQ ID NO: 11), CDR2-x (SEQ ID NO: 12), and CDR3-x (SEQ ID NO NO: 13) or b) has at least one antigen-binding site that includes complementarity-determining regions CDR1 -x, CDR2

[0133] Similarly, 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 turn, a) has complementarity-determining regions C DR'1 (SEQ ID NO: 4), CDR'2 (SEQ ID NO: 5), and CDR'3 (SEQ ID NO: 6) or b) Hypervariable region CDR1' i , CDR2' i , CDR3' i at least one immunoglobulin Robulin light chain variable domain (V L Even if it contains at least one antigen-binding site including ) Often, the aforementioned ultra-variable region CDR'1 i This is the hypervariable region of CDR'1 as shown in Sequence ID 4. and 3, preferably 2, more preferably 1 amino acid different, the hypervariable region CDR'2 i teeth As shown in Sequence ID No. 5, the ultra-variable region of CDR'2 and 3, preferably 2, more preferably 3. One amino acid difference, the aforementioned hypervariable region CDR'3 i As shown in sequence number 6, CDR'3 The hypervariable region differs from 3, preferably 2, more preferably 1 amino acid, and the IL-17 bond Compatible molecules include less than about 50 nM, less than about 20 nM, less than about 10 nM, and more than about 5 nM of said molecules. Below, a concentration of approximately 2 nM or less, or more preferably approximately 1 nM or less, is 1 nM (= 30 ng / ml). It can inhibit the activity of human IL-17 by 50%, and this inhibitory activity is equivalent to that of human dermal fibroblasts. Measurement is based on IL-6 production induced by hu-IL-17 in cells.

[0134] Alternatively, an IL-17 antagonist, for example, an IL-17 binding molecule (e.g., IL- 17. Antibodies or their antigen-binding fragments, for example, secukinumab, are heavy (V H ) and light chain ( V L ) It may also contain both variable domains, and the IL-17 binding molecule is a) in order Hypervariable region CDR1 (SEQ ID NO: 1), CDR2 (SEQ ID NO: 2), and CDR3 (SEQ ID NO: 3) immunoglobulin heavy chain variable domain (VH ) and in order the hypervariable region CDR1' (arrangement) Number 4), immunoglobulins including CDR2' (SEQ ID NO: 5) and CDR3' (SEQ ID NO: 6) Light chain variable domain (V L ), or b) in order of ultra-variable region CDR1 i , CDR2 i and CDR 3 i immunoglobulin heavy chain variable domain (V H )(The aforementioned ultra-variable region CDR1 i is an array As shown in number 1, the hypervariable region of CDR1 and 3, preferably 2, more preferably 1 amino Acids differ, the aforementioned ultra-variable region CDR2 i This is the ultra-variable region of CDR2, as shown in Sequence ID 2. and 3, preferably 2, more preferably 1 amino acid different, the hypervariable region CDR3 i teeth, As shown in Sequence ID 3, the ultra-variable region of CDR3 and 3, preferably 2, more preferably 1 (Different amino acids) and in order, the hypervariable region CDR1' i , CDR2' i , CDR3' i Includes exemption Epidemic globulin light chain variable domain (V L )(The aforementioned ultra-variable region CDR'1 i This is shown in Sequence ID No. 4. The hypervariable region of CDR'1 differs from 3, preferably 2, more preferably 1 amino acid. , the aforementioned ultra-variable region CDR'2 i As shown in Sequence ID 5, the ultra-variable region of CDR'2 and 3 Preferably two, more preferably one amino acid different, the hypervariable region CDR'3 i is, As shown in column number 6, the ultra-variable region of CDR'3 and 3, preferably 2, more preferably 1 The IL-17 binding molecule has at least one antigen-binding site containing (different amino acids) This refers to the above molecules with concentrations of approximately 50 nM or less, approximately 20 nM or less, approximately 10 nM or less, approximately 5 nM or less, and approximately 2 Human IL at concentrations of nM or less, or more preferably about 1 nM or less, with 1 nM (=30 ng / ml) human IL. -17 activity can be inhibited by 50%, and this inhibitory activity is observed in human dermal fibroblasts. It is measured based on the production of IL-6 induced by IL-17.

[0135] Alternatively, an IL-17 antagonist, for example, an IL-17 binding molecule (e.g., IL- 17. Antibodies or their antigen-binding fragments, for example, secukinumab, are heavy (V H ) and light chain ( V L ) It may also contain both variable domains, and the IL-17 binding molecule is a) in order Ultra-variable region CDR1-x (sequence number 11), CDR2-x (sequence number 12), and CDR3 -x (SEQ ID NO: 13) contains an immunoglobulin heavy chain variable domain (V H ) and in order, ultra-variable Regions CDR1' (SEQ ID NO: 4), CDR2' (SEQ ID NO: 5), and CDR3' (SEQ ID NO: 6) ) containing the immunoglobulin light chain variable domain (V L ), or b) in order of ultra-variable region CDR1 i - x, CDR2 i -x and CDR3 i -x containing the immunoglobulin heavy chain variable domain (V H )( The aforementioned ultra-variable region, ultra-variable region CDR1 i -x, CDR2 i -x, CDR3 i -x, the above-mentioned ultra-variable Area CDR1 i -x is the ultra-variable region of CDR1-x as shown in Sequence ID 11 and 3, preferred More preferably, two, or more preferably one amino acid different, the hypervariable region CDR2 i -x is the array number As shown in No. 12, the ultra-variable region of CDR2-x and 3, preferably 2, more preferably 1 Unlike amino acids, the aforementioned ultra-variable region CDR3 i -x is CDR3- as shown in sequence number 13. x is a hypervariable region and 3, preferably 2, more preferably 1 amino acid different, and in order is hypervariable Modified Region CDR1' i , CDR2' i , CDR3' i immunoglobulin light chain variable domains (V L )(The aforementioned ultra-variable region CDR'1 i As shown in Sequence ID 4, the hypervariable region of CDR'1 The region differs from the hypervariable region CDR'2 by 3, preferably 2, more preferably 1 amino acid. i As shown in Sequence ID No. 5, the ultra-variable region of CDR'2 and 3, preferably 2, more preferably It differs by one amino acid, and the hypervariable region CDR'3 i As shown in sequence number 6, CDR' 3 hypervariable regions and at least 3, preferably 2, more preferably 1 different amino acids It also contains one antigen-binding site, and the IL-17-binding molecule is approximately 50 nM or less of the molecule. , approximately 20 nM or less, approximately 10 nM or less, approximately 5 nM or less, approximately 2 nM or less, or more preferably approximately At concentrations of 1 nM or less, it inhibits the activity of 1 nM (=30 ng / ml) human IL-17 by 50%. This inhibitory activity can be induced by hu-IL-17 in human dermal fibroblasts. It is measured based on the production of IL-6.

[0136] The human IL-17 antibody disclosed herein is the same as the one shown as SEQ ID NO: 17. The heavy chain is qualitatively the same as the light chain shown as Sequence ID No. 15. May include chains. The human IL-17 antibody disclosed herein includes the heavy chain and SEQ ID NO: 17. It may contain a light chain including sequence number 15.

[0137] The human IL-17 antibody disclosed herein is essentially the same as the one shown in (a) Sequence ID No. 8. A single heavy chain containing a variable domain and a constant region of a human heavy chain, which have essentially the same amino acid sequence. b) Variable domains having substantially the same amino acid sequence as shown in SEQ ID NO: 10 It may include one light chain containing the constant portion of a human light chain.

[0138] The inhibition of IL-17 binding to its receptor is described in International Publication No. 2006 / 013107. It can be conveniently tested using various assays, including those listed. The term "to the same extent" refers to the reference and equivalent molecules in the assay referenced herein (International Public Disclosure Act). In one of the examples (see Example 1 of Publication No. 2006 / 013107), based on statistical evidence, This means that they exhibit essentially the same IL-17 inhibitory activity. For example, the I disclosed herein The L-17 binding molecule is described in Example 1 of International Publication No. 2006 / 013107. When assayed in this manner, the IC of the corresponding reference molecule 50 Preferably substantially the same as, Approximately 10 nM, more preferably approximately 9, 8, 7, 6, 5, 4, 3, 2 or less, or approximately 1 nM or less. The effect of human IL-17-induced IL-6 production in human dermal fibroblasts IC regarding the inhibition of IL-17 50 It generally has s. Alternatively, the assay used is possible. Soluble IL-17 receptor (e.g., human example 1 of International Publication No. 2006 / 013107) Binding of IL-17 by IL-17R / Fc constructs and IL-17-binding molecules of the present disclosure. This could be an assay for competitive inhibition.

[0139] This disclosure applies to CDR1, CDR2, CDR3, CDR1-x, CDR2-x, CDR3- x, CDR1', CDR2', or CDR3', or one of the amino acid residues of the framework One or more, generally a small number (e.g., 1-4), are, for example, protrusions in the corresponding DNA sequence. Natural mutations, such as site-directed mutagenesis, alter the IL-17 antagonist. For example, IL-17 binding molecules (for example, IL-17 antibodies or their antigen-binding fragments) This disclosure includes, for example, secukinumab. This disclosure includes an encoding DNA sequence. In particular, this disclosure includes one or more of CDR1' or CDR2'. The number of residues is in SEQ ID NO: 4 (for CDR1') and SEQ ID NO: 5 (for CDR2') It contains an IL-17 binding molecule that has been modified from the indicated residue.

[0140] This disclosure also relates to an IL-17-binding molecule having binding specificity to human IL-17, An IL-17 antibody and the molecule that can inhibit the binding of IL-17 to its receptor. Approximately 50 nM or less, approximately 20 nM or less, approximately 10 nM or less, approximately 5 nM or less, approximately 2 nM or less or More preferably, the activity of 1 nM (=30 ng / ml) human IL-17 at a concentration of approximately 1 nM or less. An IL-17 antagonist that can inhibit IL-17 by 50%, for example, an IL-17 binding agent Child (for example, IL-17 antibody or its antigen-binding fragment, for example, secukinumab) (the above) The inhibitory activity is related to the IL-6 induction by hu-IL-17 in human dermal fibroblasts. (Measured based on production)

[0141] This disclosure relates to therapeutically effective amounts of IL-17 antagonists, such as IL-17-binding molecules. (For example, IL-17 antibody or its antigen-binding fragment, e.g., secukinumab) for patients with RA For those treating RA, including, for example, those administering the medication to high-risk RA patients. The method is provided. In some embodiments, an IL-17 antibody, for example, secukinumab is used. , Leu74, Tyr85, His86, Met87, Asn88, Val124, Th Mature human I cells including r125, Pro126, Ile127, Val128, and His129 It binds to the L-17 epitope. In some embodiments, an IL-17 antibody, for example Secukinumab contains Tyr43, Tyr44, Arg46, Ala79, and Asp80. It binds to the epitope of mature human IL-17. In some embodiments, IL-1 7 antibodies, for example, secukinumab, are IL-17 homozygous antibodies that have two mature human IL-17 chains. The dimer is bound to an epitope, and the epitope is Leu74, Tyr85 on one chain. , His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 and Tyr43, Tyr44, A on the other chains Includes rg46, Ala79, and Asp80. The remaining values ​​used to define these epitopes. The numbering scheme is such that one of the residues is the first amino acid of a mature protein (i.e., It lacks a 23-amino acid N-terminal signal peptide and is based on IL-17A, which starts with glycine. The sequence of immature IL-17A is located at Swiss-Prot entry Q16552. It is shown.

[0142] In some embodiments, the IL-17 antibody is present at approximately 100-200 pM K D possess In some embodiments, the IL-17 antibody is approximately 0.67 nM human IL-17A Regarding the in vitro neutralization of the biological activity of approximately 0.4 nM IC50, 50 It has several implementation forms. In this state, the absolute bioavailability of IL-17 antibody administered subcutaneously (sc) is approximately It has a range of 60-80%, for example, about 76%. In some embodiments, IL- 17 antagonists, for example, IL-17 binding molecules (e.g., IL-17 such as secukinumab) -17 antibodies) or IL-17 receptor-binding molecules (e.g., IL-17 receptor antibodies) are approximately It has a half-life of 4 weeks (for example, about 23 to 30 days, for example, about 30 days). In that embodiment, an IL-17 antagonist, for example, an IL-17 binding molecule (e.g.) For example, IL-17 antibodies such as secukinumab or IL-17 receptor-binding molecules (e.g., IL-17 receptor antibody) is about 7-8 days old. max It holds.

[0143] Some practical applications of the disclosed methods, uses, pharmaceutical compositions, kits, assays, and therapeutic regimens In terms of application, the IL-17 antagonist is a) an IL-17 binding molecule or IL-1 7 Receptor-binding molecules, b) Secukinumab, c) Leu74, Tyr85, His86, M et87, Asn88, Val124, Thr125, Pro126, Ile127, V IL-17 antibodies that bind to IL-17 epitopes including al128 and His129, d ) IL-17 including Tyr43, Tyr44, Arg46, Ala79, Asp80 IL-17 antibody that binds to a pitope, e) I having two mature IL-17 protein chains IL-17 antibody that binds to the epitope of L-17 homodimer (the epitope is one Leu74, Tyr85, His86, Met87, Asn88, Val124 on the chain, Thr125, Pro126, Ile127, Val128, His129 and other chains (including Tyr43, Tyr44, Arg46, Ala79, Asp80), f) two IL-17 that binds to the epitope of an IL-17 homodimer having a mature IL-17 protein chain. -17 antibody (the epitope is Leu74, Tyr85, His86, M on one chain) et87, Asn88, Val124, Thr125, Pro126, Ile127, V al128, His129 and Tyr43, Tyr44, Arg46, Ala on the other chains 79, containing Asp80, the IL-17 binding molecule is present at approximately 100-200 pM K D Having The IL-17 binding molecule has an in vivo half-life of approximately 4 weeks, and g)i) sequence The immunoglobulin heavy chain variable domain (V) containing the amino acid sequence indicated as number 8 H ), i i) Immunoglobulin light chain variable domain containing the amino acid sequence shown as Sequence ID No. 10 ( V L ), iii) Immunoglobulin V containing the amino acid sequence shown as Sequence ID No. 8 H Domaine Immunoglobulin V containing the amino acid sequence shown as n and SEQ ID NO: 10 L Domain, i v) Immunoglobulin containing the hypervariable region indicated as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 Phosphorus V H Domain, v) Hypervariable domains shown as Sequence ID No. 4, Sequence ID No. 5 and Sequence ID No. 6 Immunoglobulin V including the region L Domain, vi) Sequence ID 11, Sequence ID 12 and Sequence ID Immunoglobulin V containing the hypervariable region shown as 13 H Domain, vii) Sequence ID 1 Immunoglobulin V containing the hypervariable region shown as SEQ ID NOs: 2 and 3. H Domaine Immunoglobulins including the hypervariable region shown as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 Brin V L The domain, and viiii) Sequence IDs 11, 12 and 13 Immunoglobulin V containing the hypervariable region shown H Domain and Sequence ID 4, Sequence ID 5 and immunoglobulin V including the hypervariable region shown as SEQ ID NO: 6 L A group consisting of domains The antibody is selected from a group consisting of IL-17 antibodies, including an antibody selected from the above.

[0144] Particularly preferred IL-17 antagonist for use in the disclosed methods, uses, kits, etc. For example, IL-17 binding molecules (for example, IL-17 antibodies or their antigen binding cleavage) (For example, secukinumab) or an IL-17 receptor-binding molecule (for example, an IL-17 antibody) Or its antigen-binding fragment) is a human antibody, in particular, International Publication No. 2006 / 013107 This is the secukinumab described in Examples 1 and 2. Secukinumab (AIN457) This is a recombinant high-affinity fully human monoclonal anti-human interopropyl alcohol of the IgG1 / kappaiiso type. It is an Ikin 17A (IL-17A, IL-17) antibody. Secukinumab (for example, international public (See Publication No. 2006 / 013107 and International Publication No. 2007 / 117749) A very high affinity for -17, i.e., K at approximately 100-200 pM. D and approximately 0.4 In vitro neutralization of the biological activity of approximately 0.67 nM human IL-17A in IC 50 possess Therefore, secukinumab inhibits the antigen in a molar ratio of approximately 1:1. This high binding affinity Because of its incompatible nature, secukinumab antibodies are particularly suitable for therapeutic application. Furthermore, secukinumab Kinumab has a very long half-life, approximately 4 weeks, which means that it is absorbed between doses. This allows for a long period of time, and is suitable for conditions such as rheumatoid arthritis (RA). It was confirmed that this is an exceptional characteristic when treating lifelong chronic diseases.

[0145] Treatment regimens, methods of treatment, pharmaceutical compositions and uses Disclosed IL-17 antagonists, for example, IL-17 binding molecules (e.g., IL- 17 antibody or its antigen-binding fragment (e.g., secukinumab) or IL-17 receptor binding Sex molecules (e.g., IL-17 antibodies or their antigen-binding fragments) are used in inflammatory arthritis (e.g., Treatment and prevention of rheumatoid arthritis (RA), spondyloarthritis, ankylosing spondylitis, and psoriatic arthritis. It is useful for improvement. Therefore, such molecules are useful for the signs of arthritis and structural changes and It is useful in causing changes in symptoms, preventing further joint erosion, and improving joint structure, etc. In some embodiments, a patient with inflammatory arthritis is a patient with RA, for example. He is a high-risk rheumatoid arthritis patient.

[0146] IL-17 antagonists, for example, IL-17 binding molecules (e.g., IL-17 antibodies) or its antigen-binding fragment, e.g., secukinumab) or IL-17 receptor-binding molecule ( For example, IL-17 antibodies or their antigen-binding fragments are used in vitro and ex vivo. It can be used, or mixed into a pharmaceutical composition, for example, to treat RA in high-risk RA patients. In vivo administration to an individual (e.g., a human subject) to treat, improve, or prevent Yes, it is possible. Pharmaceutical compositions shall be formulated to be compatible with their intended route of administration (e.g., For example, oral compositions generally contain an inert diluent or edible carrier. Other non- Limited examples include parenteral (e.g., intravenous), intradermal, subcutaneous, and oral (e.g., inhalation). These include transdermal (topical), transmucosal, and rectal administration. Pharmaceutical compositions suitable for each intended route are available. This is well known in the field of technology.

[0147] IL-17 antagonists, for example, IL-17 binding molecules (e.g., IL-17 antibodies) or its antigen-binding fragment, e.g., secukinumab) or IL-17 receptor-binding molecule ( For example, an IL-17 antibody or its antigen-binding fragment is mixed with a pharmaceutically acceptable carrier. If so, it can be used as a pharmaceutical composition. Such a composition is IL-17 an In addition to the tagonist (e.g., secukinumab), carriers, various diluents, fillers, salts, and buffers are also used. The carrier may contain agents, stabilizers, solubilizers, and other substances well known in the art. Sex depends on the route of administration.

[0148] The pharmaceutical compositions used in the disclosed method also include additional therapeutic agents for the treatment of specific target disorders. It may also include an anti-inflammatory agent. The factors / drugs produce a synergistic effect with IL-17 antagonists (e.g., secukinumab). To produce or to minimize side effects caused by IL-17 binding molecules It can be included in the pharmaceutical composition.

[0149] The pharmaceutical compositions disclosed herein include IL-17 antagonists, for example, IL-17 binding molecules ( For example, IL-17 antibody or its antigen-binding fragment (e.g., secukinumab) or IL- 17 Receptor-binding molecules (e.g., IL-17 antibody or its antigen-binding fragment) can interfere with other drugs. In addition to scientifically acceptable carriers, micelles, insoluble monolayers, liquid crystals, or lamellar layers are used in aqueous solutions. In the form of liposomes, which are bound to amphiphilic substances such as lipids that exist in an aggregated form. Suitable lipids for liposome formulations include, without limitation, monoglycerides, dig These include riserids, sulfatides, lysolecitin, phospholipids, saponins, and bile acids.

[0150] When implementing the treatment methods, regimens, and uses described herein, a therapeutically effective amount of IL- 17 Antagonists, for example, IL-17 binding molecules (for example, IL-17 antibodies or The antigen-binding fragment, for example, secukinumab, or an IL-17 receptor-binding molecule (for example, Targeting IL-17 antibodies or their antigen-binding fragments, for example, mammals (e.g., humans) Administer to the patient. An IL-17 antagonist (e.g., secukinumab) is administered by the method of this disclosure. It can be used alone or in combination with other therapies, for example, in combination with additional therapies for inflammation. It can be administered. When administered in combination with one or more drugs, the IL-17 antagonist The drug (e.g., secukinumab) can be administered concurrently or consecutively with other drugs. If administered continuously, the attending physician should use an IL-17 antagonist (e.g., secukinumab). Determine the appropriate order in which to administer other medications in combination.

