Methods for 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 claims priority to U.S. Provisional Patent Application No. 61 / 410,533, filed on Nov. 5, 2010, the disclosure of which is incorporated herein by reference in its entirety.

[0002] This disclosure relates to a novel regimen for treating rheumatoid arthritis using a therapeutically effective amount of an IL-17 binding molecule, such as an IL-17 antibody, e.g., the AIN457 antibody (also known as "secukinumab").

Background Art

[0003] Rheumatoid arthritis (RA) is a chronic inflammatory systemic autoimmune disease of unknown etiology. It is characterized by symmetric synovitis that results in cartilage damage and joint destruction and may be associated with many extra-articular symptoms. Considering the presence of autoantibodies such as rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA), RA is regarded as an autoimmune disease. RA is generally a progressive disease, and a decline in functional status, significant morbidity, and early death are recognized in patients with long-term RA. The disease can occur at any age, with the highest incidence between the fourth and sixth decades of life. The goal of long-term RA treatment is disease remission.

[0004] Disease-modifying anti-rheumatic drugs (DMARDs), a heterogeneous collection of agents classified by use and convention, are the first-line treatment for RA patients. DMARDs are used to reduce joint swelling and pain, decrease acute-phase markers, limit the progression of joint damage, and improve joint function. DMARDs, most commonly methotrexate, ​​​​​​​​​Rhexis (MTX) is usually prescribed after the diagnosis of the disease (i.e., early RA), before the appearance of the ulcerative disease and deformities observed in patients with long-term RA MTX therapy is initiated when pain and synovitis persist (especially when function is impaired) and additional DMARDs (with or without steroids) can be added to achieve disease control Unfortunately, only about 2 / 3 of patients respond to DMARDs, and DMARDs only partially control long-term RA disease. Radiological progression persists in 5-20% of DMARD-treated RA patients who have achieved remission or near-remission clinical improvement DMARDs also have many side effects that limit their long-term use (e.g., liver damage, myelosuppression, and severe pulmonary infections). Due to the inadequate response and risks associated with long-term DMARD treatment, biologics have been introduced as second-line RA therapies. Generally, anti-TNF drugs (Cimzia®, Enbrel®, Humira®, Remicade®, Simponi®) are the first biologics used in patients who are DMARD failures and those with an inadequate response to DMARDs, and TNF inhibitors are often used in combination with MTX (or other DMARDs) to actively treat long-term RA Unfortunately, 30-40% of patients with long-term RA do not respond to TNF-α antagonists, and the majority of patients who initially respond do not achieve complete remission or lose their response over time. The short and long-term tolerability and safety of long-term biologic therapy, most notably the reactivation of serious infections (e.g., tuberculosis infection) caused by TNF alpha antagonism, hepatotoxicity, increased cardiovascular disease, demyelination

[0005] ​​​​​​​​​​​​​ Concerns have also been raised regarding induction (or exacerbation) of status and 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 Vol., pp. 25-32). However, TNF inhibitors are usually continued unless they become ineffective or adverse events occur, at which point the clinician may switch to a different TNF inhibitor or a biologic agent with a different mechanism of action (e.g., Kineret® [IL-1R antagonist], MabT hera® [CD20 antagonist], Orencia® [CT LA4 fusion protein] or Actemra® [IL-6 receptor antagonist tor]) (Scott et al. (2010) The Lancet, Vol. 376, pp. 1095-1108).

[0006] Considering the aforementioned problems with current RA therapies, there is a need to develop new treatments for RA patients .

SUMMARY OF THE INVENTION

PROBLEMS TO BE SOLVED BY THE INVENTION

[0007] Secukinumab, a new biologic agent in clinical development for RA, is a high-affinity fully human monoclonal anti-human antibody that inhibits interleukin 17 A activity. In a rheumatoid arthritis proof-of-concept (P oC) trial, secukinumab was administered as a single dose and then twice (2 days apart) by escalating intravenous infusion at 1 mg / kg, 3 mg / kg, and 10 mg / kg to patients with active RA who were receiving a stable dose of MTX (Hueber et al. (2010) Sci. Transl. Med., Vol. 2 (No. 52), pp. 52- (page 72). Treatment with secukinumab led to rapid improvement of RA clinical symptoms in many patients compared to placebo. These data provide evidence that neutralization of IL-17A may be effective in RA patients with active RA. However, patients who respond to biological therapies vary, and it is desirable to avoid supplying drugs to patients who show resistance to them. Therefore, the inventors sought a method of treating RA that first identifies patients most likely to show a favorable response to antagonism of IL-17. The inventors identified an RA subgroup having

[0008] patients who show improved likelihood of responding to antagonism of IL-17, whom the inventors named "high-risk RA patients." Accordingly, one object of the present disclosure is to provide a method for identifying and treating "high-risk RA patients" with a therapeutically effective amount of an IL-17 antagonist, such as an

[0009] IL-17-binding molecule (e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor-binding molecule (e.g., an IL-17 antibody or antigen-binding fragment thereof). Another object of the present disclosure is to determine whether a

[0010] Another object of the present disclosure is to use a therapeutically effective amount of 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 ) to deliver an IL-7 antagonist as part of a therapeutic regimen, e.g., during an induction regimen and a maintenance regimen, to treat inflammatory arthritis, e.g., AS, R A, and PsA.

Means for Solving the Problem

[0011] Accordingly, disclosed herein is a method for treating rheumatoid arthritis (RA) comprising administering to a high-risk RA patient a therapeutically effective amount of an IL-17 antagonist

[0012] Also disclosed herein is a method for treating rheumatoid arthritis (RA) comprising: a) selecting a patient for treatment based on the patient being a high-risk RA patient; and b) administering to the patient a therapeutically effective amount of an IL-17 antagonist

[0013] Disclosed herein is: a) assaying a sample from a patient for 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; and b) subsequently administering an IL-17 antagonist to the patient if the patient is RF+, ACPA+, or RF+ and ACPA + and the patient has a high level of CRP, a high ESR, or both a high level of CRP and a high ESR. umatoid arthritis comprising A method for treating rheumatoid arthritis (RA).

[0014] Disclosed herein is a method for treating a patient with an IL-17 antagonist in a therapeutically effective amount, under the condition of selecting a patient for treatment based on that the patient is a) RF+, ACPA+, or both RF+ and ACPA+ and b) having a high level of CRP, a high ESR, or both a high level of CRP and a high ESR. In some embodiments, the administering step includes a) administering the IL-17 antagonist to the patient in an induction regimen, and b) subsequently administering the IL-17 antagonist to the patient in a maintenance regimen. A method for treating rheumatoid arthritis (RA). In some embodiments, the administering step includes a) administering the IL-17 antagonist to the patient in an induction regimen, and b) subsequently administering the IL-17 antagonist to the patient in a maintenance regimen. A method for treating rheumatoid arthritis (RA). In some embodiments, the administering step includes a) administering the IL-17 antagonist to the patient in an induction regimen, and b) subsequently administering the IL-17 antagonist to the patient in a maintenance regimen.

[0015] Disclosed herein is a method for treating rheumatoid arthritis (RA), including a) administering an IL-17 antagonist to a high-risk RA patient three times at a dose of about 10 mg / kg (each of the three doses is delivered every other week) and b) subsequently administering the IL-17 antagonist to the patient monthly starting from the first month after the delivery of the third intravenous dose at about 75 mg to about 150 mg. A method for treating rheumatoid arthritis (RA). In some embodiments, the administering step includes a) administering the IL-17 antagonist to the patient in an induction regimen, and b) subsequently administering the IL-17 antagonist to the patient in a maintenance regimen. A method for treating rheumatoid arthritis (RA).

[0016] Disclosed herein is a method for treating RA, including a) a step of selecting a patient having RA based on the criteria that i. the patient is RF+, ACPA+, or both RF+ and ACPA+ and ii. the patient has a high level of CRP, a high ESR, or both a high level of CRP and a high ESR, and b) administering the IL-17 antagonist to the patient three times at a dose of about 10 mg / kg (delivering the first dose at week 0, the second dose at week 2, and the third dose at week 4). A method for treating rheumatoid arthritis (RA). (delivering the first dose at week 0, the second dose at week 2, and the third dose at week 4). (reach) step, and c) then, starting from the 8th week, twice a month, once a month, every two months, or every three months, administering an IL-17 antagonist to the patient at about 75 mg to about 150 mg step, which is a treatment regimen for treating rheumatoid arthritis (RA).

[0017] Disclosed herein is a method comprising a) assaying a sample from a patient for 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, to determine if the patient is RF+, ACPA+, or RF+ and ACPA+, and if the patient has high levels of CRP, high ESR, or high levels of both CRP and ESR, the patient may respond to treatment of RA with an IL-17 antagonist, a method for determining the likelihood that an RA patient will respond to treatment with an IL-17 antagonist.