[0151] A therapeutically effective amount of IL-17 antagonist, for example, an IL-17 binding molecule (e.g., IL-17 antibody or its antigen-binding fragment (e.g., secukinumab) or IL-17 receptor When administering a body-binding molecule (e.g., IL-17 antibody or its antigen-binding fragment) orally. The binder is in the form of tablets, capsules, powders, liquids, or elixirs. If used, the pharmaceutical composition of this disclosure further comprises a solid carrier or adjuvant such as gelatin. It is also acceptable to administer it in liquid form with water, petroleum, or peanut oil (note regarding peanut allergies). Liquids such as animal or plant-derived oils, mineral oils, soybean oils, sesame oils, or synthetic oils (to be careful of) A body carrier can be added. The pharmaceutical composition in liquid form is physiological saline solution, dextrose or other sugar solutions or ethylene glycol, propylene glycol or polyethylene It may also contain other components such as glycols.

[0152] A therapeutically effective amount of IL-17 antagonist, for example, an IL-17 binding molecule (e.g., IL-17 antibody or its antigen-binding fragment (e.g., secukinumab) or IL-17 receptor Body-binding molecules (e.g., IL-17 antibody or its antigen-binding fragment) are administered intravenously, through the skin, or When administered by subcutaneous injection, the IL-17 binding molecule does not contain pyrogens and is permitted parenterally. It is in the form of an admissible solution. Pharmaceutical compositions for intravenous, cutaneous, or subcutaneous injection include IL-17 an In addition to tagonists (e.g., secukinumab), sodium chloride, Ringer's solution, and dextromethorrhea are also used. Isotonic excipients such as dextrose sodium chloride, lactated Ringer's solution, or the technical components It may also contain other excipients known in the field.

[0153] The pharmaceutical composition used in the disclosed method can be manufactured by conventional methods. In terms of form, the pharmaceutical composition is preferably provided as a lyophilized product for immediate administration. Then, dissolve it in a suitable aqueous carrier, such as sterile water for injection or sterile buffered saline. It is desirable to prepare a larger volume of solution for administration by infusion rather than injection. If deemed necessary, human serum albumin or the patient's own heparinized blood may be added during preparation. It may be advantageous to mix it with saline solution. Due to the presence of chlorine, adsorption occurs on the walls of containers and tubes used together with the injection solution. Antibody loss is prevented. When using albumin, the appropriate concentration is 0.5% of physiological saline solution. The concentration is 5 to 4.5% by weight. Other formulations include liquid or lyophilized preparations.

[0154] The appropriate dosage, of course, depends on the specific IL-17 antagonist used, for example. For example, an IL-17 binding molecule (for example, an IL-17 antibody or its antigen-binding fragment, for example) , secukinumab) or IL-17 receptor-binding molecules (e.g., IL-17 antibody or so The antigen-binding fragment, host, method of administration, nature and severity of the condition being treated, and the patient It depends on the nature of previous treatments received. Ultimately, the healthcare provider will determine the treatment for each individual patient. Determine the amount of IL-17 antagonist (e.g., secukinumab) to use for treatment. In one embodiment, the healthcare provider administers a low dose of an IL-17 binding molecule. The subject's reaction can be observed. In another embodiment, IL-17 administered to the subject The initial dose (single or multiple) of an antagonist (e.g., secukinumab) is high, followed by The dose is then reduced until signs of recurrence appear. The optimal therapeutic effect for the patient is obtained. Administer a higher dose of IL-17 antagonist (e.g., secukinumab) until [the desired result is reached]. It is possible to do so, and generally, the dosage is not increased further at that point.

[0155] IL-17 antagonists, for example, IL-17 binding molecules (e.g., IL-17 antibodies) or its antigen-binding fragment, e.g., secukinumab) or IL-17 receptor-binding molecule ( For example, IL-17 antibody or its antigen-binding fragment) can be administered parenterally, for example, in the forearm or The drug is conveniently administered intravenously, intramuscularly, or subcutaneously to other peripheral veins. The duration of intravenous (IV) therapy using the drug depends on the severity of the disease being treated and the individual patient. The effects vary depending on the patient's condition and individual response. Subcutaneous (sc) use of the pharmaceutical composition of this disclosure .) Therapy is also possible. Healthcare providers may use the pharmaceutical compositions of this disclosure in IV or S. c. Determine the appropriate duration of treatment and the timing of its administration.

[0156] Satisfactory results (treatment, prevention, delay of symptom onset) are approximately 0. 0.5 mg to approximately 30 mg, more commonly, approximately 0.1 mg to approximately 20 mg per kilogram of body weight. It is generally indicated that the desired result can be obtained with a dose of g. The frequency of administration ranges from approximately once a day to every three months. A range of once every two weeks, for example, a range of once every 12 weeks, for example It may be administered once every 4 to 8 weeks. The frequency of administration depends, in particular, on the phase of the treatment regimen. do.

[0157] HERCEPTIN (trademark) (trastuzumab), RITUXAN (trademark) (rituxi The effectiveness of antibody drugs, including products such as Mab, SYNAGIS (trademark) (palivizumab) Its use as an ingredient is now widespread. The technology for purifying antibodies to pharmaceutical grade is currently This is well known in the technical field. Antibodies, such as antibodies against IL-17, are typically administered parenterally. Prepared in aqueous form or as a lyophilized form for reconstitution with an appropriate diluent before administration. It is prescribed as follows. In some embodiments of the disclosed methods and uses, IL-17 Tagonists, such as IL-17 antibodies, such as secukinumab, are prescribed as lyophilized products. Appropriate lyophilized formulations are prepared in small volumes of liquid (e.g.,) to enable subcutaneous administration. It can be reconstituted with 2 ml or less and may provide a solution with low levels of antibody aggregation. The composition shall be normally sterile at least at the time of its formation. The composition shall be normally non-pyrogenic. It is a type of substance, for example, less than 1 EU (endotoxin units, a standard scale) per dose, and is preferred. Or it shall be less than 0.1 EU per dose. The composition preferably contains gluten. Not included. In the formulations disclosed herein, the antibody is preferably the total protein in the formulation. at least 80% by weight (for example, at least 90%, 95%, 97%, 98%, 99%) It occupies (or more than) a certain percentage. Therefore, the antibody is in a purified form.

[0158] Freeze-dried product The technique of freeze-drying antibodies is well known in this field. For example, Rey & May (2004) Freez e-Drying / Lyophilization Of Pharmaceutical & Biological Products ISBN 0824748689 International Publication No. 92 / 15331, U.S. Patent Application No. 2008 / 0286280, International Publication Publication No. 03 / 041637, International Publication No. 2008 / 116103, International Publication No. 2008 Publication No. / 029908, International Publication No. 2007 / 074880, International Publication No. 03 / 00981 See Issue 7 and International Publication No. 98 / 022136. For example, the antibody product SYNAGI. S (trademark), REMICADE (trademark), RAPTIVA (trademark), SIMULECT ( XOLAIR (trademark), XOLAIR (trademark), and HERCEPTIN (trademark) are available as freeze-dried products. These antibodies are supplied. These antibodies are reconstituted to various final concentrations, for example, SIMULECT( REMICADE (trademark) is reconstituted to a concentration of 4 mg / ml antibody, and REMICADE (trademark) is 10 ml At a concentration of g / ml, HERCEPTIN (trademark) is 21 mg / ml, SYNAGIS (Trademark) and RAPTIVA (Trademark) are at 100 mg / ml, and XOLAIR (Trademark) is It is then reconstituted to 125 mg / ml.

[0159] The lyophilized product of this disclosure has an anti-IL-17 antibody concentration of at least about 15 mg / ml It can be reconstituted into an aqueous composition. The antibody concentration is greater than approximately 15 mg / ml. Much higher, for example, >approximately 15 mg / ml, >approximately 20 mg / ml, >approximately 25 mg / ml, >about 50mg / ml, >about 75mg / ml, >about 100mg / ml, >about 125mg / m l, >approximately 150 mg / ml, >approximately 300 mg / ml or higher.

[0160] The freeze-dried product contains, in addition to the anti-IL-17 antibody, for example, (i) sugar, (ii) buffer, (i (ii) containing one or more surfactants and (iv) stabilizers, among other components. The inclusion of each of the following further components is obtained. This can result in a composition that is characteristic and has low aggregation of anti-IL-17 antibodies. Component (iv) The inclusion of this substance is advantageous because it has been shown to further reduce aggregation after storage.

[0161] If present, components (i) to (iv) are active after storage (under normal conditions) and reconstitution. This is a pre-lyophilization concentration sufficient to maintain the anti-IL-17 antibody in a soluble form. The components are assumed to still exist after reconstruction.

[0162] Suitable sugars for use with the present invention include, but are not limited to, monosaccharides, disaccharides, and trisaccharides. No. For example, sugars include sucrose, trehalose, raffinose, maltose, and sorbitol. It may be an alcohol or mannitol. The sugar may be a sugar alcohol or an amino sugar. Sucrose and trehalose (for example, about 175 mM to about 300 mM, for example, about 175 mM, about 1 80mM, about 185mM, about 190mM, about 195mM, about 200mM, about 225mM, Concentrations of approximately 250 mM, 275 mM, and 300 mM are particularly useful.

[0163] Suitable buffers for use with the present invention include histidine buffers, citrate buffers, This includes, but is not limited to, phosphate buffers, succinate buffers, acetate buffers, or Tris buffers. No. Histidine buffer (for example, approximately 5 mM to approximately 50 mM, for example, approximately 5 mM, approximately 10 mM) M, approx. 15mM, approx. 20mM, approx. 25mM, approx. 30mM, approx. 35mM, approx. 40mM, approx. 4 Concentrations of 5 mM (approximately 50 mM) are particularly useful.

[0164] Suitable surfactants for use with the present invention are nonionic surfactants and ionic surfactants. This invention includes, but is not limited to, surfactants and amphoteric surfactants. Typical surfactants used include sorbitan fatty acid esters (e.g., monocaprylic acid). Sorbitan acid, sorbitan monolaurate, sorbitan monopalmitate, trioley Sorbitan glycerinate, glycerin fatty acid ester (e.g., monocaprylate, monocaprylate) Glycerin myristate, glyceryl monostearate, polyglycerin fatty acid ester (For example, decaglyceryl monostearate, decaglyceryl distearate, monoglyceryl distearate, monoglyceryl distearate) Decaglyceryl nolate), polyoxyethylene sorbitan fatty acid ester (for example, mo Polyoxyethylene sorbitan nolaurate, polyoxyethylene sorbitan monooleate Tan, polyoxyethylene sorbitan monostearate, polyoxyethylene monopalmitate Polyethylene sorbitan, polyoxyethylene sorbitan trioleate, poly tristearate Polyoxyethylene sorbitan, polyoxyethylene sorbitol fatty acid ester (for example) For example, polyoxyethylene sorbitol tetrastearate, polyoxyethylene sorbitol tetraoleate. Ethylene sorbitol), polyoxyethylene glycerol fatty acid ester (e.g., mono Polyoxyethylene glyceryl stearate, polyethylene glycol fatty acid ester (For example, polyethylene glycol distearate), polyoxyethylene alkyl Tel (e.g., polyoxyethylene lauryl ether), polyoxyethylene polyoxy Propylene alkyl ethers (e.g., polyoxyethylene polyoxypropylene glyco) Polyoxyethylene polyoxypropylene ether, polyoxyethylene Polyoxypropylene cetyl ether, polyoxyethylene alkylphenyl ether (For example, polyoxyethylene nonylphenyl ether), polyoxyethylene hydrogenated Castor oil (e.g., polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil), Polyoxyethylene beeswax derivatives (e.g., polyoxyethylene sorbitol beeswax), Polyoxyethylene lanolin derivatives (e.g., polyoxyethylene lanolin) and polio Xyethylene fatty acid amide (e.g., polyoxyethylene stearate amide), C10 ~C18 alkyl sulfates (e.g., sodium cetyl sulfate, sodium lauryl sulfate, etc.) Polio (sodium leucolate), which has an average of 2-4 moles of ethylene oxide units added. Xyethylene C10-C18 alkyl ether sulfates (e.g., polyoxyethylene lauryl sulfates) Sodium yl sulfate and C1-C18 alkyl sulfosuccinate salts (for example, (Sodium uryl sulfosuccinate), as well as lecithin, glycerophospholipids, and sphi Natural surfactants such as ngolinolipids (e.g., sphingomyelin) and C12-C1 The composition contains, but is not limited to, sucrose esters of 8 fatty acids. It may contain one or more surfactants. Preferred surfactants are polyoxyethylene sorbitan. These are tan fatty acid esters, for example, polysorbate 20, 40, 60, or 80. Tween 80 (for example, approximately 0.01% to approximately 0.1%, for example, approximately 0. Concentrations of approximately 0.2%, 0.04%, 0.06%, 0.08%, and 0.1% are particularly useful. be.

[0165] The freeze-dried product may contain active ingredients in addition to antibodies. For example, chemotherapeutic compounds. It may contain substances with pharmacological effects. For example, it may contain methotrexate. It is also common knowledge that freeze-dried products may contain sodium methotrexate.

[0166] The pH of aqueous antibody preparations before freeze-drying can range from 4.0 to 8.0, and is approximately 5.5 to approximately Within the range of 7.4, for example, approximately 5.5, approximately 5.6, approximately 5.7, approximately 5.8, approximately 5.9, approximately 6, Approximately 6.2, 6.4, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1 pH levels of approximately 7.2, 7.3, and 7.4 are common.

[0167] Approximately 25 mg, 50 mg, 75 mg, 150 mg, or 300 mg of anti-IL-17 antibody, preferred Alternatively, 75 mg to 150 mg (for example, 75 mg or 150 mg) of anti-IL-17 antibody. Disclosed is an antibody lyophilized product containing: IL-17 antibody, e.g., secukinumab, sugar, buffer. The disclosure also includes lyophilized products containing surfactants. The compositions may also include stabilizers.

[0168] (i) IL-17 antibody, e.g., secukinumab, sugar, buffer, surfactant and optionally (ii) the step of preparing an aqueous solution containing a stabilizer, and (ii) the step of freeze-drying the aqueous solution. A method for preparing a freeze-dried product, including the above, is also disclosed.

[0169] reconstruction Before the freeze-dried product can be administered to the patient, a liquid composition (hereinafter referred to as "reconstituted product") is obtained. Therefore, it should be reconstituted with a liquid reconstituter (e.g., an aqueous liquid).

[0170] The freeze-dried product is available in various volumes (e.g., 0.25 ml, 0.5 ml, 1.0 ml, 1.5 ml). It can be reconstituted with a reconstituter (e.g., aqueous reconstituter, e.g., water) in an amount such as ml. This step redissolves the antibodies and other components in the lyophilized product, making it suitable for injection into the patient. A solution can be obtained. The volume of aqueous substance used for reconstitution is in the resulting pharmaceutical composition. This may determine the concentration of the antibody and the route of administration. The volume is less than the volume before lyophilization. Reconstitution with a volumetric reconstituter yields a composition that is more concentrated than the one before freeze-drying. As described above, the freeze-dried product of the present invention contains at least about 75 mg / ml (or higher) It can be reconstituted to obtain an aqueous composition containing a concentration of anti-IL-17 antibody, and reconstructed The volume of the compound shall be selected accordingly.

[0171] Disclosed herein are reconstitutes containing an anti-IL-17 antibody, and the reconstitutes are small in number. At least 25 mg / ml, 50 mg / ml, 75 mg / ml, 150 mg / ml, or 30 0 mg / ml, preferably 75 mg / ml to 150 mg / ml (for example, 75 mg / ml) It has an antibody concentration of 150 mg / ml (or 150 mg / ml). Ideally, it is an IL-17 antagonist. To facilitate subcutaneous administration, the volume of the reconstitute is small, for example, 0.25-2.0 ml. That is the case.

[0172] Common reconstitution agents for lyophilized antibodies are sterile water or buffer solution, sometimes containing a preservative. And so on. If the freeze-dried material contains a buffer, the reconstituter may contain an additional buffer (freeze-dried material). It may contain (the same as or different from) the buffering agent, or rather, a looser buffering agent. The catalyst does not need to be included (e.g., WFI, physiological saline). The reconstitute is co-delivered with the antibody. It may contain pharmacologically active substances such as chemotherapeutic compounds that promote [the process].

[0173] If present, the above components (i) to (iv) retain pharmacopositability at the time of use. At the same time, the anti-IL-17 antibody is converted into an active and soluble form after reconstitution under normal storage conditions. The concentration should be sufficient to maintain [the condition].

[0174] In addition to antibodies and water, the reconstitute contains further components derived from the freeze-dried product and / or the reconstituter. It may contain ingredients such as buffers, salts, stabilizers, glycerol, and alcohol. This includes, but is not limited to, preservatives, surfactants, etc. The discussion is based on Gennaro (2000) Remington: The Science and Practice of Pharmacy, 20th edition. It can be viewed at ISBN: 0683306472.

[0175] Reconstituted pharmaceuticals containing an IL-17 antibody, such as secukinumab, sugar, buffer, and surfactant. A composition is disclosed. The composition may contain a stabilizer. The freeze-dried product is used as an aqueous reconstitute. The process includes a step of mixing with the lyophilized product, which contains an IL-17 antibody, e.g., secukinumab, sugar, A method for preparing a reconstitute, including a buffer, a surfactant, and optionally a stabilizer, is also disclosed. .

[0176] This specification discloses the use of therapeutically effective doses of IL-17 antagonists in high-risk RA patients. This is a method for treating rheumatoid arthritis (RA), which includes the step of administering a drug to the patient.

[0177] Also disclosed herein is a) treatment based on the fact that the patient is a high-risk RA patient. The steps include: a) selecting patients for the purpose of, and b) administering a therapeutically effective dose of IL-17 antagonist. A method for treating rheumatoid arthritis (RA), comprising the step of administering a drug to a patient.

[0178] This specification discloses a) samples from patients i. rheumatoid factor (RF), anti-citrulline Phosphated protein antibody (ACPA), or RF and ACPA, and ii. C-reactive tan Regarding protein (CRP), erythrocyte sedimentation rate (ESR), or both CRP and ESR, The steps to be performed, and a) after the patient has RF+, ACPA+, or RF+ and ACPA The result is positive, and the patient has high levels of CRP, high ESR, or high levels of both CRP and high ESR. The procedure includes the step of administering an IL-17 antagonist to a patient if the patient has the condition. This is a method for treating rheumatoid arthritis (RA).

[0179] Disclosed herein are a) RF+, ACPA+, or both RF+ and ACPA+ a) high levels of CRP, high ESR, or both high levels of CRP and high ESR Under the condition that patients are selected for treatment purposes based on having the ability to administer a therapeutically effective dose, A step of administering an IL-17 antagonist to a patient for rheumatoid arthritis (RA) This is a method of treatment. In some embodiments, the step of administration is a) IL-1 7) The step of administering an antagonist to the patient during the introduction regimen, and b) thereafter IL-1 The procedure includes the step of administering an antagonist to the patient during the maintenance regimen.

[0180] Disclosed herein is a) an IL-17 antagonist administered at a dose of approximately 10 mg / kg The procedure involves administering the drug to high-risk RA patients in three steps (delivering each of the three doses every other week) and b) Subsequently, administer an IL-17 antagonist at approximately 75 mg to 150 mg as the third intravenous administration. A step of administering the dose to the patient monthly, starting one month after delivery, for rheumatoid arthritis (R This is a method to treat A).

[0181] Disclosed herein is a)i. a patient who has RF+, ACPA+, or RF+ and ACP Both A+ and ii. the patient has high levels of CRP, high ESR, or high CR Step 1: Select patients with RA based on the criterion of having both P and high ESR. b) Administer the patient an IL-17 antagonist at a dose of approximately 10 mg / kg three times. Step (deliver the first dose in week zero, the second dose in week two, and the third dose in week four) (Delivered in the first week), and then c) starting in the eighth week, twice a month, once a month, every two months or every three weeks. Every month, the patient is administered an IL-17 antagonist at a dose of approximately 75 mg to 150 mg. This is a treatment regimen for rheumatoid arthritis (RA), including TEP.

[0182] This specification discloses the administration of IL-17 antagonists to high-risk RA patients. IL-17 antagonists, characterized by [specific features], are used to treat rheumatoid arthritis (RA). This specification discloses treatment based on the fact that the patient is a high-risk RA patient. This method is characterized by administering an IL-17 antagonist to patients selected for the purpose of treatment. It is an IL-17 antagonist used to treat rheumatoid arthritis (RA).

[0183] Disclosed herein is an IL-17 antagonist used to treat high-risk RA patients. It is a rheumatoid factor. In some embodiments, high-risk RA patients a) rheumatoid factor ( RF+), serologically positive for anti-citrullinated protein antibody (ACPA+), or R The test is both F+ and ACPA+, and also b) has high levels of C-reactive protein (CRP). They have a high erythrocyte sedimentation rate (ESR) or both high CRP and high ESR. In one embodiment, when measured by hsCRP, a high level of CRP is 10 mg It is 28 mm / hour or more. In some embodiments, the high ESR is 28 mm / hour or more.

[0184] Disclosed herein are a) RF+, ACPA+, or both RF+ and ACPA+ a) high levels of CRP, high ESR, or both high levels of CRP and high ESR Under the condition that patients are selected for treatment purposes based on having the ability to do so, IL-17 A treatment for rheumatoid arthritis (RA) characterized by administering an antagonist to the patient. It is an IL-17 antagonist to be used.

[0185] This specification discloses an IL-17 antagonist at a dose of approximately 10 mg / kg The drug is administered to high-risk RA patients three times (each dose delivered every other week), and then b) thereafter Starting one month after the delivery of the third intravenous dose, a monthly dose of approximately 75 mg to 150 mg. IL- 17. He is an antagonist.

[0186] This specification discloses a) samples from patients i. rheumatoid factor (RF), anti-citrulline Phosphated protein antibody (ACPA), or RF and ACPA, and ii. C-reactive tan Regarding protein (CRP), erythrocyte sedimentation rate (ESR), or both CRP and ESR, b) The patient is RF+, ACPA+, or RF+ and ACPA+, and the patient In cases of high CRP, high ESR, or high CRP and high ESR, IL -17 Treatment of rheumatoid arthritis (RA) characterized by administering an antagonist to the patient. This is the IL-17 antagonist used for that purpose.

[0187] This specification discloses the administration of IL-17 antagonists to high-risk RA patients. IL-17 antagonist for the manufacture of drugs to treat RA, characterized by the following It is for use.

[0188] This specification discloses the use of an IL-17 antagonist during and after the introduction regimen. A drug for treating rheumatoid arthritis, characterized by being administered to high-risk rheumatoid arthritis patients during their ongoing treatment regimen. This involves the use of IL-17 antagonists in the manufacture of the agent.

[0189] Disclosed herein are IL-17 antagonists for administration to high-risk RA patients. This is a pharmaceutical composition for treating rheumatoid arthritis (RA), containing it as an active ingredient.

[0190] This specification discloses high-risk RAs during the introduction regimen and subsequent maintenance regimens. A drug containing an IL-17 antagonist as the active ingredient, to be administered to patients to treat rheumatoid arthritis (RA). It is a pharmaceutical composition.

[0191] Disclosed herein are a) the step of selecting high-risk RA patients, and b) 0, 2 and In the fourth week, the patient is administered an IL-17 antagonist at approximately 10 mg / kg. c) Then, starting in the 8th week, take an IL-17 antagonist once a month, approximately 75 mg to approximately 15 mg. This is a treatment regimen for treating rheumatoid arthritis (RA), which includes the step of administering 0 mg to the patient.

[0192] This specification discloses a) an IL-17 binding molecule in an introduction regimen that requires it When administered to patients, the mean peak plasma concentration of IL-17-binding molecules was approximately 360 μg / ml. C max a) a) a step that brings about IL-17 binding in the patient during the maintenance regimen After administering the molecule, i) the average concentration of IL-17-binding molecules was approximately 8 μg / ml to 30 μg / ml. Steady state trough level and / or ii) approximately 331 mg / day / L to approximately 1323 mg / day / L A step that brings forth the mean AUC-tau at steady state in patients with RA or high risk. This is a method for treating rheumatoid arthritis (RA) patients.

[0193] This specification discloses a) administering an IL-17 binding molecule to a patient during an introduction regimen. The average peak plasma concentration of IL-17-binding molecules was approximately 360 μg / ml (C max ) brings b) Subsequently, during the maintenance regimen, administer to the patient at approximately 8 μg / ml to 30 μg / ii) the mean steady-state trough level of IL-17-binding molecules in ml and / or approximately 331 mg *D / L ~ approximately 1323 mg* provides the mean AUC tau at a steady state of D / L. A characteristic feature is the IL-17 binding molecule used to treat RA patients or high-risk RA patients. That is the case.

[0194] This specification discloses a) an IL-17 binding molecule in an introduction regimen that requires it When administered to patients, the mean peak plasma concentration of IL-17-binding molecules was approximately 401 μg / ml. C max a) a) a step that brings about IL-17 binding in the patient during the maintenance regimen By administering the molecule, i) approximately 9.4 μg / ml to approximately 31 μg / ml of IL-17-binding molecules Average steady-state trough level and / or ii) approximately 314 mg / day / L to approximately 1256 mg / day High-risk RA patients, including a step that yields the mean AUC tau at steady state / L This is a method of treating it.

[0195] This specification discloses a) administering an IL-17 binding molecule to a patient during an introduction regimen. The average peak plasma concentration of IL-17-binding molecules was approximately 401 μg / ml (C max ) brings b) Subsequently, administer to the patient during the maintenance regimen, i) approximately 9.4 μg / ml to approximately 31 μg ii) the mean steady-state trough level of IL-17-binding molecules in g / ml and / or approximately 314 mg* / day / L yields a steady-state mean AUCtau of approximately 1256 mg* / day / L. It is an IL-17 binding molecule used to treat psoriasis, characterized by the following properties.

[0196] In some embodiments, the maintenance regimen ranges from approximately 9.4 μg / ml to approximately 17.3 μg This yields an average steady-state trough level of IL-17-binding molecules per ml. Several implementations In terms of morphology, maintenance is achieved with approximately 9.4 μg / ml or approximately 17.3 μg / ml of IL-17 binding. This results in an average steady-state trough level for the sex molecule. In some embodiments, the introduced resistance The regimen includes bi-weekly intravenous administration of an IL-17-binding molecule. In some embodiments, The maintenance regimen includes monthly subcutaneous administration of an IL-17-binding molecule.

[0197] Disclosed herein are a) RF+, ACPA+, or both RF+ and ACPA+ a) high levels of CRP, high ESR, or both high levels of CRP and high ESR Under the condition that patients are selected for treatment purposes based on having the ability to treat RA, It is an IL-17 antagonist used in the preparation of drugs for this purpose.

[0198] Disclosed herein are a) RF+, ACPA+, or both RF+ and ACPA+ a) high levels of CRP, high ESR, or both high levels of CRP and high ESR IL- for the manufacture of drugs for the treatment of RA in patients characterized by having the following characteristics 17 Antagonists, and the drug contains a container, with each container containing at least approximately A sufficient amount to enable the delivery of 75 mg to approximately 150 mg of IL-17 antagonists. It is prescribed to contain an IL-17 antagonist.

[0199] Disclosed herein are a) RF+, ACPA+, or both RF+ and ACPA+ a) high levels of CRP, high ESR, or both high levels of CRP and high ESR IL- for the manufacture of drugs for the treatment of RA in patients characterized by having the following characteristics 17 Antagonists, and the drug contains a container, with each container containing at least approximately It has enough IL-17 antagonist to enable delivery of 10 mg / kg. It is prescribed for sea urchin.

[0200] Disclosed herein are a) RF+, ACPA+, or both RF+ and ACPA+ a) high levels of CRP, high ESR, or both high levels of CRP and high ESR IL- for the manufacture of drugs for the treatment of RA in patients characterized by having the following characteristics It is an antagonist, and the drug can be delivered intravenously at a unit dose of approximately 10 mg / kg. It is prescribed in a dose that is effective.

[0201] Disclosed herein are a) RF+, ACPA+, or both RF+ and ACPA+ a) high levels of CRP, high ESR, or both high levels of CRP and high ESR IL- for the manufacture of drugs for the treatment of RA in patients characterized by having the following characteristics It is an antagonist, and the drug contains approximately 75 mg to 150 mg of IL- per unit dose. It is prescribed in doses that allow for subcutaneous delivery of the 17 antagonist.

[0202] Disclosed herein is i. a patient who is RF+, ACPA+, or RF+ and ACPA+ Both of the above, and ii. the patient has high levels of CRP, high ESR, or high levels of CRP and For the treatment of RA, including a step to determine whether both high ESR and high ESR are present. This is an in vitro trial method for selecting patients. Several of the disclosed in vitro trial methods are... In that embodiment, the patient undergoes the following regimen, namely, a) IL-17 antagonist The drug is administered to the patient three times at a dose of approximately 10 mg / kg, with the first dose given in week zero. The first dose is delivered, the second dose is delivered in the second week, and the third dose is delivered in the fourth week, and a) the Then, starting in the 8th week, twice a month, once a month, every two or three months, IL-17 Antah Improved therapeutic response compared to administering gonists to patients at doses of approximately 75 mg to 150 mg To have a response.

[0203] In some embodiments of the disclosed methods, kits, uses, pharmaceutical compositions, and regimens High-risk RA patients: a) Rheumatoid factor (RF+), anti-citrullinated protein antibodies ( For ACPA+, the serological reaction is positive, or both RF+ and ACPA+, and b) High levels of C-reactive protein (CRP), high erythrocyte sedimentation rate (ESR), or high levels It has both CRP and high ESR. In some embodiments, it is measured by hsCRP. When determined, a high level of CRP is 10 mg / L or higher. In some embodiments, Therefore, high ESR is 28 mm / hour or more.

[0204] In some embodiments of the disclosed methods, kits, uses, pharmaceutical compositions, and regimens The administration step involves administering an IL-17 antagonist to the patient at a dose of approximately 10 mg / kg. The procedure includes three steps of intravenous administration, with each dose administered every other week. In one embodiment, the administration step involves administering an IL-17 antagonist to the patient approximately The procedure includes a step of subcutaneous administration in doses of 75 mg to approximately 150 mg, with each of the aforementioned doses administered monthly. Administer as a single dose. In some embodiments, the administration step is a) IL-17 The steps are: a) administering a tagonist to high-risk RA patients during the initiation regimen, and b) then, The procedure includes the step of administering an L-17 antagonist to the patient during the maintenance regimen.

[0205] In some embodiments of the disclosed methods, kits, uses, pharmaceutical compositions, and regimens The initiation regimen involves administering an IL-17 antagonist at a dose of approximately 10 mg / kg to the patient three times. The step includes administering. In some embodiments, a first dose of about 10 mg / kg is administered. The first dose is delivered in week zero, and the second dose of approximately 10 mg / kg is delivered in week two, and the second dose of approximately 10 mg / kg is delivered in week two. The third dose will be delivered in the fourth week.

[0206] In some embodiments of the disclosed methods, kits, uses, pharmaceutical compositions, and regimens The maintenance regimen involves administering an IL-17 antagonist to the patient at a dose of approximately 75 mg to 300 mg. The procedure includes the following steps. In some embodiments, the maintenance regimen is twice a month, once a month, IL-17 antagonists are administered every two or three months at a dose of approximately 75 mg to 300 mg. The procedure includes the step of subcutaneous administration to the patient. In some embodiments, the maintenance regimen lasts for 8 weeks. Starting with the eyes, administer IL-17 antagonist twice a month, once a month, every two or three months. The procedure includes the step of subcutaneously administering the drug to the patient in a dose of approximately 75 mg to approximately 150 mg. Several embodiments In this case, the maintenance regimen began in week 8, with an IL-17 antagonist administered once a month for approximately 7 weeks. The procedure includes the step of subcutaneously administering 5 mg or approximately 150 mg to the patient.

[0207] In some embodiments of the disclosed methods, kits, uses, pharmaceutical compositions, and regimens Before administering an IL-17 antagonist, the patient should not be taking immunosuppressants or disease-modifying antirheumatic drugs. Disease-modifying anti-inflammatory drugs (DMARDs), pain management drugs, steroids, non-steroidal anti-inflammatory drugs (NSAIDs), A group consisting of cytokine antagonists, anabolic agents, bone antiresorbing agents, and combinations thereof. Previous RA treatment including the step of administering at least one antirheumatic drug selected from In some embodiments, before administering an IL-17 antagonist, the patient was treated. Those who are being treated with DMARDs, TNF alpha antagonists, or methotrexate The response was insufficient, unsuccessful, or intolerant.

[0208] In some embodiments of the disclosed methods, kits, uses, pharmaceutical compositions, and regimens Immunosuppressants, DMARDs, pain management drugs, steroids, NSAIDs, cytokines Treatment selected from the group consisting of gonists, anabolic agents, antiresorbing agents, and combinations thereof. The patient is further administered an effective dose of at least one anti-rheumatic drug.

[0209] In some embodiments of the disclosed methods, kits, uses, pharmaceutical compositions, and regimens , administer an IL-17 antagonist at a dose of approximately 10 mg / kg three times, and each of the above doses This is administered every other week. In some embodiments, an IL-17 antagonist is administered for approximately 75 minutes. The drug is administered in doses ranging from mg to approximately 300 mg, with each dose administered once a month.

[0210] In some embodiments of the disclosed methods, kits, uses, pharmaceutical compositions, and regimens The patient was administered an IL-17 antagonist during the induction regimen, and then during the maintenance regimen. It is administered to the patient. In some embodiments, the introduction regimen is IL-17 antagonist. The procedure includes administering Nist to the patient three times at a dose of approximately 10 mg / kg. In terms of form, a first dose of approximately 10 mg / kg is delivered in week zero, and approximately 10 mg / kg The second dose is delivered in the second week, and the third dose of approximately 10 mg / kg is delivered in the fourth week.

[0211] In some embodiments of the disclosed methods, kits, uses, pharmaceutical compositions, and regimens The maintenance regimen involves administering an IL-17 antagonist to the patient at a dose of approximately 75 mg to 300 mg. The procedure includes the following steps. In some embodiments, the maintenance regimen is twice a month, once a month, IL-17 antagonists are administered every two or three months at a dose of approximately 75 mg to 300 mg. The procedure includes the step of subcutaneous administration to the patient. In some embodiments, the maintenance regimen lasts for 8 weeks. Starting with the eyes, administer IL-17 antagonist twice a month, once a month, every two or three months. The procedure includes the step of subcutaneously administering the drug to the patient in a dose of approximately 75 mg to approximately 150 mg. Several embodiments In this case, the maintenance regimen began in week 8, with an IL-17 antagonist administered once a month for approximately 7 weeks. The procedure includes the step of subcutaneously administering 5 mg or approximately 150 mg to the patient.

[0212] In some embodiments of the disclosed methods, kits, uses, pharmaceutical compositions, and regimens High-risk RA patients: a) Rheumatoid factor (RF+), anti-citrullinated protein antibodies ( For ACPA+, the serological reaction is positive, or both RF+ and ACPA+, and b) High levels of C-reactive protein (CRP), high erythrocyte sedimentation rate (ESR), or high levels It has both CRP and high ESR.

[0213] In some embodiments of the disclosed methods, kits, uses, pharmaceutical compositions, and regimens The introductory regimen involves administering IL-17 binding agents at a concentration exceeding 80 μg / ml over a period of 10 weeks. Maintain the trough level of the child. In some embodiments, the maintenance regimen is about 8 μg This results in an average steady-state trough level of IL-17-binding molecules of approximately 17 μg / ml. In some embodiments, maintenance is performed at approximately 8 μg / ml or approximately 17 μg / ml IL -17 This results in an average steady-state trough level for binding molecules.

[0214] In some embodiments of the disclosed methods, kits, uses, pharmaceutical compositions, and regimens IL-17 antagonists are IL-17 binding molecules or IL-17 receptor binding molecules. In some embodiments, IL-17 binding molecules or IL-17 receptor binding molecules are used. The sex molecules are a) secukinumab, b) Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128 , IL-17 antibody that binds to the IL-17 epitope including His129, c) Tyr4 3. IL-17 epitopes including Tyr44, Arg46, Ala79, and Asp80 d) IL-17 antibody that binds, IL-17 with two mature IL-17 protein chains An IL-17 antibody that binds to the epitope of the monimer (the epitope is Le on one chain) u74, Tyr85, His86, Met87, Asn88, Val124, Thr12 5, Pro126, Ile127, Val128, His129 and other Tyr4 on the chain 3, including Tyr44, Arg46, Ala79, Asp80), e) two mature IL- IL-17 antibody that binds to the epitope of an IL-17 homodimer having 17 protein chains. (The aforementioned epitopes are Leu74, Tyr85, His86, Met87 on one chain, Asn88, Val124, Thr125, Pro126, Ile127, Val128 , His129 and Tyr43, Tyr44, Arg46, Ala79, As on the other chains It contains p80, and the IL-17 binding molecule is at approximately 100-200 pM K D It has IL-1 7. The binding molecule has an in vivo half-life of approximately 4 weeks, and f)i) Sequence ID No. 8 The immunoglobulin heavy chain variable domain (V) contains the amino acid sequence shown. H ), ii) Sequence number The immunoglobulin light chain variable domain (V) containing the amino acid sequence shown as No. 10 L ), i ii) Immunoglobulin V containing the amino acid sequence shown as Sequence ID No. 8 H Domain and distribution Immunoglobulin V containing the amino acid sequence shown as column number 10 L Domain, iv) Sequence Immunoglobulin V containing the hypervariable region indicated as number 1, SEQ ID NO: 2, and SEQ ID NO: 3 H The domain includes, v) a hypervariable region indicated as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6. Immunoglobulin V L The domain, vi) Sequence ID 11, Sequence ID 12, and Sequence ID 13 Immunoglobulin V containing the hypervariable region shown H Domain, vii) Sequence ID 1, Sequence No. Immunoglobulin V containing the hypervariable region, indicated as code 2 and SEQ ID NO: 3. H Domain and distribution Immunoglobulin V containing the hypervariable region shown as column number 4, sequence number 5, and sequence number 6. L The domain, and viiii) indicated as sequence numbers 11, 12 and 13 Immunoglobulin V containing a highly variable region H Domain and Sequence ID 4, Sequence ID 5 and Sequence Immunoglobulin V containing the hypervariable region indicated as number 6 L Select from a group of domains IL-17 binding molecules selected from the group consisting of IL-17 antibodies including the antibody that is subjected to the action (for example) (For example, IL-17 antibody.)

[0215] In preferred embodiments of the disclosed methods, kits, uses, pharmaceutical compositions and regimens, The IL-17 binding molecule is a human antibody. Disclosed methods, kits, uses, pharmaceutical compositions and In a more preferred embodiment of the regimen, the IL-17 binding molecule is secukinumab. be.

[0216] As used herein, "[a sufficient amount of I] to enable the delivery of the specified dose" The phrase "container containing L-17 antagonist" refers to a specific container (e.g., vial, A pen or syringe can be used to dispense the desired dose of IL-17 antagonist. To refer to the distribution of a volume of a substance (for example, as part of a pharmaceutical composition) within it. For example, if the desired dose is 75 mg, the clinician may use 37.5 mg / ml. 2 ml from a container containing an IL-17 antibody preparation with a concentration of 75 mg / ml 1 ml from a container containing an IL-17 antibody preparation with a concentration of 150 mg / ml For example, 0.5 ml from a container containing the L-17 antibody preparation can be used. In each case, these containers contain a sufficient amount to enable the delivery of the desired 75 mg dose. It has an IL-17 antagonist.

[0217] As used herein, "a dose that enables delivery of [specified dose] via [route of administration]" The phrase "prescribed by" means by the specified route of administration (e.g., sc or iv) A desired dose of IL-17 antagonist, e.g., IL-17 antibody, e.g., secchunium This term is used to indicate that a specific pharmaceutical composition can be used to supply a substance. For example, if the desired subcutaneous dose is 75 mg, the clinician will use a concentration of 37.5 mg / ml. 2 ml of the IL-17 antibody preparation that is present is used to make an IL-17 antibody preparation with a concentration of 75 mg / ml. 1 ml of the agent is used with 0.5 ml of an IL-17 antibody preparation having a concentration of 150 mg / ml. For example, these IL-17 antibody preparations can be used in each of these cases. The concentration is high enough to enable subcutaneous delivery of 17 antibodies. Subcutaneous delivery is typically about 2 The delivery requires a volume of less than ml, preferably about 1 ml or less.