[0018] Disclosed herein is an IL-17 antagonist for use in treating rheumatoid arthritis (RA), characterized by administering an IL-17 antagonist to a high-risk RA patient. Disclosed herein is an IL-17 antagonist for use in treating rheumatoid arthritis (RA), characterized by administering an IL-17 antagonist to a patient selected for treatment based on the patient being a high-risk RA patient.

[0019] Disclosed herein is an IL-17 antagonist for use in treating high-risk RA patients. In some embodiments, the high-risk RA patient is a) rheumatoid factor ( ​Serum reaction positive for rheumatoid factor (RF+), anti-citrullinated protein antibody (ACPA+), or both RF+ and ACPA+; or R both RF+ and ACPA+, and b) having a high level of C-reactive protein (CRP), high erythrocyte sedimentation rate (ESR), or both a high level of CRP and high ESR. In some embodiments, when measured by hsCRP, a high level of CRP is 10 mg / L or higher. In some embodiments, high ESR is 28 mm / hour or higher.

[0020] Disclosed herein is an IL-17 antagonist for treating rheumatoid arthritis (RA), characterized in that the IL-17 antagonist is administered to a patient on the condition that the patient is selected for treatment based on a) being RF+, ACPA+, or both RF+ and ACPA+ and b) having a high level of CRP, high ESR, or both a high level of CRP and high ESR.

[0021] Disclosed herein is an IL-17 antagonist for treating rheumatoid arthritis (RA), characterized in that the IL-17 antagonist is administered to high-risk RA patients at a dose of about 10 mg / kg three times (each of the three doses is delivered every other week), and then starting from the first month after the delivery of the third intravenous dose, the patient is administered at a dose of about 75 mg to about 150 mg per month.

[0022] Disclosed herein is a method of a) assaying a sample from a patient for i. rheumatoid factor (RF), anti-citrullinated protein antibody (ACPA), or both RF and ACPA, and ii. C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), or both CRP and ESR ​​​​​​​​Determine that, b) 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, then administer an IL-17 antagonist to the patient, characterized in that it is an IL-17 antagonist used for treating rheumatoid arthritis (RA).

[0023] Disclosed herein is the use of an IL-17 antagonist for the manufacture of a medicament for treating RA, characterized by administering the IL-17 antagonist to a high-risk RA patient.

[0024] Disclosed herein is the use of an IL-17 antagonist for the manufacture of a medicament for treating RA, characterized by administering the IL-17 antagonist to a high-risk RA patient during an induction regimen and subsequent maintenance regimen.

[0025] Disclosed herein is a pharmaceutical composition for treating RA, comprising an IL-17 antagonist as an active ingredient and administered to a high-risk RA patient.

[0026] Disclosed herein is a pharmaceutical composition for treating RA, comprising an IL-17 antagonist as an active ingredient and administered to a high-risk RA patient during an induction regimen and subsequent maintenance regimen.

[0027] Disclosed herein are: a) a step of selecting a high-risk RA patient; b) a step of administering an IL-17 antagonist to the patient at about 10 mg / kg at weeks 0, 2, and 4; and c) thereafter, starting at week 8, administering the IL-17 antagonist once monthly at about 75 mg to about 15 mg~ ​​​​​​​​A treatment regimen for treating RA, comprising the step of administering 0 mg to a patient.

[0028] Disclosed herein is a method for treating a patient in need of an IL-17 binding molecule in an induction regimen to provide an average maximum plasma concentration (C) of the IL-17 binding molecule of about 360 μg / ml. And b) subsequently administering to the patient an IL-17 binding molecule in a maintenance regimen to provide i) an average steady-state trough level of the IL-17 binding molecule of about 8 μg / ml to about 30 μg / ml and / or ii) an average AUC tau in the steady state of about 331 mg*day / L to about 1323 mg*day / L. A method for treating a patient with RA or a high-risk RA patient. C max And b) subsequently administering to the patient an IL-17 binding molecule in a maintenance regimen to provide i) an average steady-state trough level of the IL-17 binding molecule of about 8 μg / ml to about 30 μg / ml and / or ii) an average AUC tau in the steady state of about 331 mg*day / L to about 1323 mg*day / L. A method for treating a patient with RA or a high-risk RA patient. And b) subsequently administering to the patient an IL-17 binding molecule in a maintenance regimen to provide i) an average steady-state trough level of the IL-17 binding molecule of about 8 μg / ml to about 30 μg / ml and / or ii) an average AUC tau in the steady state of about 331 mg*day / L to about 1323 mg*day / L. A method for treating a patient with RA or a high-risk RA patient. And b) subsequently administering to the patient an IL-17 binding molecule in a maintenance regimen to provide i) an average steady-state trough level of the IL-17 binding molecule of about 8 μg / ml to about 30 μg / ml and / or ii) an average AUC tau in the steady state of about 331 mg*day / L to about 1323 mg*day / L. A method for treating a patient with RA or a high-risk RA patient. And b) subsequently administering to the patient an IL-17 binding molecule in a maintenance regimen to provide i) an average steady-state trough level of the IL-17 binding molecule of about 8 μg / ml to about 30 μg / ml and / or ii) an average AUC tau in the steady state of about 331 mg*day / L to about 1323 mg*day / L. A method for treating a patient with RA or a high-risk RA patient. And b) subsequently administering to the patient an IL-17 binding molecule in a maintenance regimen to provide i) an average steady-state trough level of the IL-17 binding molecule of about 8 μg / ml to about 30 μg / ml and / or ii) an average AUC tau in the steady state of about 331 mg*day / L to about 1323 mg*day / L. A method for treating a patient with RA or a high-risk RA patient.

[0029] Disclosed herein is an IL-17 binding molecule for use in treating a patient with RA or a high-risk RA patient, characterized in that it is administered to the patient in an induction regimen to provide an average maximum plasma concentration (C) of the IL-17 binding molecule of about 360 μg / ml. And b) subsequently administering to the patient an IL-17 binding molecule in a maintenance regimen to provide i) an average steady-state trough level of the IL-17 binding molecule of about 8 μg / ml to about 30 μg / ml and / or ii) an average AUC tau in the steady state of about 331 mg*day / L to about 1323 mg*day / L. max And b) subsequently administering to the patient an IL-17 binding molecule in a maintenance regimen to provide i) an average steady-state trough level of the IL-17 binding molecule of about 8 μg / ml to about 30 μg / ml and / or ii) an average AUC tau in the steady state of about 331 mg*day / L to about 1323 mg*day / L. And b) subsequently administering to the patient an IL-17 binding molecule in a maintenance regimen to provide i) an average steady-state trough level of the IL-17 binding molecule of about 8 μg / ml to about 30 μg / ml and / or ii) an average AUC tau in the steady state of about 331 mg*day / L to about 1323 mg*day / L. And b) subsequently administering to the patient an IL-17 binding molecule in a maintenance regimen to provide i) an average steady-state trough level of the IL-17 binding molecule of about 8 μg / ml to about 30 μg / ml and / or ii) an average AUC tau in the steady state of about 331 mg*day / L to about 1323 mg*day / L. And b) subsequently administering to the patient an IL-17 binding molecule in a maintenance regimen to provide i) an average steady-state trough level of the IL-17 binding molecule of about 8 μg / ml to about 30 μg / ml and / or ii) an average AUC tau in the steady state of about 331 mg*day / L to about 1323 mg*day / L. And b) subsequently administering to the patient an IL-17 binding molecule in a maintenance regimen to provide i) an average steady-state trough level of the IL-17 binding molecule of about 8 μg / ml to about 30 μg / ml and / or ii) an average AUC tau in the steady state of about 331 mg*day / L to about 1323 mg*day / L. And b) subsequently administering to the patient an IL-17 binding molecule in a maintenance regimen to provide i) an average steady-state trough level of the IL-17 binding molecule of about 8 μg / ml to about 30 μg / ml and / or ii) an average AUC tau in the steady state of about 331 mg*day / L to about 1323 mg*day / L.

[0030] Disclosed herein is a method for treating a patient in need of an IL-17 binding molecule in an induction regimen to provide an average maximum plasma concentration (C) of the IL-17 binding molecule of about 401 μg / ml. And b) subsequently administering to the patient an IL-17 binding molecule in a maintenance regimen to provide i) an average steady-state trough level of the IL-17 binding molecule of about 8 μg / ml to about 30 μg / ml and / or ii) an average AUC tau in the steady state of about 331 mg*day / L to about 1323 mg*day / L. C max And b) subsequently administering to the patient an IL-17 binding molecule in a maintenance regimen to provide i) an average steady-state trough level of the IL-17 binding molecule of about 8 μg / ml to about 30 μg / ml and / or ii) an average AUC tau in the steady state of about 331 mg*day / L to about 1323 mg*day / L. Administering a molecule to provide i) an average steady-state trough level of the IL-17 binding molecule of from about 9.4 μg / ml to about 31 μg / ml and / or ii) an average AUC tau in steady state of from about 314 mg*day / L to about 1256 mg*day / L, a method of treating a high-risk RA patient including the steps of and a method of treating a high-risk RA patient

[0031] Disclosed herein is an IL-17 binding molecule for use in treating psoriasis, which comprises administering to a patient the IL-17 binding molecule a) in an induction regimen to provide an average peak plasma concentration (C ) of the IL-17 binding molecule of about 401 μg / ml, and b) then administering to the patient in a maintenance regimen to provide i) an average steady-state trough level of the IL-17 binding molecule of from about 9.4 μg / ml to about 31 μg / ml and / or ii) an average AUC tau in steady state of from about 314 mg*day / L to about 1256 mg*day / L max and In some embodiments, the maintenance regimen provides an average steady-state trough level of the IL-17 binding molecule of from about 9.4 μg / ml to about 17.3 μg / ml. In some embodiments, the maintenance provides an average steady-state trough level of the IL-17 binding molecule of about 9.4 μg / ml or about 17.3 μg / ml. In some embodiments, the induction regimen includes intravenous administration of the IL-17 binding molecule every other week. In some embodiments the maintenance regimen includes subcutaneous administration of the IL-17 binding molecule once a month and a method of treating psoriasis

[0032] In some embodiments, the maintenance regimen provides an average steady-state trough level of the IL-17 binding molecule of from about 9.4 μg / ml to about 17.3 μg / ml. In some embodiments, the maintenance provides an average steady-state trough level of the IL-17 binding molecule of about 9.4 μg / ml or about 17.3 μg / ml. In some embodiments, the induction regimen includes intravenous administration of the IL-17 binding molecule every other week. In some embodiments the maintenance regimen includes subcutaneous administration of the IL-17 binding molecule once a month In some embodiments, the maintenance provides an average steady-state trough level of the IL-17 binding molecule of about 9.4 μg / ml or about 17.3 μg / ml. In some embodiments, the induction regimen includes intravenous administration of the IL-17 binding molecule every other week. In some embodiments the maintenance regimen includes subcutaneous administration of the IL-17 binding molecule once a month Disclosed herein is a pharmaceutical composition comprising an IL-17 antagonist for use in the treatment of rheumatoid arthritis (RA) in a patient, and b) a method of administering the pharmaceutical composition to a patient In some embodiments, the maintenance regimen provides an average steady-state trough level of the IL-17 binding molecule of from about 9.4 μg / ml to about 17.3 μg / ml. In some embodiments, the maintenance provides an average steady-state trough level of the IL-17 binding molecule of about 9.4 μg / ml or about 17.3 μg / ml. In some embodiments, the induction regimen includes intravenous administration of the IL-17 binding molecule every other week. In some embodiments

[0033] Disclosed herein is a pharmaceutical composition comprising an IL-17 antagonist for use in the treatment of rheumatoid arthritis (RA) in a patient, and b) a method of administering the pharmaceutical composition to a patient including the steps of Including the described instruction manual, the patient is i) RF+, ACPA+, or both RF+ and ACPA +, and ii) characterized by having high levels of CRP, high ESR, or both high levels of CRP and high ESR, and is a kit.

[0034] Disclosed herein is an IL-17 antagonist for the preparation of a medicament for treating RA, under the condition that patients are selected for treatment for the purpose based on a) being 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.

[0035] Disclosed herein is an IL-17 antagonist for the manufacture of a medicament for the treatment of RA in patients characterized by a) being 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, wherein the medicament comprises a container, and each container is formulated to have an amount of IL-17 antagonist sufficient to enable delivery of at least about 75 mg to about 150 mg of IL-17 antagonist per unit dose.

[0036] Disclosed herein is an IL-17 antagonist for the manufacture of a medicament for the treatment of RA in patients characterized by a) being 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, wherein the medicament comprises a container, and each container is formulated to have an amount of IL-17 antagonist sufficient to enable delivery of at least about 10 mg / kg. ​​​​​​

[0037] Disclosed herein is an IL-17 antagonist for use in the manufacture of a medicament for the treatment of RA in patients characterized as having a) RF+, ACPA+, or both RF+ and ACPA+ and b) high levels of CRP, high ESR, or both high levels of CRP and high ESR, wherein the medicament is formulated at a dose that enables intravenous delivery of about 10 mg / kg per unit dose. Disclosed herein is an IL-17 antagonist for use in the manufacture of a medicament for the treatment of RA in patients characterized as having a) RF+, ACPA+, or both RF+ and ACPA+ and b) high levels of CRP, high ESR, or both high levels of CRP and high ESR, wherein the medicament is formulated at a dose that enables subcutaneous delivery of about 75 mg to about 150 mg of IL-17 antagonist per unit dose. Disclosed herein is an in vitro test method for selecting a patient for the treatment of RA, the method comprising the step of determining whether the patient has i. RF+, ACPA+, or both RF+ and ACPA+ and ii. high levels of CRP, high ESR, or both high levels of CRP and high ESR. In some embodiments of the disclosed in vitro test method, the patient is administered an IL-17 antagonist regimen, namely, a) the IL-17 antagonist is administered to the patient three times at a dose of about 10 mg / kg, with the first dose delivered at week 0, the second dose delivered at week 2, and the third dose delivered at week 4, and a) thereafter, starting at week 8, the IL-17 antagonist is administered twice monthly, once monthly, every two months, or every three months. Disclosed herein is an IL-17 antagonist for use in the manufacture of a medicament for the treatment of RA in patients characterized as having a) RF+, ACPA+, or both RF+ and ACPA+ and b) high levels of CRP, high ESR, or both high levels of CRP and high ESR, wherein the medicament is formulated at a dose that enables intravenous delivery of about 10 mg / kg per unit dose. Disclosed herein is an IL-17 antagonist for use in the manufacture of a medicament for the treatment of RA in patients characterized as having a) RF+, ACPA+, or both RF+ and ACPA+ and b) high levels of CRP, high ESR, or both high levels of CRP and high ESR, wherein the medicament is formulated at a dose that enables subcutaneous delivery of about 75 mg to about 150 mg of IL-17 antagonist per unit dose.

[0038] Disclosed herein is an IL-17 antagonist for use in the manufacture of a medicament for the treatment of RA in patients characterized as having a) RF+, ACPA+, or both RF+ and ACPA+ and b) high levels of CRP, high ESR, or both high levels of CRP and high ESR, wherein the medicament is formulated at a dose that enables intravenous delivery of about 10 mg / kg per unit dose. Disclosed herein is an IL-17 antagonist for use in the manufacture of a medicament for the treatment of RA in patients characterized as having a) RF+, ACPA+, or both RF+ and ACPA+ and b) high levels of CRP, high ESR, or both high levels of CRP and high ESR, wherein the medicament is formulated at a dose that enables subcutaneous delivery of about 75 mg to about 150 mg of IL-17 antagonist per unit dose. Disclosed herein is an IL-17 antagonist for use in the manufacture of a medicament for the treatment of RA in patients characterized as having a) RF+, ACPA+, or both RF+ and ACPA+ and b) high levels of CRP, high ESR, or both high levels of CRP and high ESR, wherein the medicament is formulated at a dose that enables intravenous delivery of about 10 mg / kg per unit dose. Disclosed herein is an IL-17 antagonist for use in the manufacture of a medicament for the treatment of RA in patients characterized as having a) RF+, ACPA+, or both RF+ and ACPA+ and b) high levels of CRP, high ESR, or both high levels of CRP and high ESR, wherein the medicament is formulated at a dose that enables subcutaneous delivery of about 75 mg to about 150 mg of IL-17 antagonist per unit dose. Disclosed herein is an IL-17 antagonist for use in the manufacture of a medicament for the treatment of RA in patients characterized as having a) RF+, ACPA+, or both RF+ and ACPA+ and b) high levels of CRP, high ESR, or both high levels of CRP and high ESR, wherein the medicament is formulated at a dose that enables subcutaneous delivery of about 75 mg to about 150 mg of IL-17 antagonist per unit dose.