[0218] In some embodiments, the introduction regimen includes an IL-17 antagonist (e.g., Secukinumab), for example, secukinumab 1, 2, 3, 4, 5, 6 or more times IV doses, preferably delivered weekly, bi-weekly, every three weeks, or every four weeks (monthly) The administration of one, two, or three (most preferably three) doses of kinumab. Several implementations In this state, the introductory regimen is an IL-17 antagonist (e.g., secukinumab), e.g. For example, this includes administration of secukinumab at a dose of 10 mg / kg intravenously.

[0219] In some embodiments, an IL-17 antagonist (e.g., secukinumab) The introductory dose is administered every other week, i.e., week zero (e.g., day 1), week two (e.g., around day 15). ) and three intravenous infusions (e.g., 10 mg / kg) in the fourth week (e.g., around day 29). It can be administered as follows. In some embodiments, the induction dose is given every three weeks. This refers to week zero (for example, around day 1), week three (for example, around day 22), and week six (for example) If administered, it should be given as three intravenous infusions (for example, 10 mg / kg) around day 43. This is possible. In some embodiments, the introductory dose is every four weeks (monthly), i.e., zero. Week 1 (for example, around day 1), Week 4 (for example, around day 29), and Week 8 (for example, around day 57) It can be administered as three intravenous infusions (e.g., 10 mg / kg) on ​​day [number].

[0220] In some embodiments, an IL-17 antagonist (e.g., secukinumab) The introductory dose is administered every other week, i.e., in week zero (approximately day 1) and week two (for example, approximately day 15). It can be administered as two intravenous infusions (e.g., 10 mg / kg). In this embodiment, the introductory dose is given every three weeks, i.e., in week zero (for example, around day 1) and Then, in the third week (for example, around day 22), two intravenous infusions (for example, 10 mg / kg) are administered. It can be administered. In some embodiments, the induction dose is every four weeks (monthly). That is, two i in week zero (e.g., around day 1) and week four (e.g., around day 29) It can be administered by infusion (e.g., 10 mg / kg).

[0221] In some embodiments, an IL-17 antagonist (e.g., secukinumab) The induction dose can be administered as a single, high-dose infusion (e.g., 30 mg / kg). .

[0222] In a further embodiment, the introduction regimen includes an IL-17 antagonist (e.g., C Cukinumab) 1, 2, 3, 4, 5, 6 times or more in sc doses daily or weekly Preferably, this involves weekly administration of 3 to 5 (e.g., 4) doses of secukinumab. In several embodiments, the induction dose that can be administered daily or weekly is delivered via SC delivery. IL-17 antagonists (e.g., secukinumab) are administered in doses of approximately 75 mg to 300 mg. For example, approximately 75 mg to approximately 150 mg (for example, approximately 75 mg or approximately 150 mg).

[0223] In some embodiments, the introductory regimen involves delivering IL-17A on days 1-7. Daily SC dose of an antagonist (e.g., secukinumab), e.g., secukinumab Daily SC dose (for example, approximately 75mg to approximately 300mg, for example, approximately 75mg to approximately 15 This includes administration of 0 mg, for example, about 75 mg or about 150 mg. In some embodiments... The introductory regimen involves delivering IL-17 antagonists in weeks zero, one, two, and three. (For example, secukinumab) weekly sc dose, for example, weekly sc dose of secukinumab This includes administering the dose.

[0224] In other embodiments, the dose of secukinumab administered to the subject during the induction regimen (single (or multiple times) may be higher and more frequent (i.e., weekly during the first month of treatment). Subsequently, the patient can be maintained at a lower dose.

[0225] In some embodiments, the maintenance regimen is used when the patient's weight is less than 90 kg. The step involves subcutaneously administering approximately 75 mg or approximately 150 mg of an IL-17 binding molecule to the patient. Includes. In some embodiments, the maintenance regimen is for patients weighing 90 kg or more. In this case, approximately 150 mg or 300 mg of an IL-17 binding molecule is administered subcutaneously to the patient. Includes the top.

[0226] For maintenance regimens, the dosage of the IL-17 antagonist (e.g., secukinumab) This is twice a month (i.e., every two weeks, every two weeks, or every other week, i.e., every 14 days), Monthly (i.e., every 4 weeks, i.e., every 28 days), every two months (i.e., every other month) Alternatively, every 8 weeks (i.e., every 56 days) or every 3 months (i.e., every 12 weeks) That is, it can be supplied approximately every 84 days. As used herein, maintenance The date of the first dose of dimen is measured from the final dose of the introductory regimen. Therefore, for example... If the final dose of the introductory regimen is delivered in the fourth week, the maintenance regimen will be administered every two weeks. The first dose as part of the treatment can be delivered in the 6th week (approximately day 43), followed by monthly maintenance doses. The first dose as part of the regimen can be delivered at 8 weeks (approximately day 57), 2 The first dose as part of the monthly maintenance regimen is delivered at week 12 (approximately day 85). The first dose as part of a maintenance regimen every three months is given at 16 weeks (approximately 1 It can be delivered on the 13th day, etc. In some embodiments, the maintenance regime The first dose of N should be administered 1 month after the delivery of the final induction dose (e.g., sc or iv induction dose). It starts at the beginning of the month (i.e., approximately 4 weeks) and is delivered monthly (once a month, approximately every 4 weeks). In the administration regimen, the first dose of the maintenance regimen is administered 1 month after the delivery of the third IV induction dose. It starts at the beginning of the month (i.e., approximately every four weeks) and is delivered monthly (once a month, approximately every four weeks).

[0227] In some embodiments, the maintenance regimen is every two weeks, every month, every two months or every three months. Delivered monthly, for example, approximately 75mg to approximately 300mg (for example, approximately 75mg to approximately 150mg) mg of an IL-17 antagonist (for example, about 75 mg or about 150 mg) This includes administration of cukinumab. In some embodiments, an IL-17 antagonist ( For example, secukinumab is delivered via SC during the maintenance regimen. In preferred embodiments, Then, the maintenance dose is delivered once a month. In some embodiments, the initial maintenance dose is delivered as a therapeutic dose. The 6th week of Jimen (for example, around day 43), the 7th week (for example, around day 50), the 8th week (for example) For example, around day 57, week 9 (for example, around day 64), week 10 (for example, around day 71), Week 11 (for example, around day 78), Week 12 (for example, around day 85), or Week 13 (for example) If it is delivered on approximately the 92nd day, it will then be delivered once a month thereafter (for example, approximately every 4 weeks or every 28 days). In some embodiments, the maintenance regime is 4, 5, 6, 7, 8, 9, 10, 11 or Start in the 12th week, preferably the 8th week, and administer twice a month, once a month, every two months, or every three months. Approximately 75 mg to 300 mg of an IL-17 antagonist (e.g., secukinumab) (example) For example, approximately 75 mg to 150 mg (e.g., approximately 75 mg or 150 mg) is administered subcutaneously to the patient. This includes the step of administering the medication.

[0228] Patients with rheumatoid arthritis (e.g., high-risk rheumatoid arthritis) and other inflammatory arthritis, such as spondyloarthritis. For treating patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA), Table 5 shows the treatment regimens.

[0229] [Table 5]

[0230] The medication does not need to be administered at the exact time; for example, a dose scheduled for day 29 could be administered on day 24. It should be understood what can be done from day 1 to day 34.

[0231] In some embodiments, the disclosed introduction and / or maintenance regimen (as applicable) The dosage of the IL-17 antagonist (e.g., secukinumab) used is based on the patient's body weight. (For example, patients weighing 75kg, 80kg, 85kg, 90kg, 95kg, 10 Using whether the weight is less than or greater than 0 kg, 105 kg, etc., IL-17 for delivery to patients An antagonist, for example, the dose of secukinumab can be determined. (One embodiment) In cases where the patient's weight is approximately 80 kg or less, the patient is given approximately 75 mg or approximately 150 mg. (For example, sc delivery) is administered. In one embodiment, the patient's weight is approximately 90 kg If the dose is less than or equal to g, administer approximately 75 mg or 150 mg to the patient (e.g., via sc delivery). In one embodiment, if the patient's weight is about 100 kg or less, the patient is given about 7 Administer 5 mg or approximately 150 mg (e.g., via sc delivery). In other embodiments, If the patient's weight exceeds approximately 80 kg, the patient should be given approximately 150 mg or approximately 300 mg (for example, In another embodiment, if the patient's weight exceeds approximately 90 kg In combination, administer approximately 150 mg or 300 mg (e.g., via sc delivery) to the patient. In the administration method, if the patient's weight exceeds approximately 100 kg, the patient should be given approximately 150 mg or approximately 3 Administer 00 mg (e.g., via sc delivery).

[0232] Treatment of specific patients, for example, with IL-17 antagonists (e.g., secukinumab). For patients showing an insufficient response to this, an increase in dosage may be necessary (e.g., induction and / Or during the maintenance phase) it will be understood. Therefore, the IL-17 antagonist (for example) The SC dose of secukinumab is approximately 75 mg to 300 mg, which is higher than SC. For example, approximately 80mg, approximately 100mg, approximately 125mg, approximately 175mg, approximately 200mg, approximately 2 The dosage may be 50 mg, approximately 350 mg, approximately 400 mg, etc. Similarly, the IV dose is approximately 10 mg. More than g / kg, for example, approximately 11 mg / kg, 12 mg / kg, 15 mg / kg, 20 The dosage may be mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, etc. For specific patients... For example, adverse events or treatment with IL-17 antagonists (e.g., secukinumab). For patients who show adverse reactions to the treatment, dose reduction may also be necessary (for example, during induction and / or It will also be understood that this is during the maintenance phase. Therefore, the IL-17 antagonist (for example, The dosage of secukinumab is approximately 75 mg to approximately 300 mg, which is less than that of sc, for example, approximately 25mg, about 50mg, about 80mg, about 100mg, about 125mg, about 175mg, about 2 The dose may be 00 mg, 250 mg, etc., and similarly, the IV dose is less than approximately 10 mg / kg. For example, approximately 9 mg / kg, 8 mg / kg, 5 mg / kg, 4 mg / kg, 3 mg / kg The dosage may be g, 2 mg / kg, 1 mg / kg, etc.

[0233] In some embodiments of the methods, uses, pharmaceutical compositions, kits, and therapeutic regimens described above And, approximately 3 mg / L or more (for example, 3 mg / L), approximately 5 mg / L or more (for example, 5 mg / L) ), approximately 10 mg / L or more (for example, 10 mg / L), approximately 15 mg / L or more (for example, 15 A CRP level of mg / L is considered a high level of CRP. In some embodiments... Furthermore, CRP levels of 200 nmol / L or higher, or 240 nmol / L or higher, are considered high CRP levels. It is considered to be at a level. In a preferred embodiment, for example, by a highly sensitive CRP assay When measuring, a CRP level of approximately 10 mg / L or higher (for example, 10 mg / L) indicates high CRP levels. This is considered an RP level. In some embodiments, a high level of CRP is approximately 10m A concentration exceeding g / L, exceeding approximately 20 mg / L, or exceeding approximately 30 mg / L.

[0234] In some embodiments of the methods, uses, pharmaceutical compositions, kits, and therapeutic regimens described above Therefore, "high ESR" can be determined based on the following rule: that is, normal maximum E SR (mm / hour) ≤ (age (years) + 10 (for females)) / 2. As a result, "High ESR 」>(age (years) + 10 (for females)) / 2. In some embodiments, "High ESR" can be determined based on the following rule: that is, normal maximum ESR ( mm / hour) ≤ (age (years) + 5 (for women)) / 2. As a result, "high ESR" > (years) The formula is age (years) + 5 (for females) / 2. In some embodiments, it is 20 mm / hour. The above ESR is a high ESR in women. In some embodiments, 15 mm ESR of 28m / hour or more is considered high ESR in men. In a preferred embodiment, 28m ESRs of m / hour or higher are considered high ESRs.

[0235] In some embodiments of the methods, uses, pharmaceutical compositions, kits, and therapeutic regimens described above If the patient's RF value is greater than 20 IU / ml or greater than 30 IU / ml, the patient It is RF+. In some embodiments, when measured by turbidimetric testing, the patient's R If the F value is greater than 40 units / ml or greater than 60 units / ml, the patient is RF+. In some embodiments, when measured by a dilution test, the patient's RF titer is 1: If the value is greater than 20 or greater than 1:80, the patient is RF+. In a preferred embodiment... For example, when measuring by the turbidimetric method, the patient's RF value is 12 kU / L (in kilograms / If the reading is (in liters) or more, the patient is RF+.

[0236] In some embodiments of the methods, uses, pharmaceutical compositions, kits, and therapeutic regimens described above For example, when measured by an anti-CCP ELISA test, the patient's ACPA value is 1 U / If the value is greater than ml, greater than 3U / ml, or greater than 5U / ml, the patient should undergo ACPA. It is positive. In a preferred embodiment, the patient's ACPA value is 20 units / ml (20U). If the level is high, the patient is ACPA+.

[0237] Also disclosed herein are a) IL-17 antagonists, for example, IL-17 bonds Complementary molecules (e.g., IL-17 antibody or its antigen-binding fragment, e.g., secukinumab) or IL-17 receptor-binding molecules (e.g., IL-17 antibody or its antigen-binding fragment) Approximately 75mg to approximately 300mg (for example, approximately 75mg to approximately 150mg, for example, approximately 75mg The step of administering 4 or 5 doses (or approximately 150 mg) to high-risk RA patients (for example, skin (The following steps are taken): (4 or 5 doses are delivered once a week), and b) thereafter, L-17 antagonist (e.g., secukinumab) approximately 75 mg to approximately 300 mg (e.g., Approximately 75mg to 150mg (for example, approximately 75mg or 150mg) twice a month for one month. A step comprising administering to the patient every 2 months or every 3 months, for rheumatoid arthritis (R This is a method to treat A).

[0238] Furthermore, this specification discloses a)i.) patients who are RF+, ACPA+, or RF+ and Both ACPA+ and ii) the patient has high levels of CRP, high ESR, or high levels Patients with rheumatoid arthritis based on the criteria of having both high CRP and high ESR. The steps are: b) selecting an IL-17 antagonist, for example, an IL-17 binding molecule (For example, IL-17 antibody or its antigen-binding fragment, for example, secukinumab) or IL Approximately 75 of the IL-17 receptor-binding molecules (e.g., IL-17 antibodies or their antigen-binding fragments) mg to approximately 300 mg (for example, approximately 75 mg to approximately 150 mg, for example, approximately 75 mg or approximately 1 The step involves administering 50 mg to the patient once a week for 4 or 5 weeks (for example, subcutaneously). (step) and (c) then approximately 75 mg to approximately 300 mg of IL-17 binding molecules (for example) For example, take approximately 75mg to 150mg (for example, approximately 75mg or 150mg) twice a month. Steps to administer to the patient monthly, every two months, or every three months (for example, subcutaneous administration) This is a treatment regimen for treating RA, including (Tep).

[0239] Disclosed herein are therapeutically effective doses of IL-17 antagonists, for example, IL- 17-binding molecules (e.g., IL-17 antibody or its antigen-binding fragment, e.g., seckin) Mab) or IL-17 receptor-binding molecule (e.g., IL-17 antibody or its antigen-binding) (Fragment) indicates an increase in baseline CRP levels (e.g., higher than approximately 10 mg / L, approximately 20 mg / L). The step includes administering the drug to RA patients showing a level higher than g / L (approximately 30 mg / L), This is a method of treating rheumatoid arthritis (RA).

[0240] Furthermore, this specification discloses a)i.) patients with elevated baseline CRP levels (e.g. For example, higher than approximately 10 mg / L, higher than approximately 20 mg / L, higher than approximately 30 mg / L) The steps of selecting patients with rheumatoid arthritis based on the criterion of having, and b)i) IL-17 antagonists, for example, IL-17 binding molecules (for example, IL-17 antibodies) or its antigen-binding fragment, for example, secukinumab, or an IL-17 receptor-binding molecule (e.g., For example, approximately 75 mg to approximately 300 mg of IL-17 antibody or its antigen-binding fragment (for example) Approximately 75 mg to approximately 150 mg (for example, approximately 75 mg or approximately 150 mg) in 4 or 5 doses. Therefore, the step of administering to the patient once a week (for example, the step of subcutaneous administration), or ii) I L-17 antagonists, for example, IL-17 binding molecules (for example, IL-17 antibodies or or its antigen-binding fragment, for example, secukinumab or an IL-17 receptor-binding molecule (for example) Then, approximately 10 mg / kg of IL-17 antibody or its antigen-binding fragment is administered in three doses, spaced apart. The steps are to administer the drug to the patient weekly (for example, the step of administering it intravenously), and c) then, I L-17 antagonist (e.g., secukinumab) approximately 75 mg to approximately 300 mg (e.g., Approximately 75mg to 150mg (for example, approximately 75mg or 150mg) twice a month for one month. The step of administering to the patient every, every two months, or every three months, preferably once a month (for example, This is a treatment regimen for treating rheumatoid arthritis (RA), including the step of subcutaneous administration.

[0241] In this specification, introduction regimens, for example, IL-17 antagonists, for example, IL -17 binding molecules (e.g., IL-17 antibody or its antigen-binding fragment, e.g., secchus keratin) Numab) or IL-17 receptor-binding molecules (e.g., IL-17 antibody or its antigen-binding molecule) Approximately 10 mg / kg of the combined fragment is administered in two or three introductory doses (preferably three introductory doses) to rheumatoid arthritis. A group consisting of rheumatoid arthritis (RA), spondyloarthritis, ankylosing spondylitis (AS), and psoriatic arthritis (PsA). Steps to administer to patients with arthritis selected from (for example, step to administer intravenously) The invention also provides a method for treating inflammatory arthritis, including (P). In some embodiments, the first The first dose is delivered in week zero, the second dose in week two, and the third dose in week four. In some embodiments, the first dose is delivered in week zero, and the second dose in week three. The third dose is delivered at week 6. In some embodiments, the method is maintained The treatment regimen, for example, approximately 75 mg of an IL-17 antagonist (e.g., secukinumab). ~approximately 300mg (for example, approximately 75mg to approximately 150mg, for example, approximately 75mg or approximately 150mg) Steps to administer (for example, subcutaneous administration) (IL-17 binding) to the patient (e.g., subcutaneous administration) The regimen further includes administering the molecule to the patient twice a month, once a month, every two months, or every three months. In some embodiments, the patient is a high-risk RA patient, for example, a rheumatoid factor (RF+) patient. ), serologically positive for anti-cyclic citrullinated protein antibody (ACPA+), or RF Both + and ACPA+, and high levels of C-reactive protein (CRP) and hypererythrocytes. The sample has either a high ballistic sedimentation rate (ESR) or both high CRP and high ESR. In the application method, a high level of CRP is defined as 10 mg / dL or higher. Several embodiments In this case, high ESR is 28 mm / hour or more. In a further embodiment, inflammatory relationship Arthritis is selected from rheumatoid arthritis (RA), spondyloarthritis, ankylosing spondylitis, and psoriatic arthritis. In some embodiments, the patient has RA. In further embodiments, RA patients are high-risk RA patients. In a further embodiment, high-risk RA patients a) Regarding rheumatoid factor (RF+) and anti-citrullinated protein antibody (ACPA+) serologically positive, or both RF+ and ACPA+, and b) high levels of C-reactive cells. Protein (CRP), high erythrocyte sedimentation rate (ESR), or high levels of CRP and high ESR It possesses both.