[0039] Disclosed herein is an in vitro test method for selecting a patient for the treatment of RA, the method comprising the step of determining whether the patient has i. RF+, ACPA+, or both RF+ and ACPA+ and ii. high levels of CRP, high ESR, or both high levels of CRP and high ESR. In some embodiments of the disclosed in vitro test method, the patient is administered an IL-17 antagonist regimen, namely, a) the IL-17 antagonist is administered to the patient three times at a dose of about 10 mg / kg, with the first dose delivered at week 0, the second dose delivered at week 2, and the third dose delivered at week 4, and a) thereafter, starting at week 8, the IL-17 antagonist is administered twice monthly, once monthly, every two months, or every three months. Disclosed herein is an in vitro test method for selecting a patient for the treatment of RA, the method comprising the step of determining whether the patient has i. RF+, ACPA+, or both RF+ and ACPA+ and ii. high levels of CRP, high ESR, or both high levels of CRP and high ESR. In some embodiments of the disclosed in vitro test method, the patient is administered an IL-17 antagonist regimen, namely, a) the IL-17 antagonist is administered to the patient three times at a dose of about 10 mg / kg, with the first dose delivered at week 0, the second dose delivered at week 2, and the third dose delivered at week 4, and a) thereafter, starting at week 8, the IL-17 antagonist is administered twice monthly, once monthly, every two months, or every three months. Disclosed herein is an in vitro test method for selecting a patient for the treatment of RA, the method comprising the step of determining whether the patient has i. RF+, ACPA+, or both RF+ and ACPA+ and ii. high levels of CRP, high ESR, or both high levels of CRP and high ESR. In some embodiments of the disclosed in vitro test method, the patient is administered an IL-17 antagonist regimen, namely, a) the IL-17 antagonist is administered to the patient three times at a dose of about 10 mg / kg, with the first dose delivered at week 0, the second dose delivered at week 2, and the third dose delivered at week 4, and a) thereafter, starting at week 8, the IL-17 antagonist is administered twice monthly, once monthly, every two months, or every three months. Disclosed herein is an in vitro test method for selecting a patient for the treatment of RA, the method comprising the step of determining whether the patient has i. RF+, ACPA+, or both RF+ and ACPA+ and ii. high levels of CRP, high ESR, or both high levels of CRP and high ESR. In some embodiments of the disclosed in vitro test method, the patient is administered an IL-17 antagonist regimen, namely, a) the IL-17 antagonist is administered to the patient three times at a dose of about 10 mg / kg, with the first dose delivered at week 0, the second dose delivered at week 2, and the third dose delivered at week 4, and a) thereafter, starting at week 8, the IL-17 antagonist is administered twice monthly, once monthly, every two months, or every three months. Disclosed herein is an in vitro test method for selecting a patient for the treatment of RA, the method comprising the step of determining whether the patient has i. RF+, ACPA+, or both RF+ and ACPA+ and ii. high levels of CRP, high ESR, or both high levels of CRP and high ESR. In some embodiments of the disclosed in vitro test method, the patient is administered an IL-17 antagonist regimen, namely, a) the IL-17 antagonist is administered to the patient three times at a dose of about 10 mg / kg, with the first dose delivered at week 0, the second dose delivered at week 2, and the third dose delivered at week 4, and a) thereafter, starting at week 8, the IL-17 antagonist is administered twice monthly, once monthly, every two months, or every three months. Disclosed herein is an in vitro test method for selecting a patient for the treatment of RA, the method comprising the step of determining whether the patient has i. RF+, ACPA+, or both RF+ and ACPA+ and ii. high levels of CRP, high ESR, or both high levels of CRP and high ESR. In some embodiments of the disclosed in vitro test method, the patient is administered an IL-17 antagonist regimen, namely, a) the IL-17 antagonist is administered to the patient three times at a dose of about 10 mg / kg, with the first dose delivered at week 0, the second dose delivered at week 2, and the third dose delivered at week 4, and a) thereafter, starting at week 8, the IL-17 antagonist is administered twice monthly, once monthly, every two months, or every three months. Disclosed herein is an in vitro test method for selecting a patient for the treatment of RA, the method comprising the step of determining whether the patient has i. RF+, ACPA+, or both RF+ and ACPA+ and ii. high levels of CRP, high ESR, or both high levels of CRP and high ESR. In some embodiments of the disclosed in vitro test method, the patient is administered an IL-17 antagonist regimen, namely, a) the IL-17 antagonist is administered to the patient three times at a dose of about 10 mg / kg, with the first dose delivered at week 0, the second dose delivered at week 2, and the third dose delivered at week 4, and a) thereafter, starting at week 8, the IL-17 antagonist is administered twice monthly, once monthly, every two months, or every three months. Disclosed herein is an in vitro test method for selecting a patient for the treatment of RA, the method comprising the step of determining whether the patient has i. RF+, ACPA+, or both RF+ and ACPA+ and ii. high levels of CRP, high ESR, or both high levels of CRP and high ESR. In some embodiments of the disclosed in vitro test method, the patient is administered an IL-17 antagonist regimen, namely, a) the IL-17 antagonist is administered to the patient three times at a dose of about 10 mg / kg, with the first dose delivered at week 0, the second dose delivered at week 2, and the third dose delivered at week 4, and a) thereafter, starting at week 8, the IL-17 antagonist is administered twice monthly, once monthly, every two months, or every three months. Administering a gonist to a patient at about 75 mg to about 150 mg results in an improved treatment response. Have a response.

[0040] Disclosed herein is a method for creating information in a transmissible form regarding a patient having RA, comprising: a) assaying a sample from the patient for 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; and b) embodying the results of step a) in information in a form transmissible. Protein antibody (ACPA), or RF and ACPA, and ii) C-reactive Protein (CRP), erythrocyte sedimentation rate (ESR) or both CRP and ESR Step of assaying; and b) embodying the results of step a) in information in a form transmissible. A method for creating information in a transmissible form regarding a patient having RA, comprising: a) assaying a sample from the patient for 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; and b) embodying the results of step a) in information in a form transmissible.

[0041] As used herein, an IL-17 antagonist, such as an IL-17 binding molecule (such as an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) or an IL-17 receptor binding molecule (such as an IL-17 antibody or an antigen-binding fragment thereof), is administered to a patient having an inflammatory arthritis selected from the group consisting of rheumatoid arthritis (RA), spondyloarthritis, ankylosing spondylitis (spondyloarthritis), and psoriatic arthritis at an induction dose of about 10 mg / kg (such as an i.v. induction dose) three times or an induction dose of about 150 mg (such as an s.c. induction dose) several times (such as 1, 2, 3, 4, or 5 times). For example, an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) or an IL-17 Receptor binding molecule (such as an IL-17 antibody or an antigen-binding fragment thereof) at an induction dose of about 10 mg / kg (such as an i.v. induction dose) three times or an induction dose of about 150 mg ( For example, an s.c. induction dose) several times (such as 1, 2, 3, 4, or 5 times), rheumatoid (RA), spondyloarthritis, ankylosing spondylitis (spondyloarthritis), and psoriatic arthritis. Selected from the group consisting of inflammatory arthritis. In some embodiments, the induction dose is delivered every other week, and then, for example, Starting at the first month after the delivery of the final induction dose, an IL-17 antagonist (such as Secukinumab) is administered to the patient once a month at a maintenance dose of about 75 mg to about 300 mg (such as about 75 mg to about 150 mg, such as For example, about 75 mg or about 150 mg) (such as an s.c. maintenance dose). Administer to the patient.

[0042] In this specification, a step of selecting a patient with RA (e.g., a high-risk RA patient) or a patient having an elevated baseline CRP level, and a step of administering an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody or its antigen-binding fragment, such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 antibody or its antigen-binding fragment), to the patient at about 10 mg / kg (e.g., by the i.v. route) every other week (e.g., at weeks 0, 2, and 4), and then starting at once a month (e.g., at week 8), administering an IL-17 antagonist to the patient at about 75 mg to about 300 mg (e.g., about 75 mg to about 15 0 mg, e.g., about 75 mg or about 150 mg) (e.g., by the s.c. route) are included in a method for treating RA. In some embodiments of the disclosed methods, kits, uses, pharmaceutical compositions, and regimens, a high-risk RA patient is a) seropositive for rheumatoid factor (RF+) and anti-citrullinated protein antibody ( ACPA+), or both RF+ and ACPA+, and b) has a high level of C-reactive protein (CRP), a high erythrocyte sedimentation rate (ESR), or both a high level of CRP and a high ESR. In some embodiments of the disclosed methods, kits, uses, pharmaceutical compositions, and regimens,

[0043] the IL-17 antagonist is an IL-17 binding molecule or an IL-17 receptor binding molecule. In some embodiments, the IL-17 binding molecule or the IL-17 receptor binding molecule is a) secukinumab, b) Leu74, Tyr85, His86, Met87, and so on. and so on. and so on.

[0044] In some embodiments of the disclosed methods, kits, uses, pharmaceutical compositions, and regimens, the IL-17 antagonist is an IL-17 binding molecule or an IL-17 receptor binding molecule. In some embodiments, the IL-17 binding molecule or the IL-17 receptor binding molecule is a) secukinumab, b) Leu74, Tyr85, His86, Met87, and so on. 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 Le 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, an IL-17 antibody that binds to an epitope of an IL-17 homodimer having two mature IL-17 protein chains (the epitope contains 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 of about 100 - 200 pM D 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 ), iii) 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 domain containing the amino acid sequence shown as SEQ ID NO: 8 and an immunoglobulin V L domain containing the amino acid sequence shown as SEQ ID NO: 10, iv) SEQ ID NO: 1. An immunoglobulin V domain comprising hypervariable regions shown as SEQ ID NO: 2 and SEQ ID NO: 3 H domain in, v) An immunoglobulin V domain comprising hypervariable regions shown as SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 immunoglobulin V L domain, vi) An immunoglobulin V domain comprising hypervariable regions shown as SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 shown H domain, vii) SEQ ID NO: 1, SEQ ID NO: 2 and an immunoglobulin V domain comprising hypervariable regions shown as SEQ ID NO: 3 H domain as well as the sequence number 4, an immunoglobulin V domain comprising hypervariable regions shown as SEQ ID NO: 5 and SEQ ID NO: 6 L domain, and viii) An immunoglobulin V domain comprising hypervariable regions shown as SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 shown H domain as well as SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID number 6, an immunoglobulin V domain comprising hypervariable regions shown L selected from the group consisting of domains is an IL-17 binding molecule (e.g., an IL-17 antibody).

[0045] In a preferred embodiment of the disclosed method, kit, use, pharmaceutical composition and regimen the IL-17 binding molecule is a human antibody. In a more preferred embodiment of the disclosed method, kit, use, pharmaceutical composition and regimen, the IL-17 binding molecule is secukinumab is.

Brief Description of the Drawings

[0046]

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Mode for Carrying Out the Invention

[0047] The 1987 American College of Rheumatology (ACR) classification criteria for RA distinguish patients with long-standing RA from individuals with other established rheumatologic diagnoses. These criteria were not useful for identifying patients with early RA disease who could benefit from early intervention. In 201 0, the ACR developed a new classification system (hereinafter the "2010 ACR / EULAR" criteria) that focused on features of RA in earlier stages of the disease related to persistence and / or erosiveness of the disease. focused on features of RA in earlier stages of the disease related to persistence and / or erosiveness of the disease. was defined by (Aletaha et al. (2010) Ann. Rheum. Dis., 69, 1580-1588). In 2010, A The CR / EULAR classification system focuses on six criteria. The first two criteria define the subjects to be tested for RA, while the remaining four criteria are for scoring (Table 1). A score of 6 or more indicates definite RA. (Table 1). A score of 6 or more indicates definite RA.

[0048]

Table 1

[0049] When exploring indicators predictive of the response of RA patients to treatment with IL-17-binding molecules, such as IL-17 antibodies like secukinumab, the inventors analyzed two of the four 2010 ACR / EULAR scoreable criteria to determine whether these criteria affect the response to treatment with IL-17-binding molecules, such as secukinumab. First, the inventors analyzed the serological tests of the patients to determine whether the patients were RF+ and / or ACPA+. Second, the inventors analyzed the presence of acute-phase reactants to determine whether the patients had high levels of C-reactive protein (CRP) and / or high erythrocyte sedimentation rate (ESR). In the process, the inventors found that patients who were 1) RF+ or ACPA+ (or both) and 2) had high levels of CRP or ESR (or both) were more likely to have a good response to treatment with IL-17-binding molecules, such as IL-17 antibodies like secukinumab. Such patients (referred to herein as "high-risk RA patients") are patients with the most prominent features of RA (e.g., Yildirim ACR / EULAR scoreable criteria to determine whether these criteria affect the response to treatment with IL-17-binding molecules, such as secukinumab. First, the inventors analyzed the serological tests of the patients to determine whether the patients were RF+ and / or ACPA+. Second, the inventors analyzed the presence of acute-phase reactants to determine whether the patients had high levels of C-reactive protein (CRP) and / or high erythrocyte sedimentation rate (ESR). In the process, the inventors found that patients who were 1) RF+ or ACPA+ (or both) and 2) had high levels of CRP or ESR (or both) were more likely to have a good response to treatment with IL-17-binding molecules, such as IL-17 antibodies like secukinumab. Such patients (referred to herein as "high-risk RA patients") are patients with the most prominent features of RA (e.g., Yildirim ACR / EULAR scoreable criteria to determine whether these criteria affect the response to treatment with IL-17-binding molecules, such as secukinumab. First, the inventors analyzed the serological tests of the patients to determine whether the patients were RF+ and / or ACPA+. Second, the inventors analyzed the presence of acute-phase reactants to determine whether the patients had high levels of C-reactive protein (CRP) and / or high erythrocyte sedimentation rate (ESR). In the process, the inventors found that patients who were 1) RF+ or ACPA+ (or both) and 2) had high levels of CRP or ESR (or both) were more likely to have a good response to treatment with IL-17-binding molecules, such as IL-17 antibodies like secukinumab. Such patients (referred to herein as "high-risk RA patients") are patients with the most prominent features of RA (e.g., Yildirim ACR / EULAR scoreable criteria to determine whether these criteria affect the response to treatment with IL-17-binding molecules, such as secukinumab. First, the inventors analyzed the serological tests of the patients to determine whether the patients were RF+ and / or ACPA+. Second, the inventors analyzed the presence of acute-phase reactants to determine whether the patients had high levels of C-reactive protein (CRP) and / or high erythrocyte sedimentation rate (ESR). In the process, the inventors found that patients who were 1) RF+ or ACPA+ (or both) and 2) had high levels of CRP or ESR (or both) were more likely to have a good response to treatment with IL-17-binding molecules, such as IL-17 antibodies like secukinumab. Such patients (referred to herein as "high-risk RA patients") are patients with the most prominent features of RA (e.g., Yildirim ACR / EULAR scoreable criteria to determine whether these criteria affect the response to treatment with IL-17-binding molecules, such as secukinumab. First, the inventors analyzed the serological tests of the patients to determine whether the patients were RF+ and / or ACPA+. Second, the inventors analyzed the presence of acute-phase reactants to determine whether the patients had high levels of C-reactive protein (CRP) and / or high erythrocyte sedimentation rate (ESR). In the process, the inventors found that patients who were 1) RF+ or ACPA+ (or both) and 2) had high levels of CRP or ESR (or both) were more likely to have a good response to treatment with IL-17-binding molecules, such as IL-17 antibodies like secukinumab. Such patients (referred to herein as "high-risk RA patients") are patients with the most prominent features of RA (e.g., Yildirim ACR / EULAR scoreable criteria to determine whether these criteria affect the response to treatment with IL-17-binding molecules, such as secukinumab. First, the inventors analyzed the serological tests of the patients to determine whether the patients were RF+ and / or ACPA+. Second, the inventors analyzed the presence of acute-phase reactants to determine whether the patients had high levels of C-reactive protein (CRP) and / or high erythrocyte sedimentation rate (ESR). In the process, the inventors found that patients who were 1) RF+ or ACPA+ (or both) and 2) had high levels of CRP or ESR (or both) were more likely to have a good response to treatment with IL-17-binding molecules, such as IL-17 antibodies like secukinumab. Such patients (referred to herein as "high-risk RA patients") are patients with the most prominent features of RA (e.g., Yildirim ACR / EULAR scoreable criteria to determine whether these criteria affect the response to treatment with IL-17-binding molecules, such as secukinumab. First, the inventors analyzed the serological tests of the patients to determine whether the patients were RF+ and / or ACPA+. Second, the inventors analyzed the presence of acute-phase reactants to determine whether the patients had high levels of C-reactive protein (CRP) and / or high erythrocyte sedimentation rate (ESR). In the process, the inventors found that patients who were 1) RF+ or ACPA+ (or both) and 2) had high levels of CRP or ESR (or both) were more likely to have a good response to treatment with IL-17-binding molecules, such as IL-17 antibodies like secukinumab. Such patients (referred to herein as "high-risk RA patients") are patients with the most prominent features of RA (e.g., Yildirim ACR / EULAR scoreable criteria to determine whether these criteria affect the response to treatment with IL-17-binding molecules, such as secukinumab. First, the inventors analyzed the serological tests of the patients to determine whether the patients were RF+ and / or ACPA+. Second, the inventors analyzed the presence of acute-phase reactants to determine whether the patients had high levels of C-reactive protein (CRP) and / or high erythrocyte sedimentation rate (ESR). In the process, the inventors found that patients who were 1) RF+ or ACPA+ (or both) and 2) had high levels of CRP or ESR (or both) were more likely to have a good response to treatment with IL-17-binding molecules, such as IL-17 antibodies like secukinumab. Such patients (referred to herein as "high-risk RA patients") are patients with the most prominent features of RA (e.g., Yildirim ACR / EULAR scoreable criteria to determine whether these criteria affect the response to treatment with IL-17-binding molecules, such as secukinumab. First, the inventors analyzed the serological tests of the patients to determine whether the patients were RF+ and / or ACPA+. Second, the inventors analyzed the presence of acute-phase reactants to determine whether the patients had high levels of C-reactive protein (CRP) and / or high erythrocyte sedimentation rate (ESR). In the process, the inventors found that patients who were 1) RF+ or ACPA+ (or both) and 2) had high levels of CRP or ESR (or both) were more likely to have a good response to treatment with IL-17-binding molecules, such as IL-17 antibodies like secukinumab. Such patients (referred to herein as "high-risk RA patients") are patients with the most prominent features of RA (e.g., Yildirim ACR / EULAR scoreable criteria to determine whether these criteria affect the response to treatment with IL-17-binding molecules, such as secukinumab. First, the inventors analyzed the serological tests of the patients to determine whether the patients were RF+ and / or ACPA+. Second, the inventors analyzed the presence of acute-phase reactants to determine whether the patients had high levels of C-reactive protein (CRP) and / or high erythrocyte sedimentation rate (ESR). In the process, the inventors found that patients who were 1) RF+ or ACPA+ (or both) and 2) had high levels of CRP or ESR (or both) were more likely to have a good response to treatment with IL-17-binding molecules, such as IL-17 antibodies like secukinumab. Such patients (referred to herein as "high-risk RA patients") are patients with the most prominent features of RA (e.g., Yildirim ACR / EULAR scoreable criteria to determine whether these criteria affect the response to treatment with IL-17-binding molecules, such as secukinumab. First, the inventors analyzed the serological tests of the patients to determine whether the patients were RF+ and / or ACPA+. Second, the inventors analyzed the presence of acute-phase reactants to determine whether the patients had high levels of C-reactive protein (CRP) and / or high erythrocyte sedimentation rate (ESR). In the process, the inventors found that patients who were 1) RF+ or ACPA+ (or both) and 2) had high levels of CRP or ESR (or both) were more likely to have a good response to treatment with IL-17-binding molecules, such as IL-17 antibodies like secukinumab. Such patients (referred to herein as "high-risk RA patients") are patients with the most prominent features of RA (e.g., Yildirim ACR / EULAR scoreable criteria to determine whether these criteria affect the response to treatment with IL-17-binding molecules, such as secukinumab. First, the inventors analyzed the serological tests of the patients to determine whether the patients were RF+ and / or ACPA+. Second, the inventors analyzed the presence of acute-phase reactants to determine whether the patients had high levels of C-reactive protein (CRP) and / or high erythrocyte sedimentation rate (ESR). In the process, the inventors found that patients who were 1) RF+ or ACPA+ (or both) and 2) had high levels of CRP or ESR (or both) were more likely to have a good response to treatment with IL-17-binding molecules, such as IL-17 antibodies like secukinumab. Such patients (referred to herein as "high-risk RA patients") are patients with the most prominent features of RA (e.g., Yildirim See, e.g., (2004) Annals Clin. Lab. Sci, 34:423. Accordingly, disclosed herein is a method for treating rheumatoid arthritis (RA) comprising administering to a high-risk RA patient a therapeutically effective amount of an IL-17 binding molecule. See, e.g., (2004) Annals Clin. Lab. Sci, 34:423. Accordingly, disclosed herein is a method for treating rheumatoid arthritis (RA) comprising administering to a high-risk RA patient a therapeutically effective amount of an IL-17 binding molecule. See, e.g., (2004) Annals Clin. Lab. Sci, 34:423. Accordingly, disclosed herein is a method for treating rheumatoid arthritis (RA) comprising administering to a high-risk RA patient a therapeutically effective amount of an IL-17 binding molecule.