[0242] In some embodiments, insufficient treatment with one or more TNF antagonist therapies. Treatment of adult patients with moderate to severe active rheumatoid arthritis who had a moderate response. Therefore, IL-17 antagonists, for example, IL-17 binding molecules (for example, IL-17 inhibitors) The body or its antigen-binding fragments (e.g., secukinumab) or IL-17 receptor-binding molecules (For example, IL-17 antibody or its antigen-binding fragment) used in combination with methotrexate In some embodiments, adult patients with moderate to severe active disease are treated. It reduces signs and symptoms (e.g., swelling, restricted movement) and induces major clinical responses. , IL-17 antagonists (e.g., to suppress the progression of structural damage and improve physical function) For example, secukinumab alone or methotrexate or other disease-modifying antirheumatic drugs It is used in combination with disease-modifying drugs (DMARDs). In some embodiments, it is used for moderate to severe active diseases. To reduce signs and symptoms in patients with rheumatoid arthritis (RA) and to improve major clinical responses. To induce, suppress the progression of structural damage, and improve physical function, IL-17 antagonists Use a drug (e.g., secukinumab) alone or in combination with methotrexate. In that embodiment, the symptoms in patients with moderate to severe active rheumatoid arthritis In order to reduce symptoms, suppress the progression of structural damage, and improve physical function, IL-17A An antagonist (e.g., secukinumab) is used in combination with methotrexate. In one embodiment, treatment of adults with moderate to severe active rheumatoid arthritis (RA) For this purpose, an IL-17 antagonist (e.g., secukinumab) is used. Several implementations Morphologically, to treat moderate to severe active rheumatoid arthritis (RA) in adults Therefore, an IL-17 antagonist (for example, secukinumab) is used in combination with methotrexate. In some embodiments, one or more disease-modifying antirheumatic drugs (DMAs) are used. Signs of moderate to severe active rheumatoid arthritis in patients who have been unsuccessful with RD And to reduce symptoms and slow the progression of structural damage, IL-17 antagonists (e.g.) For example, secukinumab is used. In some embodiments, moderate to severe activity To reduce signs and symptoms and induce major clinical responses in adult patients with rheumatoid arthritis. , IL-17 antagonists (e.g., to suppress the progression of structural damage and improve physical function) For example, secukinumab can be used as monotherapy or in combination with disease-modifying antirheumatic drugs (DMARDs). It is used in several embodiments. One or more TNF antagonist therapies Adult patients with moderate to severe active rheumatoid arthritis who had an inadequate response to the treatment. To treat patients, IL-17 antagonists (e.g., secukinumab) are used alone or in combination. It is used in combination with totrexate or other disease-modifying agents (DMARDs).

[0243] Combination therapy for the treatment of arthritis When carrying out the therapeutic methods or uses disclosed herein, a therapeutically effective amount of IL-17 antagonist may be used. Nist, for example, an IL-17 binding molecule (e.g., an IL-17 antibody or its antigen binding) Fragments, e.g., secukinumab) or IL-17 receptor-binding molecules (e.g., IL-17 inhibitors) The body or its antigen-binding fragments are administered to the target, for example, a mammal (for example, a human). An IL-17-binding antagonist (e.g., secukinumab) alone can be used by the method of this disclosure. Or, for example, in combination with other drugs and therapies for treating RA, for example, immunosuppression Drugs, disease-modifying antirheumatic drugs (DMARDs), pain management drugs, steroids, non-steroidal anti-inflammatory drugs (NSAIDs) Inflammatory drugs (NSAIDs), cytokine antagonists, anabolic agents, bone antiresorption agents, and so on. These are used in combination with at least one antirheumatic drug, such as in combination therapy with two or three drugs. (Medical therapy), can be administered. When administered in combination with one or more additional drugs, IL -17 Antagonists (e.g., secukinumab) should be administered concurrently or consecutively with other drugs. It is possible. When administering continuously, the attending physician should use an IL-17 antagonist (for example, Determine the appropriate sequence for administering secukinumab in combination with other drugs.

[0244] RA patients, for example, IL-17 antagonists for the treatment of high-risk RA patients (for example) For example, nonsteroidal anti-inflammatory drugs and pain management drugs that are useful in combination with secukinumab are propio. Enolic acid derivatives, acetic acid derivatives, enolic acid derivatives, fenamic acid derivatives, Cox inhibitors, for example Lumiracoxib, ibuprofen, fenoprofen, ketoprofen, flurbipro Fen, oxaprozin, indomethacin, slindac, etodrug, ketrolac Nabumeton, aspirin, naproxen, valdecoxib, etoricoxib, MK09 66. Rofecoxib, Acetominovene, Celecoxib, Diclofenac, Tramadol Lu, Pyroxicam, Meloxicam, Tenoxicam, Doroxicam, Lornoxicam, Iso Xicam, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic, bal Decoxib, Parecoxib, Etodolac, Indomethacin, Aspirin, Ibuprofen Examples include firocoxib.

[0245] RA patients, for example, IL-17 antagonists for the treatment of high-risk RA patients (for example) For example, a disease-modifying antirheumatic drug (DMARD) that is useful in combination with secukinumab is methotrexate. Lexate (MTX), antimalarial drugs (e.g., hydroxychloroquine and chloroquine) Sulfasalazine, leflunomide, azathioprine, cyclosporine, gold salt, minosai Clin, cyclophosphamide, D-penicillamine, minocycline, auranofin, Examples include chlorimus, myoclysin, and chlorambucil.

[0246] RA patients, for example, IL-17 antagonists for the treatment of high-risk RA patients (for example) For example, a useful biological agent for use in combination with secukinumab is adalimumab (Humira ( (Registered Trademark)), Etanercept (Enbrel (Registered Trademark)), Infliximab (Rem icade(registered trademark); TA-650), certolizumab pegol (Cimzia(registered trademark); Registered trademark; CDP870), Golimumab (Simponi(registered trademark); CNTO148) ), Anakinra (Kineret(registered trademark)), Rituximab (Rituxan(registered trademark) Trademarks: MabThera (registered trademark), Abatacept (Orencia (registered trademark)) Examples include tocilizumab (RoActemra / Actemra®), etc.

[0247] RA patients, for example, IL-17 antagonists for the treatment of high-risk RA patients (for example) Other biological agents useful in combination with secukinumab include, for example, integrin antarctica IL-1 antagonist (TYSABRI (registered trademark) (natalizumab)), IL-1 antagonist ( ACZ885 (Ilaris), Anakinra (Kineret®), CD4A Tagonist, IL-17 Antagonist (LY2439821, RG4934, AMG8) 27, SCH900117, R05310074, MEDI-571, CAT-2200 ), IL-23 Antagonist, IL-20 Antagonist, IL-6 Antagonist, TNF alpha antagonist (for example, TNF alpha antagonist or TNF alpha pha receptor antagonists (e.g., pegsnercept), BlyS antagonists ( For example, Atasicept, Benlysta (registered trademark) / LymphoStat-B (registered trademark) (Registered trademark) (Belimumab), P38 inhibitor, CD20 antagonist (ocrelizumab, Ofatumumab (Arzerra®), interferon-gamma-antagonis Examples include "T" (fontrhythmab).

[0248] RA patients, for example, IL-17 antagonists for the treatment of high-risk RA patients (for example) For example, steroids (e.g., glucocorticoids) that are useful in combination with secukinumab are... Rednisolone, Prednisone, Dexamethasone, Cortisol, Cortisone, Hydrocortisone Zon, methylprednisolone, betamethasone, triamcinolone, beclomethasone, flu These include dolocotisone, deoxycorticosterone, and aldosterone.

[0249] RA patients, for example, IL-17 antagonists for the treatment of high-risk RA patients (for example) Other drugs useful in combination with secukinumab include SB-681323, Rob803, AZD5672, AD452, SMP114, HZT-501, CP-195,543, Doxycycline, vancomycin, CRx-102, AMG108, pioglitazone, SBI-087, SCIO-469, Cura-100, Oncoxin + Biucid, Tw HF, PF-04171327, AZD5672, Methoxsalen, ARRY-43816 2. Vitamin D-ergocalciferol, milnacipran, paclitaxel, GW40 6381, Rosiglitazone, SC12267 (4SC-101), LY2439821, BTT-1023, ERB-041, ERB-041, KB003, CF101, ADL 5859, MP-435, ILV-094, GSK706769, GW856553, A SK8007, MOR103, HE3286, CP-690, 550 (tasocitinib), REGN88(SAR153191), TRU-015, BMS-582949, SBI -087, LY2127399, E-551S-551, H-551, GSK31523 14A, RWJ-445380, Tacrolimus (Prograf®), RAD 001, Rapamune, Rapamycin, Hostamatinib, Fentanyl, XOMA052 CNTO136, JNJ38518168, Imatinib, ATN-103, ISIS1 04838, Folic Acid, Folate, TNFα-Quinoid, MM-093, Type II Collagen, VX -509, AMG82770, macitinib (AB1010), LY2127399, sic Rosporin, SB-681323, MK0663, NNC0151-0000-0000 ATN-103, CCX354-C, CAM3001, LX3305, Cetrorelics MDX-1342, TMI-005, MK0873, CDP870, Tranilast, C F101, mycophenolic acid (and its esters), VX-702, GLPG0259, SB-681323, BG9924, ART621, LX3305, T-614, Hosta Matinib disodium (R935788), CCI-779, ARRY-371797, CDP6038, AMG719, BMS-582949, GW856553, Rosiglita Zon, CH-4051, CE-224, 535, GSK1827771, GW27415 0, BG9924, PLX3397, TAK-783, INCB028050, LY21 27399, LY3009104, R788, Curcumin (Longvida (trademark)) Rosuvastatin, PRO283698, AMG714, MTRX1011A, Maravilo K, MEDI-522, MK0663, STA5326 Mesylate, CE-224, 53 5, AMG108, BG00012, Lamipril, VX-702, CRx-102, LY 2189102, SBI-087, SB-681323, CDP870, Milnashiplan , PD0360324, PH-797804, AK106-001616, PG-760 564, PLA-695, MK0812, ALD518, Cobiprostone, Somatropin tgAAC94 gene therapy vector, MK0359, GW856553, esomeprazo Calcium, everolimus, trastuzumab, anabolic agents and bone antiresorbing agents (e.g., PTH, Bisphosphonates (e.g., zoledronic acid), JAK1 and JAK2 inhibitors, pan-A1 Potassium inhibitors, for example, tetracyclic pyridone 6 (P6), 325, PF-956980, sclero Sting antagonists (for example, whose content is incorporated herein by reference as a whole) International Publication No. 09047356, International Publication No. 2000 / 32773, International Publication Patent Application Publication No. 2006102070, U.S. Patent Application Publication No. 20080227138, U.S. Patent Patent Application Publication No. 20100028335, U.S. Patent Application Publication No. 20030229041, International Publication No. 2005003158, International Publication No. 2009039175, International Publication No. 20 Publication No. 09079471, International Publication No. 03106657, International Publication No. 2006119062 International Publication No. 08115732, International Publication No. 2005 / 014650, International Publication No. Publication No. 2005 / 003158, International Publication No. 2006 / 119107, International Publication No. 2008 Publication No. / 061013, International Publication No. 2008 / 133722, International Publication No. 2008 / 115 U.S. Patent No. 732, U.S. Patent No. 7592429, U.S. Patent No. 7879322, U.S. Patent No. 77 Disclosed in Patent No. 44874 [Disclosed method, pharmaceutical composition, kit and use in The preferred anti-sclerostin antibody and its antigen-binding fragment are described in International Publication No. 0904735. Patent No. 6 (equivalent to U.S. Patent No. 7,879,322), International Publication No. 06119107 (U.S. Patent) (equivalent to U.S. Patent No. 7872106 and U.S. Patent No. 7592429) and International Publication No. 0811 [Found in Patent No. 5732 (equivalent to U.S. Patent No. 7744874)], denosumab, I L-6 Antagonist, CD20 Antagonist, CTLA4 Antagonist, IL-1 7 Antagonist, IL-8 Antagonist, IL-21 Antagonist, IL-22 Antagonist Integrin antagonist (Tysarbri(registered trademark)(Natalis) Mab)), scleronstin antagonist, VGEF antagonist CXCL antagonist, MMP antagonist, Defensin antagonist, IL -1 Antagonists (including IL-1 Beta Antagonists) and IL-23 Antagonists Examples include receptor decoys and antagonist antibodies.

[0250] In some embodiments, an IL-17 antagonist (e.g., secukinumab) is used. Immunosuppressants, DMARDs, pain management drugs, steroids, NSAIDs, cytokines A small number of drugs selected from the group consisting of gonists, anabolic agents, bone antiresorbing agents, and combinations thereof. It is administered in combination with at least one antirheumatic drug. In some embodiments, IL-17 Antagonists (e.g., secukinumab), TNF antagonists, DMARDs (e.g., MTX (e.g., 7.5-30 mg once weekly), steroids, or combinations thereof. It is administered in combination with [another drug].

[0251] Those skilled in the art will find that the above for co-delivery with an IL-17 antagonist (e.g., secukinumab) The appropriate dosage of the listed medication can be recognized.

[0252] Kits and Products Disclosed herein are IL-17 antagonists for the treatment of RA, for example, I L-17 binding molecules (e.g., IL-17 antibody or its antigen-binding fragment, e.g., sec Kinumab) or an IL-17 receptor-binding molecule (e.g., an IL-17 antibody or its antigen) A kit (i.e., product) that is useful for providing binding fragments. This is an IL-17 antagonist (e.g., secukinumab) (e.g., liquid or lyophilized form). A pharmaceutical composition containing (as) or an IL-17 antagonist (e.g., secukinumab) It may include. Furthermore, such kits include IL-17 antagonists (e.g., Seckinu). This may include means for administering mab (e.g., a syringe or pre-filled pen) and instructions for use. These kits, for example, can be used in conjunction with the enclosed IL-17 antagonist (e.g., secukinumab). This may include further therapeutic agents (as described above) for treating RA, delivered by means of the device.

[0253] Disclosed herein are a) IL-17 antagonists, e.g., IL-17 binding A molecule (e.g., IL-17 antibody or its antigen-binding fragment, e.g., secukinumab) or IL-17 receptor-binding molecules (e.g., IL-17 antibodies or their antigen-binding fragments), b) Administer an IL-17 antagonist (e.g., secukinumab) to high-risk RA patients. Instructions regarding the following, and c) administering an IL-17 antagonist (e.g., secukinumab) to the patient. Means of administering and d) depending on the case, immunosuppressants, disease-modifying antirheumatic drugs (DMARDs) ), pain management drugs, steroids, non-steroidal anti-inflammatory drugs (NSAIDs), cytokines Treatment selected from the group consisting of agonists, anabolic agents, bone antiresorbing agents, and combinations thereof. A kit comprising a therapeutically effective amount of at least one anti-rheumatic drug. Several embodiments In this context, high-risk RA patients are a) RF+, ACPA+, or RF+ and ACPA+ Both and a) high levels of CRP, high ESR, or high levels of CRP and high ESR It has both.

[0254] Disclosed herein are (a) ILs used in the treatment of rheumatoid arthritis (RA) in patients. -17 antagonists, for example, IL-17 binding molecules (for example, IL-17 antibodies or This refers to the antigen-binding fragment, for example, secukinumab, or an IL-17 receptor-binding molecule (for example, Medical products containing IL-17 antibodies or their antigen-binding fragments, or IL-17 antagonists. a) a pharmaceutical composition and b) instructions for use describing a method for administering the pharmaceutical composition to a patient, The patient is i) RF+, ACPA+, or both RF+ and ACPA+, and ii) high Characterized by having high CRP levels, high ESR, or both high CRP and high ESR levels. It's a kit that can be kicked.

[0255] Also disclosed herein is i. a patient who is RF+, ACPA+, or RF+ and ACP Both A+ and ii. the patient has high levels of CRP, high ESR, or high CR A treatment for RA, including a step to determine whether the patient has both P and high ESR. This is an in vitro trial method for selecting patients. In some embodiments of the trial method... In this case, the patient is expected to have an improved treatment response to the next regimen. a)i) IL-17 antagonists, for example, IL-17 binding molecules (e.g., I L-17 antibody or its antigen-binding fragment (e.g., secukinumab) or IL-17 receptor A binding molecule (e.g., IL-17 antibody or its antigen-binding fragment) is added at a concentration of approximately 10 mg / kg. The drug is administered to the patient in three doses (the first dose is delivered in week zero, and the second dose is delivered in week two). (i) deliver the third dose in the fourth week), or ii) an IL-17 antagonist, for example, IL-17 binding molecules (e.g., IL-17 antibody or its antigen-binding fragment, e.g., se cukinumab) or IL-17 receptor-binding molecule (e.g., IL-17 antibody or its anti- Approximately 75 mg or approximately 150 mg of the original binding fragment is divided into 4 or 5 (preferably 5) doses. a) Administer to the patient once a week, then starting in the 8th week, twice a month, once a month, or every two months. This involves taking an IL-17 antagonist every three months (preferably once a month) at a dose of approximately 75 mg to 300 mg. Administer to the patient in mg. These in vitro methods involve biological samples taken from patients. This can be performed on samples (e.g., blood, cartilage, bone, serum, etc.) and is tailored to each individual patient. The manner or course of treatment, for example, administering an IL-17 antagonist to the patient (alone or For example, whether it is used in combination with other compounds such as methotrexate, or as an alternative therapy. For example, it can be used to decide whether or not to choose anti-TNF therapy.

[0256] Method for creating diagnostic information and a format for communication. This specification discloses that RA patients can use IL-17 antagonists, for example, IL-17 Binding molecules (e.g., IL-17 antibody or its antigen-binding fragment, e.g., secukinumab) ) or IL-17 receptor-binding molecules (e.g., IL-17 antibody or its antigen-binding fragment) A favorable response to treatment by (e.g., reduction of signs and symptoms, reduction of joint damage, life This is a method for determining (predicting) the likelihood of improvements in the quality of activities, etc. This helps doctors determine the course of treatment for individual RA patients.

[0257] Furthermore, this specification discloses a) rheumatoid factor (RF), anti-citrol, and other substances obtained from patient samples. Phosphorylated protein antibody (ACPA), or RF and ACPA, and b) C-reactive protein Regarding CRP, erythrocyte sedimentation rate (ESR), or both CRP and ESR, Steps to be taken include RA patients using IL-17 antagonists, for example, IL-17 Complementary molecules (e.g., IL-17 antibody or its antigen-binding fragment, e.g., secukinumab) or IL-17 receptor-binding molecules (e.g., IL-17 antibody or its antigen-binding fragment) This is a method to determine the likelihood of responding to treatment with RF+, ACPA+ , or RF+ and ACPA+, and the patient has high levels of CRP, high ESR, or high RED If Bell has high CRP and high ESR, the patient should be treated with an IL-17 antagonist (e.g., It may respond to treatment of rheumatoid arthritis (RA) with secukinumab in some embodiments. Before the assay step, first obtain the sample from the patient (e.g., blood or other samples from the patient). (By extracting biological tissue).

[0258] Furthermore, this specification discloses that a) the patient is RF+ and / or ACPA, and 2) RA includes a step of determining whether the patient has high levels of CRP and / or high ESR. The patient is IL-17 antagonist, for example, an IL-17 binding molecule (e.g., IL-17 Antibodies or their antigen-binding fragments (e.g., secukinumab) or IL-17 receptor-binding fragments The possibility of responding to treatment with a child (for example, IL-17 antibody or its antigen-binding fragment) This is a method of prediction, where the patient is RF+, ACPA+, or RF+ and ACPA+. In cases where there are high levels of CRP, high ESR, or high levels of both CRP and high ESR In addition, the patient has a high probability of responding to or being able to respond to treatment with an IL-17 antagonist. In some embodiments, the sample is first obtained from the patient before the confirmation step. (For example, by extracting blood or other biological tissue from the patient.)

[0259] Furthermore, this specification discloses the process of using patient samples as a base for C-reactive protein (CRP). The procedure includes a step of assaying for rheumatoid arthritis (RA) patients with IL-17 antagonists. For example, IL-17 binding molecules (for example, IL-17 antibodies or their antigen binding cleavage) (For example, secukinumab) or an IL-17 receptor-binding molecule (for example, an IL-17 antibody) This is a method for determining the likelihood of responding to treatment with either the antigen-binding fragment or the antigen-binding fragment, and here If the patient has elevated baseline CRP, the patient should be treated with an IL-17 antagonist. For example, it may respond to treatment of RA with secukinumab. In this process, before the assay step, the sample is first obtained from the patient (for example, blood from the patient). (Or by extracting other biological tissue.)

[0260] In these diagnostic and predictive methods, patient samples are used for factors (RF, ACPA, CR). Any conventional means for detecting the levels of P, ESR, or other factors, for example, radioimmunodiffusion, Electroimmunoassay, immunoturbidimetry, Western blot, Northern blot, ELISA, Turbidimetric method, fluorescence polarization immunoassay, laser turbidimetric analysis, agglutination test, turbidimetric test, red blood cell tubule The assay is performed by measuring the distance the sample settles over time (for example, in the case of ESR). This can be done. The terms "assay" and "confirm" refer to the use of the sample in physical testing. The transformation of a substance from one state to another by doing so, for example, a biological sample, for example Furthermore, it is intended for the conversion of blood samples or other tissue samples. Therefore, the terms “assay” and “confirm” mean “test and / or measure.” Used to refer to the act of... For example, "to assay a sample from a patient for..." The phrase refers to the presence or absence of a given factor, or the level of a specific factor, in relation to the sample. It is used to mean that the presence of a substance can be tested (directly or indirectly). In situations where one possibility is that the absence of matter means a different possibility, such matter It should be understood that the presence or absence of a quality can be used as a guideline for treatment decisions. In some embodiments, before treatment with an IL-17 antagonist, a skilled... The clinician determines whether the patient is a high-risk rheumatoid arthritis patient.