[0050] The inventors further confirmed that an increase in baseline CRP levels (e.g., > about 10 mg / L) is also associated with responsiveness to secukinumab. Accordingly, disclosed herein is a method for treating rheumatoid arthritis (RA) comprising administering to an RA patient exhibiting an increase in baseline CRP level (e.g., greater than about 10 mg / L, greater than about 20 mg / L, greater than about 30 mg / L) a therapeutically effective amount of an IL-17 binding molecule. The inventors further confirmed that an increase in baseline CRP levels (e.g., > about 10 mg / L) is also associated with responsiveness to secukinumab. Accordingly, disclosed herein is a method for treating rheumatoid arthritis (RA) comprising administering to an RA patient exhibiting an increase in baseline CRP level (e.g., greater than about 10 mg / L, greater than about 20 mg / L, greater than about 30 mg / L) a therapeutically effective amount of an IL-17 binding molecule. The inventors further confirmed that an increase in baseline CRP levels (e.g., > about 10 mg / L) is also associated with responsiveness to secukinumab. Accordingly, disclosed herein is a method for treating rheumatoid arthritis (RA) comprising administering to an RA patient exhibiting an increase in baseline CRP level (e.g., greater than about 10 mg / L, greater than about 20 mg / L, greater than about 30 mg / L) a therapeutically effective amount of an IL-17 binding molecule. The inventors further confirmed that an increase in baseline CRP levels (e.g., > about 10 mg / L) is also associated with responsiveness to secukinumab. Accordingly, disclosed herein is a method for treating rheumatoid arthritis (RA) comprising administering to an RA patient exhibiting an increase in baseline CRP level (e.g., greater than about 10 mg / L, greater than about 20 mg / L, greater than about 30 mg / L) a therapeutically effective amount of an IL-17 binding molecule. The inventors further confirmed that an increase in baseline CRP levels (e.g., > about 10 mg / L) is also associated with responsiveness to secukinumab. Accordingly, disclosed herein is a method for treating rheumatoid arthritis (RA) comprising administering to an RA patient exhibiting an increase in baseline CRP level (e.g., greater than about 10 mg / L, greater than about 20 mg / L, greater than about 30 mg / L) a therapeutically effective amount of an IL-17 binding molecule. The inventors further confirmed that an increase in baseline CRP levels (e.g., > about 10 mg / L) is also associated with responsiveness to secukinumab. Accordingly, disclosed herein is a method for treating rheumatoid arthritis (RA) comprising administering to an RA patient exhibiting an increase in baseline CRP level (e.g., greater than about 10 mg / L, greater than about 20 mg / L, greater than about 30 mg / L) a therapeutically effective amount of an IL-17 binding molecule.

[0051] The inventors further discovered that a treatment regimen useful for treating high-risk RA patients is even more useful for treating RA and other inflammatory arthritides, e.g., ankylosing spondylitis (AS) or psoriatic arthritis (PsA) in non-high-risk patients. Accordingly, disclosed herein is an administration and treatment regimen for addressing inflammatory arthritis (e.g., RA, AS, PsA) comprising administering to a patient having inflammatory arthritis a therapeutically effective amount of an IL-17 binding molecule. The inventors further discovered that a treatment regimen useful for treating high-risk RA patients is even more useful for treating RA and other inflammatory arthritides, e.g., ankylosing spondylitis (AS) or psoriatic arthritis (PsA) in non-high-risk patients. Accordingly, disclosed herein is an administration and treatment regimen for addressing inflammatory arthritis (e.g., RA, AS, PsA) comprising administering to a patient having inflammatory arthritis a therapeutically effective amount of an IL-17 binding molecule. The inventors further discovered that a treatment regimen useful for treating high-risk RA patients is even more useful for treating RA and other inflammatory arthritides, e.g., ankylosing spondylitis (AS) or psoriatic arthritis (PsA) in non-high-risk patients. Accordingly, disclosed herein is an administration and treatment regimen for addressing inflammatory arthritis (e.g., RA, AS, PsA) comprising administering to a patient having inflammatory arthritis a therapeutically effective amount of an IL-17 binding molecule. The inventors further discovered that a treatment regimen useful for treating high-risk RA patients is even more useful for treating RA and other inflammatory arthritides, e.g., ankylosing spondylitis (AS) or psoriatic arthritis (PsA) in non-high-risk patients. Accordingly, disclosed herein is an administration and treatment regimen for addressing inflammatory arthritis (e.g., RA, AS, PsA) comprising administering to a patient having inflammatory arthritis a therapeutically effective amount of an IL-17 binding molecule. The inventors further discovered that a treatment regimen useful for treating high-risk RA patients is even more useful for treating RA and other inflammatory arthritides, e.g., ankylosing spondylitis (AS) or psoriatic arthritis (PsA) in non-high-risk patients. Accordingly, disclosed herein is an administration and treatment regimen for addressing inflammatory arthritis (e.g., RA, AS, PsA) comprising administering to a patient having inflammatory arthritis a therapeutically effective amount of an IL-17 binding molecule. The inventors further discovered that a treatment regimen useful for treating high-risk RA patients is even more useful for treating RA and other inflammatory arthritides, e.g., ankylosing spondylitis (AS) or psoriatic arthritis (PsA) in non-high-risk patients. Accordingly, disclosed herein is an administration and treatment regimen for addressing inflammatory arthritis (e.g., RA, AS, PsA) comprising administering to a patient having inflammatory arthritis a therapeutically effective amount of an IL-17 binding molecule.

[0052] The term "comprising" includes "including" as well as "consisting of", e.g., a composition "comprising" X may consist exclusively of X or may well or alternatively include something else (e.g., X + Y). The term "comprising" includes "including" as well as "consisting of", e.g., a composition "comprising" X may consist exclusively of X or may well or alternatively include something else (e.g., X + Y). The term "comprising" includes "including" as well as "consisting of", e.g., a composition "comprising" X may consist exclusively of X or may well or alternatively include something else (e.g., X + Y).

[0053] The term "about" with respect to a numerical value x means + / - 10% unless otherwise indicated in the context. When used with respect to pharmacokinetic (PK) parameters (e.g., AUC, C max , t max , trough level, etc.), the term "about" indicates a treatment (e.g., dose and / or dosing regimen) that is considered by one of ordinary skill in the art to be biologically equivalent to a reference treatment. With respect to biological equivalence, the standard method for demonstrating biological equivalence is that the ratio of a given PK parameter (e.g., AUC, C ) between two treatments (i.e., reference treatment and test treatment) is statistically proven to be between 0.8 and 1.25, as indicated by the 90% confidence interval (CI) around the ratio (the lower limit of this CI exceeds 0.8 and the upper limit of this CI is less than 1 max ). Thus, for example, during a study comparing the PK profiles of a reference treatment and a test treatment, if a reference C of 10 μg / ml is obtained, the test treatment is considered "about 10 μg / ml" if one of ordinary skill in the art considers the test treatment to be biologically equivalent. As used herein, pharmacokinetic terms such as t , t , AUC, AUC max AUC (AUC up to the end of a given dosing period, hereinafter "AUC tau"), C max have the meanings accepted in those art max areas. 1 / 2 (0-tau)

[0054] The term "administer" with respect to a compound, e.g., an IL-17 binding molecule or an anti-rheumatic drug, is used to refer to the delivery of the compound by any route.

[0055] The phrase "active rheumatoid arthritis" or "active RA" refers to visible signs and symptoms (e.g.,​​​​​​ is used to refer to RA with swelling, difficulty in flexion, etc.

[0056] The term "assay" is used to refer to the act of detecting, identifying, screening, or measuring and that act can be carried out by any conventional means. For example, a sample can be assayed for the presence of a particular marker by using an ELISA assay, Northern blot, imaging, etc. to detect whether the marker is present in the sample.

[0057] The term "substantially" does not exclude "completely". For example, a composition "substantially free of" Y may be completely free of Y. If necessary, the term "substantially" can be excluded from the definitions of the present disclosure.

[0058] As used herein, "mg / kg" means mg of drug per 1 kg of the body weight of the patient to whom the drug is administered.

[0059] As used herein, an "IL-17 antagonist" is a molecule that can antagonize (e.g., reduce, inhibit, decrease, block, delay) the function, expression, and / or signaling of IL-17 (e.g., by blocking the binding of IL-17 to the IL-17 receptor). Non-limiting examples of IL-17 antagonists include IL-17 binding molecules and IL-17 receptor binding molecules. In some embodiments of the disclosed methods, regimens, kits, processes, uses, and compositions, an IL-17 antagonist is used.

[0060] "IL-17 binding molecule" refers to an IL-17 binding molecule that binds to IL-17, either alone or in association with other molecules. The term "binding molecule" refers to a molecule capable of binding to the human IL-17 antigen. However, with reference to a negative control test using an antibody of the same isotype, e.g., an anti-CD25 antibody , e.g., binding assays to measure inhibition of binding of IL-17 to its receptor, competitive Standard methods such as assays or bioassays (qualitative assays) or any type of Non-limiting examples of IL-17 binding molecules include , small molecules, IL-17 receptor decoys, and antibodies produced by B cells or hybridomas. and chimeric, CDR-grafted or human antibodies or fragments thereof, e.g., F(ab')2 and Fab fragments, as well as single chain or single domain antibodies. The synthetic molecule antagonizes (e.g., reduces) the function, expression, and / or signaling of IL-17. The disclosed methods, regimens, kits, steps, In some embodiments of the uses and compositions, an IL-17 binding molecule is used.

[0061] "IL-17 receptor-binding molecule" refers to a molecule that binds to the human IL-17 receptor, either alone or in association with other molecules. A binding reaction is a reaction that is independent of specificity but is homogeneous. With reference to a negative control test using an antibody of the same isotype, e.g., an anti-CD25 antibody, e.g., I Binding assays to measure inhibition of IL-17 receptor binding to IL-17, competitive assays Standard methods such as bioassays (qualitative assays) or any type of binding assay Non-limiting examples of IL-17 receptor binding molecules include , small molecules, IL-17 decoys, and antibodies and chimeras, CDR grafts or human antibodies or fragments thereof produced by B cells or hybridomas against the IL-1 7 receptor, such as F(ab’)2 and Fab fragments, and single-chain or single-domain antibodies. Preferably, the IL-17 receptor-binding molecule antagonizes (e.g., reduces, inhibits, decreases, delays) the function, expression and / or signaling of IL-17. In some embodiments of the disclosed methods, regimens, kits, processes, uses and compositions, an IL-17 receptor-binding molecule is used. The term "antibody" as used herein includes whole antibodies and antigen-binding portions or single chains thereof, as described herein. Naturally occurring "antibodies" are glycoproteins comprising at least two heavy (H) chains and two light (L) chains linked to each other by disulfide bonds. Each heavy chain is composed of a heavy-chain variable region (abbreviated herein as V

[0062] and a heavy-chain constant region. The heavy-chain constant region is composed of three domains, CH1, CH2 and CH3. Each light chain is composed of a light-chain variable region (abbreviated herein as VL) and a light-chain constant region. The light-chain constant region is composed of one domain, CL. The V and V regions can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs) interspersed by more conserved regions called framework regions (FRs). Each V and V is composed of three CDRs and four FRs arranged in the following order from the amino terminus to the carboxy terminus: FR1, CDR1, FR2, CDR2, FR3 H and a heavy-chain constant region. The heavy-chain constant region is composed of three domains, CH1, CH2 and CH3. Each light chain is composed of a light-chain variable region (abbreviated herein as VL) and a light-chain constant region. The light-chain constant region is composed of one domain, CL. The V and V regions can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs) interspersed by more conserved regions called framework regions (FRs). Each V and V is composed of three CDRs and four FRs arranged in the following order from the amino terminus to the carboxy terminus: FR1, CDR1, FR2, CDR2, FR3 and a light-chain constant region. The light-chain constant region is composed of one domain, CL. The V H and V L regions can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs) interspersed by more conserved regions called framework regions (FRs). Each V and V is composed of three CDRs and four FRs arranged in the following order from the amino terminus to the carboxy terminus: FR1, CDR1, FR2, CDR2, FR3 regions can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs) interspersed by more conserved regions called framework regions (FRs). Each V and V is composed of three CDRs and four FRs arranged in the following order from the amino terminus to the carboxy terminus: FR1, CDR1, FR2, CDR2, FR3 H and V L regions can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs) interspersed by more conserved regions called framework regions (FRs). Each V and V is composed of three CDRs and four FRs arranged in the following order from the amino terminus to the carboxy terminus: FR1, CDR1, FR2, CDR2, FR3​ , CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigens . The constant region of the antibody can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system . In some embodiments of the disclosed methods, regimens, kits, processes, uses, and compositions , an antibody against IL-17 or an IL-17 receptor is used.