[0261] Typically, the presence or absence of a particular factor, or the level of a particular factor, is confirmed. If so, the results can be communicated to a doctor, genetic counselor, patient, or other researcher. Specifically, the results will be shared with other researchers, doctors, genetic counselors, or patients. It can be transmitted or converted into information in a form that can be transmitted. The form can change, and may be tangible or intangible. RF and / or relating to the presence or absence of ACPA, and / or the levels of CRP and / or ESR The results may be embodied in descriptive expressions, figures, photographs, charts, images, or any other visual form. This is possible. For example, images of PCR product gel electrophoresis can be used to explain the results. This is possible. Descriptive and visual forms include paper, floppy disks, and compact disks. On tangible media such as computer-readable media, or intangible media such as the internet On an electronic medium in the form of email or website on an intranet or network. It can be recorded. Furthermore, the presence of RF and / or ACPA in the tested individual. Or non-existence, and / or results regarding CRP and / or ESR levels are also voice Recorded in the form of telephone, facsimile, wireless mobile phone, internet phone and similar Therefore, any suitable medium, such as analog or digital cable lines or optical fibers, can be used. - It can be transmitted via cables, etc. All such forms (tangible and intangible). This constitutes "information in a form that can be transmitted." Therefore, information regarding test results Reports and data can be created anywhere in the world and transmitted to different locations. For example, When performing genotyping assays overseas, information and data regarding the test results should be handled as described above. It can be generated and converted into a form that can be transmitted. The test results can be imported into the United States. Therefore, this disclosure is not for personal use. The presence or absence of F and / or ACPA, and / or the level of CRP and / or ESR. This also includes methods for creating information about the subject in a form that can be communicated.

[0262] This specification discloses a) a sample from a patient and i) rheumatoid factor (RF), anti-citrulline Phosphated protein antibody (ACPA), or RF and ACPA, and ii) C-reactive tan Regarding protein (CRP), erythrocyte sedimentation rate (ESR), or both CRP and ESR, The steps of a) assay and a) the results of the assay step are embodied in information in a form that can be communicated. A method for creating a communicable form of information about a patient with RA, including the steps of: In some embodiments, after the step of implementation, the healthcare provider (for example) A physician may use the IL-17 antagonist disclosed herein. Use a form of information that can be communicated when making a decision to prescribe one of the treatment regimens. In that embodiment, after the step of embodiment, the healthcare provider (e.g., a physician) communicates If the patient is identified as a high-risk RA patient based on the available information, the IL-17 antagonist Administer the drug to the patient.

[0263] general All patents, published patent applications, publications, references and other materials referred to herein are subject to change without notice. The materials are incorporated herein by reference as a whole. Details of the embodiments are shown in the appendix above. Similar or equivalent to those described herein. Any method and substance of the present disclosure may be used in the implementation or testing of the present disclosure, but preferred methods and The substances will be described below. Other features, purposes, and advantages of this disclosure are described in the description and claims. This will be evident from the context. Unless otherwise specified, the singular form includes plural referents. Unless otherwise defined herein, All technical and scientific terms used are generally understood by engineers in the field of the art to which this disclosure pertains. It has the same meaning as to be interpreted as. All patents and publications cited herein refer to The following embodiments are intended to better illustrate preferred embodiments of the present disclosure. These examples illustrate the patient condition disclosed by the appended claims. It should never be interpreted as limiting the scope of the patient matter. [Examples]

[0264] Use of secukinumab to treat rheumatoid arthritis (RA) (CAIN457F220) 1) (Example 1.1) Test Design The study population met the ACR1987 revised classification criteria for RA for at least three months. The study consists of a representative group of patients (males or non-pregnant, non-lactating women) who are at least 18 years old. In order to ensure the ability to detect a response to treatment using the ACR criteria, at randomization In addition to tender joints in 6 or more out of 28 joints and swollen joints in 6 or more out of 28 joints, the concentration is 10 mg / L or higher. Active activity is defined by hsCRP or ESR of 28 mm / hour or more (mm / hour) or more. Demonstration of dynamic RA was required. Eligible candidates were to receive MTX for at least 3 months. At the time of selection, a stable dose of MTX once a week (≥7.5mg) for at least 4 weeks is required. The patient was receiving treatment with a dose of 25mg / week (or less).

[0265] Adult RA patients (n=237) who were receiving methotrexate were treated with secukinumab 25 Receive monthly SC injections of mg, 75 mg, 150 mg, 300 mg, or placebo. Patients with prior exposure to biologics were uniformly randomized. (18-22%) included. The primary endpoint was the American College of Rheumatology (ACR) at 16 weeks. This was the percentage of patients who achieved 20 weeks (8th visit). Patients who were randomized to either esophagus or secukinumab but did not achieve an ACR20 response at week 16 Patients who have been treated will receive double-blind treatment starting at week 20 and continuing until week 48, as follows: Patients were reassigned, and a final efficacy evaluation was conducted at week 52, with follow-up visits at week 60. (Figure 1): Patients who were responders and receiving active drug treatment continued their administration regimens. • All placebo patients receive active medication every four weeks (once a month), regardless of disease activity. I switched to 150mg, sc. • Patients who were unresponsive were treated with 25 mg or 75 mg of secukinumab every four weeks. All patients switched to 150 mg of sc every four weeks. • Non-responders in the 150mg group should be given the next highest dose - 300mg every 4 weeks, then switched to sc. I changed it. • All patients in the 300 mg group were exposed for a period longer than 16 weeks. To evaluate whether they induce a clinical response, each of these doses was left unchecked.

[0266] Efficacy evaluation was conducted using ACR20, 50, 70 (Felson et al. (1995) Arthritis Rheum, Vol. 38 (No. 6)). ), pp. 727-735) and DAS28 response / remission (Fransen et al. (2003) Ann Rheum Dis, Vol. 62 (Supplement 1) ), p. 10, Prevoo et al. (1995) Arthritis Rheum, vol. 38 (no. 1), pp. 44-48). Main efficacy The variables are the clinical response to treatment, following individual improvement in disease activity (ACR20) at week 16. The results will be evaluated by the percentage of patients who achieve the ACR20 response criteria at week 16. A patient is considered a responder according to the ACR20 criteria if they meet the following criteria: A) At least 20% improvement in the following two measures • Tenderness: 28 joints (counted) • Swelling count of 28 joints, and B) Improvement of at least 20% in at least three of the following five measures. • Patient assessment of RA pain (VAS 100mm) • Comprehensive assessment of disease activity by patients (VAS 100mm) • Comprehensive assessment of disease activity by a physician (VAS 100mm) • Patient's self-assessment of physical disability (Health Assessment Questionnaire [HAQ(C)] score) • Acute-phase reactive substances (C-reactive protein [hsCRP] or erythrocyte sedimentation rate (ESR)) ) Further scales include the ACR50 (item B(upper) 50 in at least 3 of the 5 scales). % improvement and 50% improvement in swelling and tenderness joint counts, and ACR70 (5 scales) 70% improvement in at least three items B (above) and 7% improvement in swelling and tenderness joint counts. Examples include 0% improvement.

[0267] DAS28 (Disease Activity Score -28) is a well-established measure of disease activity in RA. This is a scale that measures the number of tender and swollen joints (out of a total of 28) and the rate of erythrocyte sedimentation rate. ESR or hsCRP and comprehensive assessment by patients regarding overall health (very good and not good) The complex formula involves marking a 100mm straight line between always bad and bad. It is calculated from the following: A DAS28 score greater than 5.1 indicates active disease, while a score less than 3.2 indicates active disease. The core score indicates a well-controlled disease, and a score of less than 2.6 signifies remission.

[0268] To calculate the DAS28 score, the following disease variables are required. • The number of swollen and tender joints is assessed using a 28-joint count (28 tender and 28 swollen). It should be done. • Erythrocyte sedimentation rate (ESR) should be measured in mm / hour units. • Patient's general health status (G) as measured on a 100mm visual analog scale (VAS) You must obtain H) or a comprehensive disease activity level (both can be used for this purpose). .

[0269] Using this data, DAS28 can be calculated using the following formula. DAS28 = 0.56 * square root (tenderness 28) + 0.28 * square root (swelling 28) + 0.70 *ln(ESR)+0.014*GH

[0270] C-reactive protein (CRP) is used in the DAS or DAS28 calculation using the following formula. It can be used as an alternative to SR. CRP is a more direct measure of inflammation than ESR. It is a degree and is more sensitive to short-term changes. CRP production is related to the radiological progression of RA. It is considered to be at least as effective as ESR in measuring the activity level of RA disease. Another advantage of measuring CRP is that it reduces the waiting time for clinical test results, and in multicenter studies... For the trial, a central facility can be used. Using CRP (mg / L) D The following formula for calculating AS28 is a good estimate of the first DAS28 at the group level. give. DAS28-4(crp)=0.56*square root(TJC28)+0.28*square root(SJ C28)+0.36*ln(CRP+1)+0.014*GH+0.96 TJC28: 28 tender joint counts; SJC28: 28 swollen joint counts; CRP: C-positive Responsive proteins; GH: General health status on a 100mm visual analog scale

[0271] HAQ(C) is a validated scale for physical disability and functional status. It has four dimensions: disability, pain, drug side effects, and dollar costs (the latter three are almost always observed in clinical trials). (Although it is rarely used). In this test, only the physical disability dimension was used. Physical disability dimension This includes clothing and grooming, standing up, eating, walking, reaching out to pick up, personal hygiene, and grasping. Twenty multiple-choice questions regarding difficulties in performing eight common activities of daily living, such as walking and walking. It consists of four categories ranging from "without difficulty" to "unable to do". Select from the response categories. Rheumatology regarding outcome measures in ACR for RA The ACR Rheumatology Committee on Outcome Measures in RA is working on clinical trials. The use of this questionnaire is recommended in Stampede, California. HAQ(C) is developed in Stampede, California. Scoring will follow the developer recommendations outlined in Ward College's "HAQ PACK". .

[0272] (Example 1.2) Statistical analysis To test the superiority of secukinumab treatment over placebo, the treatment method, facilities and vein Based on a logistic regression model with line DAS28 as a covariate, secukinumab The ACR20 response rate (percentage) for each treatment group was compared to the placebo control group. The change from baseline in DAS28-CRP was used as the primary effect of the treatment, with covariates from the center and Analysis of covariance (ANCOVA, SAS PROC MIX) adjusted for baseline values ED) The analysis was performed using a fixed-effects model. For pair comparison of secukinumab treatment group versus placebo. All statistical tests were performed at a two-sided 5% significance level. Missing values ​​for the effectiveness variable were treated as follows: The Long-Term Follow-Up (LOCF) method was used. Up to week 16 (or week 52 as appropriate). We created diagrams showing responses over a period of time or at specific points in time. Notably, 52 The chart showing the results up to week 24 is based on data from patients who continued treatment at week 24. Including the 'mi'.

[0273] The largest analysis group (FAS) was used to report the efficacy results. The FAS was divided into groups based on the number of subjects taking the investigational drug. This included all patients who were assigned to the treatment. It adhered to the intent-to-treat (ITT) principle. Therefore, we analyzed patients by the treatment method and stratification to which they were assigned at the time of randomization.

[0274] (Example 1.3) Results after 16 weeks Patient characteristics and baseline traits were similar across all groups. At week 16... ACR20 responders showed a higher response rate compared to placebo (36.0%) with secukinumab 25 mg. (34%) In comparison, the secukinumab 75 mg, 150 mg and 300 mg dose groups ( The percentages were higher at 46.9%, 46.5%, and 53.7%, respectively (Figure 2A). However, 12 The significant and Due to unexplained increases, these results did not achieve statistical significance. DAS2 Clinically relevant reduction in 8-CRP was observed in the secukinumab 75-300 mg treatment group versus placebo group. Observed in the vo (Figure 5A). Serum CRP levels at week 16 were 75- for secukinumab. The 300 mg group showed a significant decrease compared to the placebo group (p=0.0012, 0.0081, and 0.0). 241) (Data not shown). ACR50 and ACR70 were administered over 16 weeks. Mab showed consistent and greater improvement at doses of 75-300 mg versus placebo (Figure 3A and (4A) Compared to placebo, the baseline HAQ(C) score was lower in the 150-300 mg group. An average decrease of approximately four times the initial level occurred at week 16 (Figure 6A).

[0275] (Example 1.4) Results at 24 weeks By week 24, an ACR20 response was observed following secukinumab treatment from week 16 to week 24. The condition was maintained, and the DAS28 CRP response further improved in the 75-300 mg group. The Q(C) score was 75-300m after secukinumab treatment from week 16 to week 24. In group g, the levels were maintained or further decreased. 75-300 mg ACR20 responder treatment group The ACR50 showed early improvement in HAQ(C) scores during the period up to week 24. The response was initially randomized to each dose cohort, with a portion of the patients receiving a dose escalation at week 20. In this case, 19 to 24% (75 mg), 21 to 25% (150 mg), and 19 to 24 Further improvement was observed in %(300mg), and similar improvements were seen in the ACR in the 75mg-150mg group. 70 responses were observed. Participants were randomized to placebo between weeks 16 and 24. An increase in ACR20 / 50 / 70 responses in patients is also noteworthy. (Up to week 16) All patients receiving placebo were switched to secukinumab 150 mg at week 20.

[0276] (Example 1.5) Results at week 52 Regarding the temporal progression of secukinumab efficacy, patients who responded at week 16 were generally... Regarding ACR20 (Figure 2C), ACR50 (Figure 3B), and ACR70 (Figure 4B), These responses were maintained, with the best response observed in the 150 mg responder cohort. This indicates that DAS2 was maintained in responders at week 16 through week 52. The same applies to 8-CRP and HAQ score responses, in which case the best response is 15. Observed in the 0 mg responder cohort (Figures 5B, 6B). ACR20, 50 and at week 52 The 70 reactions are shown in Figure 7, and in this case as well, the highest reaction for all these parameters is 1 This was observed in the 50 mg responder cohort.

[0277] Biological failure accounted for 18–22% of patients in each cohort at the start of the trial. Patients previously exposed to biologics who received 150 mg of secukinumab after week 0. Of these, 62% (8 out of 13 cases) achieved ACR20 at week 52, and 38% (5 out of 13 cases) ) achieved ACR50, and 23% achieved ACR70. This indicates that secukinumab is effective against This can treat rheumatoid arthritis in patients who have failed with TNF and other biological therapies. This provides evidence to that effect. [Examples]

[0278] Analysis of a subset of high-risk RA patients in CAIN457F2201 (Example 2.1) Statistical analysis In exploring indicators to predict the response of RA patients to secukinumab treatment, this development The researchers used data from the CAIN457F2201 test database to determine the basis To what extent can the quasi- Four 2010 ACR / EULAR scoring options are available to determine whether they could have an impact. Two criteria (see Table 1) were analyzed. Firstly, the inventors determined that patients have RF+ and / or anti- Serological tests are analyzed to determine whether or not the patient is CCP+ (i.e., ACPA+). Secondly, the inventors have found that patients have high levels of C-reactive protein (CRP) and / or To determine whether or not hypererythrocyte sedimentation rate (ESR) is present, the presence of acute-phase reactants is assessed. I analyzed it.

[0279] The analysis was primarily conducted at week 16 (or week 52 for patients who continued at week 24). Summary statistics were generated over time to observe the reaction up to that point (for binary reaction variables, the summaries were divided). For continuous variables, the mean value was used. Missing values ​​for effectiveness variables were considered in the final analysis. The Loose-Based Complementary Scenario (LOCF) method was used. The period covered was up to week 16 (or week 52, as appropriate). It generated data showing responses over a period of time or at a specific point in time. Notably, 5 The data showing the results up to week 2 is based on data from patients who continued to receive treatment at week 24. Includes only the data.

[0280] (Example 2.2) Analysis of response to secukinumab in high-risk RA patients Patients at "high risk" of disease progression (high CRP and / or ESR and positive RF) Analysis of subgroups (i.e., "high-risk RA patients") based on / or ACPA This is compared to the overall trial results for CAIN457F2201 in patients treated with secukinumab. While promising results were observed, the response in the placebo group did not show a similar increasing trend. Regarding CR20, in FAS, secukinumab 75, 150, and 300 mg were administered at week 16. The response rates observed in the group with (Figure 2A and Table 6), on the other hand, in the high-risk subgroup, at week 16, the values ​​were 48.8 and 57. Reactions of 0.6%, 58.1%, and 41.0% were observed (Figure 2B and Table 6). Similarly, FAS In comparison with ACR50 / 70 (Table 6), DAS28-CRP (Table 7) and HAQ( C) (data not shown) For other variables, 16 and in the high-risk subgroup A high response rate was observed at week 52.

[0281] FAS, ACR at 16 and 52 weeks in high-risk and non-high-risk RA patients Table 6 (ACR) and Table 7 (DA) summarize the 20 / 50 / 70% and DAS28-CRP reactions. (S28-CRP) is shown. 16-week results in high-risk RA patients and non-high-risk RA patients. Figures 8A and 8B show graphs of ACR20 / 50 / 70% and DAS28-CRP reactions. show.

[0282] [Table 6]

[0283] [Table 7]

[0284] Tables 6 and 7 show the data for week 52, categorized by the treatment plan initially assigned. Note the following regarding ACR20 non-responders (and all placebo patients): 16 The treatment was started in week 1 and the dosage was adjusted. Of the 45 patients, 18 received their "first" 25 mg dose. Although the dose remained at mg, 27 patients had their dose increased to 150 mg. Similarly, 46 Of the 23 patients who were initially given 75 mg, all 23 remained on the 75 mg dose. The dosage was adjusted up to 50 mg. Of the 43 patients, 20 received the "initial" 150 mg dose. The dosage remained unchanged, but 23 cases were adjusted upward to 300 mg. All 44 cases were "initial" Placebo patients were switched to 150 mg, and all "initial" 300 mg patients were switched to 300 mg. The dosage remained at mg.

[0285] As can be seen from Tables 6 and 7 and Figures 8A and 8B, high-risk RA patients are generally not Compared to high-risk RA patients, this shows improved response to IL-17 inhibition. (Week 16) ACR20% and ACR50% response rates in high-risk RA patients and non-high-risk RA patients in this study. Comparing (Table 6 and Figure 8A), IL-17 inhibition by secukinumab was observed in high-risk RA patients. The dose-response in the response to harm can be confirmed. Similar dose-response patterns were observed at 16 and 52 weeks. Observed in the DAS28-CRP score in high-risk RA patients (Table 7 and Figure 8B) Furthermore, the 20% ACR response at week 16 in the high-risk RA patient subset was higher than in the non-high-risk RA patient subset. Compared to the 20% ACR response observed in high-risk RA patients, secukinumab at doses exceeding 25 mg is more effective. Improvements have been observed at all doses (Table 6 and Figure 8A). Furthermore, 150 mg of secchunum ACR 50 / 70% response at weeks 16 and 52 in high-risk RA patients treated with [the drug]. This refers to the ACR50 / 7 ratio in non-high-risk RA patients treated with the same dose of secukinumab. Higher than 0% response. Similar results were observed with 150 mg secukinumab at week 16 and week 52. Observable in the DAS28-CRP score for all doses of secukinumab in the eye. (Table 7 and Figure 8B). [Examples]

[0286] Patients with elevated baseline CRP levels will benefit from secukinumab. (Example 3.1) Test Design In patients with RA treated with various doses of secukinumab compared to placebo, baseline performance was observed. Dose distribution of DAS28 and ACR response at week 16, categorized by high-sensitivity (hs) CRP level. To evaluate the reaction relationship.

[0287] As mentioned above, in the trial CAIN457F2201, methotrexate was administered. Adult RA patients (n=237) who were receiving treatment were given secukinumab 25mg, 75mg, and 150mg doses. Participants were randomized to receive either a 300 mg or placebo injection once a month. These are various baseline hsCRP levels (≧0mg / L, ≧10mg / L, ≧20mg Dose-response relationship between DAS28 and ACR responses at week 16 (for both / L and ≥30 mg / L) I evaluated the person in charge.

[0288] (Example 3.2) Results Patient characteristics and baseline traits were similar across all groups. DAS28-C Rapid reduction in RP was observed in patients in the secukinumab 75 mg, 150 mg, and 300 mg groups at 2 weeks. This was recognized early on. By week 12, these patients were 1% better than placebo patients. A clinically significant reduction in DAS28 of more than 0.2 was achieved (P<0.05). The response persisted until week 16 (Table 8). As can be seen in Table 8 and Figure 9, the placebo or Compared to the secukinumab 25 mg and 75 mg groups, the secukinumab 150 mg and 300 mg groups showed better results. For the g-dose cohort, DAS2 at week 16 was based on baseline hsCRP levels. A dose-dependent relationship exists in the responses to 8-CRP, ACR20, and ACR50. (20 weeks) The safety profile of secukinumab up to the eye was comparable to that of placebo. Most AEs The severity was mild or moderate and did not lead to discontinuation of the investigational drug.

[0289] [Table 8]

[0290] The results showed that secukinumab led to a rapid reduction in disease activity, and baseline hsC 150 mg or 300 mg with evidence of high inflammatory load as demonstrated by RP levels It can be seen that the greatest improvement is observed in patients who receive the drug. From this, it can be seen that secukinumab is effective in treating patients This will benefit RA patients, including those with factors that increase their risk of developing progressive disease. This suggests that... [Examples]

[0291] Modeling and Simulation: Rheumatoid Arthritis Induction Regimen Design Using a PK / PD approach that describes longitudinal data, the dose / regime of secukinumab The relationship between secukinumab plasma concentration and ACR20 response was modeled. This will facilitate the design of the Phase III trial of secukinumab in the treatment of rheumatoid arthritis. It was used for that purpose.

[0292] (Example 4.1) Method Pharmacokinetic modeling of secukinumab For the pharmacokinetic (PK) model (Figure 10), various clinical trials (CAIN457A11) 01, CAIN457A2101, CAIN457A2102, CAIN457A210 3, CAIN457A2104, CAIN457A2206, CAIN457A2208 The data from CAIN457A2209 and CAIN457F2201 was pooled. Population approach using compartment model to determine P K was described. The parameters were estimated along with their between-individual variances. The parameter is the volume of distribution. V1 = 2.96 L and V2 = 2.52 L, primary clearance CL from the first volume = 0. The volume was 169 L / day, with an intercompartmental exchange coefficient Q = 0.784 L / day, and was administered subcutaneously. The absorption rate and absolute bioavailability were KA = 0.192 l / day and F = 76%, respectively. Yes, body weight was identified as a covariate for secukinumab clearance and volume. .

[0293] Modeling of ACR20 response rates in placebo and secukinumab treatment groups ACR20 modeling data for patients with insufficient methotrexate response (Table 9) Therefore, the data from two clinical trials (CAIN457A2101 and CAIN457F2201) Data was used. The concentration-responder probability approach was used for the placebo and treatment groups. The R20 response rate was modeled. The assumption was that the ACR20 response rate differed between the placebo and treatment groups. The increase was monotonically maintained until week 16. The monotonically increasing curve is shown on the logarithmic and quadratic curves of time. It depended on the square root of the kinumab concentration. Week 4 (day 29), Week 8 (day 57), 12 Observations of ACR20 (LoCF) at week 86 (day 86) and week 113 (day 16) were performed. The model was developed in two stages, comparing the racebo group and the treatment group.

[0294] Placebo group ACR 20-hour profile model Time t of the jth patient in the placebo group i (i=1, 2, 3, 4 is 4, 8, 12 and The observation ACR20 for week 16 was written as follows: ACR20 0j (t i )≒binomial(1,p0(t i )) Logit(p0(t i ))=α+βlog(t i ) / log(t4)

[0295] Therefore, the logit of the ACR20 response rate in the placebo group at week 16 is α + β And at time 0, it corresponds to -∞, which is the probability of a response of 0 at time zero. there were.

[0296] ACR 20-hour profile model of the secukinumab treatment group Time t of the jth patient in the secukinumab treatment group i Observations in ACR20 are as follows: That's how I wrote it. ACR20 j (t i )≒binomial(1,p(t i )) Logit(p(t i ))=Logit(p0(t i ))+γ(t i )h(conc j (t i )), where h() was the square root of the individual model predicted concentrations. Here, γ is time. t i This was the change in sensitivity of the ACR20 responder rate to the concentration in [location]. γ(t i ) = γ0log(t i ) / log(t4)

[0297] Therefore, the effect of secukinumab is γ(t i )h(conc j (t i Described by )) The functional form γ was chosen to be the logarithm of the test days, which is the same as the placebo time effect. In other words, we assumed proportional odds at h(conc).

[0298] A generalized estimation formula was used for evaluation, and the intra-patient correlation of ACR20 observational responses was determined by compound symmetry. This was assumed.

[0299] (Example 4.2) Results (Example 4.2.1) PK Modeling Results As can be seen in Figure 10, the model shows that secukinumab is effective compared to the regimen without introduction. Higher plasma concentrations can be achieved using IV or SC induction regimens. The model predicts that 10 mg will be delivered intravenously at weeks 0, 2, and 4. The induction regimen using secukinumab at weeks 0, 1, 2, 3, and 4 involves sc Higher plasma concentrations of secukinumab than those achieved with induction regimens using 300 mg secukinumab. It further predicts that this could lead to (and at a rapid pace). Furthermore, the IV induction regimen showed improved response compared to the administration regimen without the induction regimen. It brought about a response.

[0300] (Example 4.2.4) ACR20 Simulation Results The results of the ACR20 responder modeling are shown in Table 9. The ACR20 simulation was performed without Compared to the introductory regimen (35%), the introductory regimen of IV (63%) or SC (57%) We predict that a higher ACR20 response rate can be achieved by using men. Furthermore, the model involves 10 mg / kg secukinumab delivered intravenously at weeks 0, 2, and 4. The introductory regimen using this method involves 300 mg delivered via SC at weeks 0, 1, 2, 3, and 4. It may result in a higher ACR20 response rate than induction regimens using secukinumab. Furthermore, it is predicted that the modeled SC and IV initiation regimens are the initiation regimens. It resulted in an improved response compared to dosing regimens lacking it.

[0301] [Table 9] [Examples]

[0302] Secukinumab demonstrates good safety and efficacy in the treatment of active ankylosing spondylitis. (Example 5.1) Test design CAIN457A2209 CAIN457A2209 is a phase II polyamorticoid in patients with moderate to severe atrial fibrillation (AS). This is a center-based, randomized, double-blind, parallel-group, placebo-controlled proof-of-concept trial. The study population was revised II. AS diagnosed according to the New York criteria, back pain of 4 or higher, and nocturnal pain score (0-10 points) (Intonation scale), BASDAI score of 4 or higher (0-10 point scale), and the most Currently, at least one NSAID administered at the recommended dose for at least three months is also These are patients aged 18-65 years with an inadequate response to previous use. Patients using alpha-blockers may be admitted after an appropriate washout period. The patient was given a stable dose of NSAIDs during the trial, methotrexate (MTX), and sulfasal. The combination therapy with radin and prednisolone was permitted to be continued. However, active tumors Patients with evidence of nuclear exposure were excluded.

[0303] Thirty patients received secukinumab (AIN457) at 10 mg / kg at 3-week intervals. In a 4:1 ratio, patients receive two IV infusions: one IV and one placebo. The patient will be followed up for safety until week 28. AIN457 and placebo A Bayesian analysis was performed on the ASAS20 response rate at week 6 of the Bo study. The prior distribution of the response rate was beta. The distribution was determined, and a binomial distribution was assumed for the number of observers in each group. Anti-TN in AS Placebo response obtained from a meta-analysis of eight randomized, placebo-controlled trials of F-alpha treatment. The predictive distribution of the response rate was used as the prior distribution of the placebo response rate. This prior distribution was based on the responses of 43 cases. This was equivalent to observing 11 of the subjects (i.e., a response rate of 26%). The prior distribution was used for the active response rate (0.5 out of 1.5 responders). (Equivalent to observation).

[0304] The primary endpoint was achieving an International Society for Assessment of Spondyloarthritis (ASAS) 20 response at week 6. This was the percentage of patients who did so.

[0305] (Example 5.2) Results Patient characteristics and baseline traits were similar between groups. Mean baseline ( SD)BASDAI was 7.1 (1.4) in patients treated with secukinumab, compared to placebo treatment. The patient ratio was 7.2 (1.8). This included 3 patients who received placebo and 2 patients who received AIN457. The patient in question discontinued the trial before reaching the primary endpoint, primarily due to insufficient treatment efficacy. Efficacy data for one patient was not obtained due to a protocol violation after randomization. In the 6th week, 14 out of 23 secukinumab-treated patients who entered the efficacy analysis were ASAS20 In contrast to the placebo group, only 1 out of 6 patients achieved a response (61% vs. 17%). The probability of a positive treatment difference is 99.8%, with a confidence interval of 99.8%. 11.5%, 56.3%. ASAS40 and ASAS5 / 6 reactions in patients treated with secukinumab. The responses were 30% and 35%, respectively, and the mean (range) change was -1.8. (-5.6~0.8) In the majority of ASAS20 responders, secukinumab was A response was induced within one week of treatment. The pharmacokinetic profile for IgG1 mAb was obtained. This was as expected and was comparable to secukinumab administered for other indications.

[0306] Since secukinumab induced a significantly higher ASAS20 response than placebo at week 6, The primary endpoint of this study was achieved. Early safety in this study population No signs were observed. The interim data presented here shows that secukinumab is effective in treating active ankylosing vertebrae. This suggests that it may be effective in treating inflammation. [Examples]

[0307] Secukinumab was shown in a 24-week multicenter, double-blind, randomized, placebo-controlled trial for psoriasis Reduce the signs and symptoms of genital arthritis. (Example 6.1) Study design and patient characteristics 42 patients with active psoriatic arthritis (PsA) meeting the CASPAR criteria were selected for a study involving 3 Receive two injections of secukinumab (10 mg / kg) or placebo, spaced one week apart. Participants were randomized in a 2:1 ratio. The primary efficacy endpoint was compared to the placebo recipient. This was the percentage of ACR20 responders at week 6 (one-sided p-value < 0.1). Therefore, data imputation was not performed for missing data (omissions were treated as missing data).

[0308] 25 patients (89%) who received secukinumab and 10 patients (71%) who received placebo were tested. The trial was completed. Five patients (four receiving secukinumab and one receiving placebo) followed the protocol. Due to violations, the patient was excluded from the efficacy analysis. Three patients (11%) who received secukinumab and the patient were excluded. In the four cases (29%) receiving the racebo, treatment was discontinued early due to lack of efficacy or withdrawal of consent. Subject background and baseline characteristics include age, sex, and mean (SD) SJC (secukinumab vs. planar). Cebo: 8.3 (5.6) vs. 9.5 (5.4), TJC: 23.5 (19.4) vs. 22. 6 (11.0), DAS28 4.8 (1.2) vs 4.8 (1.2), MASES 3. The parameters, including 0 (4.1) versus 3.4 (2.3), were in equilibrium between the groups. For psoriasis, prior exposure to TNFi, and concomitant administration with DMARDs, secukinumab administration is recommended. Placebo was administered to 23 (98%), 11 (46%), and 21 (88%) of the patients. It was present in 11 cases (89%), 5 cases (38%), and 10 cases (70%).

[0309] (Example 6.2) Results The ACR20 response rate at week 6 was 39% (9 / 23) with secukinumab administration, compared to The response rate was 23% (3 / 13) in the placebo group (P=0.27). 39% (9 / 23) vs. 15% (2 / 13) in week 12, and 43% (10 / 23) in week 28. The results were 18% (2 / 11) for secukinumab versus placebo (each for secukinumab versus placebo). ACR at week 6 The response rates for 50 and ACR70 (secukinumab vs. placebo) were 17% vs. 8% and 9%, respectively. The results were % vs. 0%. The reduction in CRP at week 6 compared to baseline was due to secukinumab administration. Approved (median [range] of 5.0 [0.3, 43.0] at baseline vs. 6 weeks) 3.0 [0.2, 15.2] in the eye, but this was not observed with placebo administration (Bayer). 3.9 [1.3, 39.7] in Sline versus 5.0 [0.8, 29.7] in week 6. 6]). A similar reduction was observed for ESR, and the reduction in acute-phase parameters continued until week 28. The overall rate of adverse events (AEs) was comparable between secukinumab and placebo. The ratio was 26 cases (94%) versus 11 cases (79%). There was one severe adverse event (cellulitis of the hand). ) occurred with secukinumab administration, and it was suspected by the principal investigator to be related to the investigational drug. There were 7 serious adverse events (AEs) in 4 patients treated with secukinumab (tendon rupture / carpal tunnel syndrome / honeycomb cell rupture). Inflammation, obesity, falls, breast cancer (diagnosed before administration; inclusion constitutes a protocol violation) And it was reported in one case of placebo (polyarthritis). Infection was observed in 16 cases (57%) of secchus kinesiology. This was reported in patients treated with mab and in 7 patients (50%) treated with placebo.

[0310] The safety profile of secukinumab was generally favorable. The primary endpoint was Although not achieved, a substantial percentage of patients maintained their clinical scores and acute-phase parameters until week 28. The patient showed rapid and sustained improvement. The trend of beneficial clinical effects is clinical. This supports the rationale for larger clinical trials designed to evaluate efficacy. ru. [Examples]

[0311] Pharmacokinetic (PK) information on secukinumab Based on the data obtained from various tests, including those described in the above examples, Seckinu The following PK information regarding Mab was obtained (Table 10).

[0312] [Table 10]

[0313] Furthermore, secukinumab has a 7-8 day T max And it has a half-life of approximately 30 days. Confirmed. This PK information is useful for the treatment of arthritis, e.g., RA, e.g., high-risk RA. This can be used to design various administration regimens. Therefore, a different dose of IL-17 antagonist than the dose used in the example, for example, IL-17 Binding molecules (e.g., IL-17 antibodies such as secukinumab) or IL-17 receptor binding molecules The molecule (e.g., IL-17 receptor antibody) is delivered, or the same dose used in the example ( It is possible to deliver the same P (which is supplied at a different time than in the example). Maintaining the K profile means that even if the administration regimen or dose changes... Those skilled in the art can use IL-17 antagonists for the treatment of arthritis, including the treatment of high-risk RA patients. For example, IL-17 binding molecules (for example, IL-17 antibodies such as secukinumab) or IL-17 receptor-binding molecules (e.g., IL-17 receptor antibodies) can be used. This is what is expected. [Examples]

[0314] Pharmaceutical compositions / drugs containing IL-17 antagonists Open a vial containing a high-potency product, for example, a unit dose of 150 mg of secukinumab. With the aim of generating results, prescription trials using the secukinumab active pharmaceutical ingredient were initiated. Various stabilizers (mannito Four sucrose-based formulations combined with glycine and arginine HCl, This was included in a 12-month stability program under actual, accelerated, and stressed conditions (Table 11). ).

[0315] [Table 11]

[0316] All formulations use a Flurotec® B2 coated dispersion configuration. n) Fill a 6 mL Type I glass vial, which has been sealed with a stopper, with 3.6 mL (20% overfill). Freeze-drying was performed using a conservative freeze-drying cycle (Table 12).

[0317] [Table 12]

[0318] The stability of secukinumab is determined by the appearance of the cake, pH, reconstitution time, and Karl Fischer scale. Residual moisture, aggregates and decomposition products by SE-HPLC, and SDS-PA under reducing conditions. Impurities by GE, average molecular weight by LLS, degradation products and cis by RP-HPLC. The theoretical activity was monitored in the formulation by measuring it using Tamin CEX. Osmolality by weight. The degree and viscosity were measured after 3:1 reconstruction with sterile water for injection at the initial time point (Table 13).

[0319] [Table 13]

[0320] The weight osmolality value is higher than 240 mOsm / kg, which is the limit of the European Pharmacopoeia acceptance criteria. It was sufficiently present within the bounds, and the viscosity results were within the acceptable range of 10 mPa*s. Under actual temperature conditions... The 12-month stability data of stored samples is a purity profile between formulations containing different stabilizers. No significant difference was observed. After storage, there were no significant differences in the appearance and pH of the freeze-dried cake between the formulations. Although not confirmed, formulations containing mannitol were slightly longer-lasting compared to other formulations. The reconstitution time was shown to be 6 minutes vs. 3 minutes. The water content was approximately 0.2% to 0.4%, regardless of the formulation. It increased to % (data not shown). The aggregates detected by SEHPLC increased from approximately 0.9% to 1.4%. While the percentage increased to %, the degradation products were below the limit of quantification (data not shown). The average molecular weight of IN457 remained unchanged at approximately 155 kDa after storage. Total RP -The starting level of HPLC species is approximately 8.5-10%, and after 12 months of storage at 5°C it reaches 14%. It increased significantly to 0.6% (data not shown). These levels were observed with storage for more than one month. It is noteworthy that it reached Lato. The AIN457 activity mediated by cystamine CEX is It was maintained at 98-99% (data not shown). It was stored under accelerated and stress temperature conditions. Based on 6-month stability data of the samples, formulations containing sucrose + mannitol showed the best stability after storage. Longer reconstitution time (6 minutes vs. 3 minutes), highest aggregation product level, and RP-HPLC degradation product production It became clear that it was distinctly different from other formulations in terms of composition. After storage, freeze-dried form No significant differences were observed in the appearance or pH of the formulations. The water content was measured at 40°C for 6 months. After storage, the concentration increased from approximately 0.2% to 0.6-0.7%, regardless of the composition (data not shown). Preparations containing sucrose may further contain mannitol, glycine, and arginine HCl. It showed a slightly lower aggregation level than other formulations (5.2% vs. 5% by SE-HPLC). (0.8-6.8%). For all formulations, degradation products were below the limit of quantification (data (Not shown). The average molecular weight of AIN457 is approximately 160 kD after 6 months of storage at 40°C. a remained unchanged. The total RP-HPLC degradation products were obtained after storage at 40°C for 6 months. In a standalone sucrose-based formulation or a formulation containing arginine HCl, the other two Compared to 32.8% and 35.6% in the formulation, up to 31.0% and 31.4% It was at a slightly low level (data not shown). AIN457 by cystamine CEX Activity was maintained at 94-95% (data not shown).

[0321] The test results showed that the formulation based on 90 mM sucrose at 50 mg / mL in 10 mM histidine, 0.02% polysorbate 80, and pH 5.8, before lyophilization, was the most suitable candidate for a commercially available formulation containing 150 mg / mL AIN457, 30 mM L-histidine buffer pH 5.8, 270 mM sucrose, and 0.06% polysorbate 80 after 3:1 reconstitution with 1.0 mL of sterile water for injection. This invention encompasses the following inventions. [Item 1] A method for treating rheumatoid arthritis (RA), comprising the step of administering a therapeutically effective dose of an IL-17 antagonist to a high-risk RA patient. [Item 2] a) A step of selecting patients for treatment based on the fact that the patient is a high-risk RA patient, b) The step of administering a therapeutically effective dose of IL-17 antagonist to the patient. Methods of treating rheumatoid arthritis (RA), including [mention specific treatments]. [Clause 3] The method according to Clause 1 or 2, wherein the administration step comprises administering an IL-17 antagonist intravenously to the patient three times at a dose of approximately 10 mg / kg, with each dose administered every other week. [Clause 4] The method according to Clause 1 or 2, wherein the administration step comprises subcutaneously administering an IL-17 antagonist to the patient in a dose of approximately 75 mg to approximately 150 mg, with each of the doses administered once a month. [Item 5] The administration step is, a) A step of administering an IL-17 antagonist to high-risk RA patients during the introduction regimen, b) The method according to item 1 or 2, further comprising the step of administering an IL-17 antagonist to the patient during the maintenance regimen. [Section 6] The method according to item 5, wherein the introductory regimen includes the step of intravenously administering an IL-17 antagonist to the patient three times at a dose of approximately 10 mg / kg. [Section 7] The method according to item 6, wherein a first dose of approximately 10 mg / kg is delivered in week zero, a second dose of approximately 10 mg / kg is delivered in week two, and a third dose of approximately 10 mg / kg is delivered in week four. [Section 8] The method according to item 5, wherein the maintenance regimen includes the step of subcutaneously administering an IL-17 antagonist to the patient at a dose of approximately 75 mg to approximately 300 mg. [Section 9] The method according to item 8, wherein the maintenance regimen includes the step of subcutaneously administering an IL-17 antagonist to the patient at a dose of approximately 75 mg to approximately 300 mg twice a month, once a month, every two months, or every three months. [Section 10] The method according to item 9, wherein the maintenance regimen includes the step of subcutaneously administering an IL-17 antagonist to the patient at approximately 75 mg to approximately 150 mg twice a month, once a month, every two months, or every three months, starting at week 8. [Section 11] The method according to item 10, wherein the maintenance regimen includes the step of subcutaneously administering an IL-17 antagonist to the patient at approximately 75 mg or approximately 150 mg once a month, starting at week 8. [Section 12] High-risk RA patients, a) Serologically positive for rheumatoid factor (RF+) and anti-citrullinated protein antibody (ACPA+), or both RF+ and ACPA+, and b) Having high levels of C-reactive protein (CRP), high erythrocyte sedimentation rate (ESR), or both high levels of CRP and high ESR, The method described in any one of items 1 to 11. [Section 13] The method according to item 12, wherein when measured by hsCRP, a high level of CRP is 10 mg / L or higher. [Section 14] The method according to item 12, wherein the high ESR is 28 mm / hour or more. [Section 15] a) RF+, ACPA+, or both RF+ and ACPA+, and b) Having high levels of CRP, high ESR, or both high levels of CRP and high ESR. A method for treating rheumatoid arthritis (RA), comprising the step of administering a therapeutically effective dose of an IL-17 antagonist to a patient, on the condition that the patient is selected for treatment purposes based on [Clause 16]. The aforementioned administration step is a) The step of administering an IL-17 antagonist to the patient during the introduction regimen, b) The method of item 15, further comprising the step of administering an IL-17 antagonist to the patient during the maintenance regimen. [Section 17] The method according to item 16, wherein the introductory regimen includes the step of administering an IL-17 antagonist to the patient three times at a dose of approximately 10 mg / kg. [Section 18] The method according to item 17, wherein a first dose of approximately 10 mg / kg is delivered in week zero, a second dose of approximately 10 mg / kg is delivered in week two, and a third dose of approximately 10 mg / kg is delivered in week four. [Section 19] The method according to item 16, wherein the maintenance regimen includes the step of administering an IL-17 antagonist to the patient at a dose of approximately 75 mg to approximately 300 mg. [Section 20] The method according to item 19, wherein the maintenance regimen includes the step of subcutaneously administering an IL-17 antagonist to the patient at a dose of approximately 75 mg to approximately 300 mg twice a month, once a month, every two months, or every three months. [Section 21] The method according to item 20, wherein the maintenance regimen includes the step of subcutaneously administering an IL-17 antagonist to the patient at approximately 75 mg to approximately 150 mg twice a month, once a month, every two months, or every three months, starting at week 8. [Section 22] The method according to item 21, wherein the maintenance regimen includes the step of subcutaneously administering an IL-17 antagonist to the patient at approximately 75 mg or approximately 150 mg once a month, starting at week 8. [Section 23] The method according to any one of claims 1 to 22, wherein the patient has received prior treatment for RA, comprising the step of administering at least one antirheumatic drug selected from the group consisting of immunosuppressants, disease-modifying antirheumatic drugs (DMARDs), pain managers, steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), cytokine antagonists, anabolic steroids, bone antiresorbing agents, and combinations thereof, before administering an IL-17 antagonist. [Section 24] The method according to item 23, wherein, prior to administration of an IL-17 antagonist, the patient had shown an inadequate response, failure, or intolerance to treatment with a DMARD, TNF-alpha antagonist, or methotrexate. [Section 25] The method according to any one of claims 1 to 24, further comprising the step of administering to the patient a therapeutically effective amount of at least one antirheumatic drug selected from the group consisting of immunosuppressants, DMARDs, pain management agents, steroids, NSAIDs, cytokine antagonists, anabolic agents, bone antiresorbing agents, and combinations thereof. [Section 26] a) A step in which an IL-17 antagonist is administered to high-risk RA patients at a dose of approximately 10 mg / kg three times (each of the three doses is delivered every other week), b) Subsequently, an IL-17 antagonist is administered to the patient monthly, starting one month after the delivery of the third intravenous dose, at a dose of approximately 75 mg to 150 mg. Methods of treating rheumatoid arthritis (RA), including [mention specific treatments]. [Section 27] a) i. The patient is RF+, ACPA+, or both RF+ and ACPA+, and ii. The patient has high levels of CRP, high ESR, or both high levels of CRP and high ESR. The steps include selecting patients with RA based on the following criteria, b) The patient is administered an IL-17 antagonist at a dose of approximately 10 mg / kg in three doses (the first dose is delivered in week zero, the second dose in week two, and the third dose in week four), c) Subsequently, starting in the 8th week, administer an IL-17 antagonist to the patient at a dose of approximately 75 mg to 150 mg twice a month, once a month, every two months, or every three months. A treatment regimen for treating rheumatoid arthritis (RA), including [specific treatments]. [Section 28] a) Samples from patients i. Rheumatoid factor (RF), anti-citrullinated protein antibody (ACPA), or RF and ACPA, and ii. C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), or both CRP and ESR The steps involve assaying and b) The step of administering an IL-17 antagonist to the patient if the patient is RF+, ACPA+, or RF+ and ACPA+ and the patient has high levels of CRP, high ESR, or high levels of CRP and high ESR. Methods of treating rheumatoid arthritis (RA), including [mention specific treatments]. [Section 29] a) Rheumatoid factor (RF), anti-citrullinated protein antibody (ACPA), or RF and ACPA, and b) C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), or both CRP and ESR The step includes assaying a sample from a patient, If a patient is RF+, ACPA+, or RF+ and ACPA+, and has high levels of CRP, high ESR, or high levels of CRP and high ESR, the patient may respond to treatment of RA with an IL-17 antagonist. A method for determining the likelihood of RA patients responding to IL-17 antagonist treatment. [Section 30] An IL-17 antagonist used to treat rheumatoid arthritis (RA), characterized by administering the IL-17 antagonist to high-risk RA patients. [Section 31] An IL-17 antagonist for use in treating rheumatoid arthritis (RA), characterized by administering the IL-17 antagonist to patients selected for treatment purposes based on the fact that the patient is a high-risk RA patient. [Section 32] An IL-17 antagonist used as described in item 30 or 31, administered in three doses of approximately 10 mg / kg, with each dose administered every other week. [Section 33] An IL-17 antagonist used as described in item 30 or 31, administered in doses of approximately 75 mg to approximately 300 mg, with each dose administered once a month. [Section 34] An IL-17 antagonist used as described in paragraph 30 or 31, to be administered to patients who require it during the induction regimen and the subsequent maintenance regimen. [Section 35] The IL-17 antagonist used as described in paragraph 34, wherein the introduction regimen includes the step of administering the IL-17 antagonist intravenously to the patient three times at a dose of approximately 10 mg / kg. [Section 36] An IL-17 antagonist used as described in paragraph 35, delivered in the following order: a first dose of approximately 10 mg / kg in week zero, a second dose of approximately 10 mg / kg in week two, and a third dose of approximately 10 mg / kg in week four. [Section 37] The IL-17 antagonist used as described in paragraph 34, wherein the maintenance regimen includes the step of subcutaneously administering the IL-17 antagonist to the patient at a dose of approximately 75 mg to approximately 300 mg. [Section 38] The IL-17 antagonist used as described in paragraph 37, wherein the maintenance regimen includes the step of subcutaneously administering the IL-17 antagonist to the patient at approximately 75 mg to approximately 300 mg twice a month, once a month, every two months, or every three months, starting at week 8. [Section 39] The IL-17 antagonist used as described in paragraph 38, wherein the maintenance regimen includes the step of subcutaneously administering the IL-17 antagonist to the patient at approximately 75 mg to approximately 150 mg twice a month, once a month, every two months, or every three months, starting at week 8. [Section 40] The method according to paragraph 39, wherein the maintenance regimen includes the step of subcutaneously administering an IL-17 antagonist to the patient at approximately 75 mg or approximately 150 mg once a month, starting at week 8. [Section 41] High-risk RA patients, a) Serologically positive for rheumatoid factor (RF+) and anti-citrullinated protein antibody (ACPA+), or both RF+ and ACPA+, and b) Having high levels of C-reactive protein (CRP), high erythrocyte sedimentation rate (ESR), or both high levels of CRP and high ESR, An IL-17 antagonist used as described in any one of paragraphs 30 to 40. [Section 42] An IL-17 antagonist used as described in item 41, which, when measured by hsCRP, produces a high level of CRP of 10 mg / L or higher. [Section 43] An IL-17 antagonist used as described in item 41, with a high ESR of 28 mm / hour or more. [Section 44] a) RF+, ACPA+, or both RF+ and ACPA+, and b) Having high levels of CRP, high ESR, or both high levels of CRP and high ESR. An IL-17 antagonist for use in treating rheumatoid arthritis (RA), characterized by administering the IL-17 antagonist to patients under the condition that patients are selected for treatment purposes based on [specific criteria]. [Section 45] The IL-17 antagonist used according to paragraph 44, characterized in that the IL-17 antagonist is administered to the patient during the induction regimen and then to the patient during the maintenance regimen. [Section 46] The IL-17 antagonist used as described in paragraph 45, wherein the introductory regimen includes the step of administering the IL-17 antagonist to the patient three times at a dose of approximately 10 mg / kg. [Section 47] An IL-17 antagonist used as described in paragraph 46, delivered in the following order: a first dose of approximately 10 mg / kg in week zero, a second dose of approximately 10 mg / kg in week two, and a third dose of approximately 10 mg / kg in week four. [Section 48] The IL-17 antagonist used as described in paragraph 45, wherein the maintenance regime includes the step of administering the IL-17 antagonist to the patient at a dose of approximately 75 mg to approximately 300 mg. [Section 49] The IL-17 antagonist used as described in paragraph 48, wherein the maintenance regimen includes the step of subcutaneously administering an IL-17 antagonist to the patient at a dose of approximately 75 mg to approximately 300 mg twice a month, once a month, every two months, or every three months. [Section 50] The IL-17 antagonist used as described in paragraph 49, wherein the maintenance regimen includes the step of subcutaneously administering the IL-17 antagonist to the patient at approximately 75 mg to approximately 150 mg twice a month, once a month, every two months, or every three months, starting at week 8. [Section 51] The use as described in paragraph 50, wherein the maintenance regimen includes the step of subcutaneously administering an IL-17 antagonist to the patient at approximately 75 mg or approximately 150 mg once a month, starting at week 8. [Section 52] Prior to administering the IL-17 antagonist, the patient has received prior treatment for RA, which includes the step of administering at least one antirheumatic drug selected from the group consisting of immunosuppressants, disease-modifying antirheumatic drugs (DMARDs), pain management agents, steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), cytokine antagonists, anabolic agonists, bone antiresorbing agents, and combinations thereof, as described in any one of paragraphs 30 to 51. [Section 53] Prior to administration of the IL-17 antagonist, the patient had shown an inadequate response, failure, or intolerance to treatment with a DMARD, TNF-alpha antagonist, or methotrexate, and the IL-17 antagonist to be used as described in paragraph 53. [Section 54] An IL-17 antagonist used according to any one of claims 30 to 51, comprising the step of further administering to the patient a therapeutically effective amount of at least one antirheumatic drug selected from the group consisting of immunosuppressants, DMARDs, pain management agents, steroids, NSAIDs, cytokine antagonists, anabolic agents, bone antiresorbing agents, and combinations thereof. [Section 55] IL-17 Antagonist a) Administer approximately 10 mg / kg to high-risk RA patients three times (delivering each of the three doses every other week). b) Subsequently, starting one month after the delivery of the third intravenous dose, administer to the patient a monthly dose of approximately 75 mg to 150 mg. An IL-17 antagonist used to treat rheumatoid arthritis (RA), characterized by the following features. [Section 56] a) Samples from patients i. Rheumatoid factor (RF), anti-citrullinated protein antibody (ACPA), or RF and ACPA, and ii. C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), or both CRP and ESR Assayed on this, b) Administer an IL-17 antagonist to the patient if the patient is RF+, ACPA+, or RF+ and ACPA+ and has high levels of CRP, high ESR, or high levels of CRP and high ESR. An IL-17 antagonist used to treat rheumatoid arthritis (RA), characterized by the following features. [Section 57] The use of an IL-17 antagonist for the manufacture of a drug for treating RA, characterized by administering the IL-17 antagonist to high-risk RA patients. [Section 58] The use of IL-17 antagonists for the manufacture of drugs for treating RA, characterized by administering IL-17 antagonists to high-risk RA patients during the induction regimen and subsequent maintenance regimen. [Section 59] A pharmaceutical composition for treating rheumatoid arthritis (RA), containing an IL-17 antagonist as an active ingredient, for administration to high-risk RA patients. [Section 60] A pharmaceutical composition for treating rheumatoid arthritis (RA), comprising an IL-17 antagonist as an active ingredient, to be administered to high-risk RA patients during the induction regimen and subsequent maintenance regimen. [Section 61] High-risk RA patients, a) Serologically positive for rheumatoid factor (RF+) and anti-citrullinated protein antibody (ACPA+), or both RF+ and ACPA+, and b) Having high levels of C-reactive protein (CRP), high erythrocyte sedimentation rate (ESR), or both high levels of CRP and high ESR, The use described in item 57 or 58, or the pharmaceutical composition described in item 59 or 60. [Section 62] a) Steps to select high-risk RA patients, b) A step in which the patient is administered an IL-17 antagonist at approximately 10 mg / kg during weeks 0, 2, and 4, c) Subsequently, starting in the 8th week, administer an IL-17 antagonist to the patient once a month at a dose of approximately 75 mg to 150 mg. Treatment regimens for treating rheumatoid arthritis (RA), including [specific treatments]. [Section 63] a) During the introductory regimen, administer IL-17 binding molecules to patients who require them, achieving an average peak plasma concentration (C) of approximately 360 μg / ml of IL-17 binding molecules. max ) the steps that bring about, b) Subsequently, during the maintenance regimen, the patient is administered an IL-17 binding molecule. i) Average steady-state trough levels of IL-17-binding molecules ranging from approximately 8 μg / ml to approximately 30 μg / ml and / or ii) Mean AUC tau in steady state at approximately 331 mg / day / L to approximately 1323 mg / day / L Steps that bring about A method for treating RA patients or high-risk RA patients, including [specific example]. [Section 64] IL-17 binding molecule a) Administered to the patient during the introductory regimen to achieve an average peak plasma concentration (C) of approximately 360 μg / ml of IL-17-binding molecules. max ) brings about, b) Subsequently, administer to the patient during the maintenance regimen, i) Average steady-state trough levels of IL-17-binding molecules ranging from approximately 8 μg / ml to approximately 30 μg / ml and / or ii) Mean AUC tau in steady state at approximately 331 mg / day / L to approximately 1323 mg / day / L Bringing about An IL-17-binding molecule characterized by the above, used for treating RA patients or high-risk RA patients. [Section 65] The method described in item 63 or the use described in item 64, wherein the introduction regimen maintains a trough level of IL-17-binding molecules greater than 80 μg / ml over a period of 10 weeks. [Section 66] The method described in item 63 or the use described in item 64, wherein the maintenance regimen results in an average steady-state trough level of IL-17 binding molecules of approximately 8 μg / ml to approximately 17 μg / ml. [Section 67] The method or use described in Section 66 results in a maintenance that yields an average steady-state trough level of approximately 8 μg / ml or approximately 17 μg / ml of IL-17-binding molecules. [Section 68] a) During the introductory regimen, administer IL-17 binding molecules to patients who require them to achieve an average peak plasma concentration (C) of approximately 401 μg / ml of IL-17 binding molecules. max Steps that bring about P and, b) Subsequently, during the maintenance regimen, the patient is administered an IL-17 binding molecule. i) Average steady-state trough levels of IL-17-binding molecules ranging from approximately 9.4 μg / ml to approximately 31 μg / ml and / or ii) Mean AUC tau in steady state at approximately 314 mg / day / L to approximately 1256 mg / day / L Steps that bring about Methods for treating high-risk RA patients, including [specific example]. [Section 69] IL-17 binding molecule a) Administered to the patient during the introductory regimen to achieve an average peak plasma concentration (C) of approximately 401 μg / ml of IL-17-binding molecules. max ) brings about, b) Subsequently, administer to the patient during the maintenance regimen, i) Average steady-state trough levels of IL-17-binding molecules ranging from approximately 9.4 μg / ml to approximately 31 μg / ml and / or ii) Mean AUC tau in steady state at approximately 314 mg / day / L to approximately 1256 mg / day / L An IL-17-binding molecule used to treat psoriasis, characterized by the following effect. [Section 70] The method described in item 68 or the use described in item 69, wherein the maintenance regime results in an average steady-state trough level of IL-17 binding molecules of approximately 9.4 μg / ml to approximately 17.3 μg / ml. [Section 71] The method or use described in Section 70 results in an average steady-state trough level of IL-17-binding molecules of approximately 9.4 μg / ml or approximately 17.3 μg / ml. [Section 72] The method described in item 63 or 68, or the use described in item 64 or 69, wherein the introductory regimen includes bi-weekly intravenous administration of an IL-17 binding molecule. [Section 73] The method described in item 63 or 68, or the use described in item 64 or 69, wherein the maintenance regimen includes a monthly sc dose of an IL-17-binding molecule. [Section 74] a) A pharmaceutical composition containing an IL-17 antagonist for use in the treatment of rheumatoid arthritis (RA) in patients, b) Instructions for use describing a method for administering the pharmaceutical composition to a patient. A kit comprising a patient characterized by i) being RF+, ACPA+, or both RF+ and ACPA+, and ii) having high levels of CRP, high ESR, or both high levels of CRP and high ESR. [Section 75] a) RF+, ACPA+, or both RF+ and ACPA+, and b) Having high levels of CRP, high ESR, or both high levels of CRP and high ESR. The use of IL-17 antagonists in the preparation of medications for treating RA, on the condition that patients are selected for treatment purposes based on the following criteria. [Section 76] a) RF+, ACPA+, or both RF+ and ACPA+, and b) Use of an IL-17 antagonist for the manufacture of a drug for the treatment of RA in patients characterized by having high levels of CRP, high ESR, or both high levels of CRP and high ESR, wherein the drug comprises containers, and each container is formulated to have a sufficient amount of IL-17 antagonist to enable the delivery of at least about 75 mg to about 150 mg of IL-17 antagonist per unit dose. [Section 77] a) RF+, ACPA+, or both RF+ and ACPA+, and b) Use of an IL-17 antagonist for the manufacture of a drug for the treatment of RA in patients characterized by having high levels of CRP, high ESR, or both high levels of CRP and high ESR, wherein the drug comprises containers and is formulated so that each container has a sufficient amount of IL-17 antagonist to allow delivery of at least about 10 mg / kg per unit dose. [Section 78] a) RF+, ACPA+, or both RF+ and ACPA+, and b) Use of an IL-17 antagonist for the manufacture of a drug for the treatment of RA in patients characterized by having high levels of CRP, high ESR, or both high levels of CRP and high ESR, wherein the drug is prescribed in doses that allow for intravenous delivery of approximately 10 mg / kg per unit dose. [Section 79] a) RF+, ACPA+, or both RF+ and ACPA+, and b) Use of an IL-17 antagonist for the manufacture of a drug for the treatment of RA in patients characterized by having high levels of CRP, high ESR, or both high levels of CRP and high ESR, wherein the drug is prescribed in doses that allow subcutaneous delivery of an IL-17 antagonist of about 75 mg to about 150 mg per unit dose. [Section 80] i. The patient is RF+, ACPA+, or both RF+ and ACPA+, and ii. An in vitro study method for selecting patients for the treatment of rheumatoid arthritis, comprising the step of determining whether the patient has high levels of CRP, high ESR, or both high levels of CRP and high ESR. [Section 81] The patient is in the next regimen, namely, a) The IL-17 antagonist is admini...

Claims

1. A composition comprising secukinumab for use in the treatment of inflammatory arthritis by method, wherein the method comprises (a) subcutaneously administering a dose of 75 mg to 300 mg of secukinumab four or five times, with each of the four or five doses being delivered weekly, and (b) subsequently administering 75 mg to 300 mg of secukinumab twice a month, every four weeks, every two months or every three months.

2. The composition according to claim 1, wherein secukinumab is administered subcutaneously during the maintenance regimen (b).

3. The composition according to claim 1 or 2, wherein a maintenance dose (b) is delivered every four weeks.

4. A composition comprising secukinumab for use in the treatment of inflammatory arthritis, wherein secukinumab is a) administered subcutaneously five times in doses of 150 mg or 300 mg, each of the five doses being delivered weekly, with the first weekly dose administered in week 0, the second weekly dose administered in week 1, the third weekly dose administered in week 2, the fourth weekly dose administered in week 3, and the fifth weekly dose administered in week 4, and b) thereafter, a maintenance regimen is administered every four weeks in doses of 150 mg or 300 mg.

5. The composition according to any one of claims 1 to 4, wherein the inflammatory arthritis is polymyalgia rheumatica.

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