[0063] As used herein, the term "antigen-binding portion" of an antibody refers to a fragment of the antibody that retains the ability to specifically bind to an antigen (e.g., IL-17). It has been shown that the antigen-binding function of an antibody can be performed by fragments of the full-length antibody. Examples of binding fragments included in the term "antigen-binding portion" of an antibody include a Fab fragment, which is a monovalent fragment consisting of the V , V L , CL, and CH1 domains; an F(ab)2 fragment, which is a bivalent fragment containing two H Fab fragments linked by a disulfide bridge in the hinge region; an Fd fragment consisting of the V and CH1 domains; an Fv fragment consisting of the V and V H domains of one arm of the antibody; a dAb fragment consisting of the V domain (Ward et al., 1989 Nature 341, 544-546), and an isolated complementarity-determining region (C L DR), etc. Specific examples of antigen-binding sites include the CDRs of secukinumab shown in SEQ ID NOs: 1-6 and 11-13 (Table H 4), preferably the heavy chain CDR3, etc. Furthermore H the two domains V and V of the Fv fragment are encoded by separate genes, but they are V and V L and V H are encoded by separate genes, but they are V Land V H A single protein chain in which regions pair to form a monovalent molecule (single-chain Fv (scFv), known for example from Bird et al., 1988 Science 242, pp. 423-426, and Huston et al., 1988 Proc. Natl. Acad. Sci. 85, pp. 5879-5883), can be prepared by recombinant methods and linked by a synthetic linker that enables this. Such single-chain antibodies are also to be included within the term "antibody". Single-chain antibodies and antigen-binding portions are obtained using conventional techniques known to those skilled in the art. In some embodiments of the disclosed methods, regimens, kits, processes, uses, and compositions, an IL-17 (e.g., secukinumab) or a single-chain antibody or antigen-binding portion of an antibody against an IL- 17 receptor is used. The term "pharmaceutically acceptable" means a non-toxic substance that does not interfere with the biological activity of the active ingredient(s).

[0064]

[0065] "Isolated antibody", as used herein, refers to an antibody that is substantially free of other antibodies having different antigen specificities (e.g., an isolated antibody that specifically binds to IL-17 is substantially free of antibodies that specifically bind to antigens other than IL -17). An isolated antibody may be substantially free of other cellular substances and / or chemical substances. However, an isolated antibody that "specifically binds" to IL-17 may be cross-reactive with other antigens such as IL-17 molecules of other species. In some embodiments of the disclosed methods, regimens, kits, processes, uses, and compositions, an IL-17 antagonist is an isolated antibody.

[0066] ​​​​The term "monoclonal antibody" or "monoclonal antibody composition" as used herein refers to a formulation of antibody molecules of a single molecular composition. A monoclonal antibody composition exhibits a single binding specificity and affinity for a particular epitope. In some embodiments of the disclosed methods, regimens , kits, processes, uses, and compositions, the IL-17 antagonists are monoclonal antibodies.

[0067] The term "human antibody" as used herein is intended to include antibodies having a variable region in which both the framework and CDR regions are derived from human-derived sequences. Further , when the antibody includes a constant region, the constant region is also a human sequence such as described in Knappik et al. (2000 J Mol Biol 296:57-86 ), for example, a human germline sequence or a variant of a human germline sequence or a consensus framework sequence obtained from human framework sequence analysis. A "human antibody" is not necessarily produced by a human, human tissue, or human cell. The human antibodies of the present disclosure may include amino acid residues not encoded by human sequences (e.g., mutations introduced by random or site-directed mutagenesis in vitro or by somatic mutation in vivo). However, the term "human antibody" as used herein does not include antibodies in which CDR sequences from the germline of other mammalian species, such as mice, are grafted onto human framework sequences. In some embodiments of the disclosed methods, regimens, kits, processes, uses, and compositions, the IL- 17 antagonists are human antibodies.

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

[0069] The term "K D " refers to the dissociation constant obtained from the ratio of K d to K a (i.e., K d / K a ) and is expressed as molar concentration (M). The K D value of an antibody can be determined using methods well established in the art . Methods for measuring the K D of an antibody include using surface plasmon resonance or a biosensor -system such as a Biacore® system. In some embodiments of the present invention, an IL-17 agonist, 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-1 7 antibody or an antigen-binding fragment thereof) binds to human IL-17 with a K of about 100 - 250 pM D

[0070] As used herein, the term "affinity" refers to the strength of the interaction between an antibody and an antigen at a single antigenic site ​​​​​​​Refers to the strength of the interaction with the 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 are known in the art for assessing the binding affinity of antibodies to various species of IL -17, such as ELISA, Western blot, and RIA. The antibody kinetics (e.g., binding affinity) can also be evaluated by standard assays known in the art, such as Biacore analysis . Assays for assessing the effect of antibodies on the functional properties of IL-17 (e.g., receptor binding, preventing or ameliorating osteolysis) will be described in more detail in the examples . As used herein, the terms "subject (test subject)" and "patient" include human 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, and non-mammals such as amphibians, reptiles, etc

[0071] . An antibody that "inhibits" one or more of the IL-17 functional properties (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 what is observed in the absence of the antibody (or in the presence of a control antibody of irrelevant specificity) . An antibody that inhibits IL-17 activity causes a statistically significant decrease in, for example, at least 10%, at least 50%, 80%, or 90% of the measurement parameters . In certain embodiments, the antibodies of the present disclosure inhibit 95%, 9 % of the IL-17 functional activity

[0072] . ​ It may inhibit 8% or 99% or more.

[0073] Unless otherwise indicated, the term "derivative" refers to an IL-17 antagonist, for example, an IL-17 binding molecule according to the present disclosure (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 is used to define amino acid sequence variants and covalent modifications of a specified sequence. A "functional derivative" includes a molecule having the same qualitative biological activity as the disclosed IL-17 antagonist, for example, 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). Functional derivatives include fragments and peptide analogs of the IL-17 antagonists disclosed herein. Fragments include regions within the polypeptide according to the present disclosure, e.g., regions within a specified sequence. Functional derivatives of the IL-17 antagonists disclosed herein preferably have at least about 65%, 75%, 85%, 95%, 96%, 97%, 98% or even 99% overall sequence identity with the V H and / or V L sequences (e.g., the V H and / or V L sequences of Table 4) of the IL-17 binding molecules disclosed herein, or at least about 65%, 75%, 85%, 95%, 96%, 97%, 98% or even 99% overall sequence identity with the CDRs of the IL-17 antagonists (e.g., secukinumab) disclosed herein. H and / or V L domains, or at least about 65%, 75%, 85%, 95%, 96%, 97%, 98% or even 99% overall sequence identity with the CDRs of the IL-17 antagonists (e.g., secukinumab) disclosed herein. %、75%、85%、95%、96%、97%、98% or even having a CDR having properties (differing from the CDR shown in Table 4 by 1, 2 or 3 amino acids) and binding to human IL -17 or substantially retaining the ability to inhibit the production of IL-6 in, for example, IL-17-induced human skin fibroblasts .

[0074] "Inhibiting IL-6", as used herein, refers to the ability of an IL-17 antagonist (e.g., secukinumab) to reduce the production of IL-6 from primary human skin fibroblasts . The production of IL-6 in primary human (skin) fibroblasts is IL-17-dependent (Hwang SY et al., (2004) Arthritis Res Ther, Vol. 6, pp. R120-128). In short, human skin fibroblasts are stimulated with recombinant IL-17 in the presence of various concentrations of an IL-17-binding molecule or a human IL-17 receptor having an Fc portion . The 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 . 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) disclosed herein, when tested as described above, i.e., when measuring the inhibitory activity against the production of IL-6 induced by hu-IL-17 in human skin fibroblasts, generally has an IC for the inhibition of the production of IL-6 of about 50 nM or less (e.g., about 0 .01 to about 50 nM) in the presence of 1 nM of human IL-17 . The disclosed methods, regimens, kits, processes, uses and compositions are as described above . When measuring the inhibitory activity against the production of IL-6 induced by hu-IL-17 in human skin fibroblasts, they generally have an IC for the inhibition of the production of IL-6 of about 50 nM or less (e.g., about 0 .01 to about 50 nM) in the presence of 1 nM of human IL-17 50 . The disclosed methods, regimens, kits, processes, uses and compositions 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 the recombinant host cell on the 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 phosphorylation of serine, tyrosine or threonine. are 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 the recombinant host cell on the 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, phosphorylation of serine, tyrosine or threonine, and glycosylation of asparagine, serine or threonine. 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, phosphorylation of serine, tyrosine or threonine, and glycosylation of asparagine, serine or threonine. ​Phosphorylation of the hydroxyl group of the Ru residue, α-amino of the lysine, arginine, and histidine side chains and methylation of the group, etc. For example, see T. E. Creighton, Proteins: Structure and Molec ular Properties, W. H. Freeman & Co., San Francisco, pages 79-86 (1983). Covalent modifications include, for example, polypeptides according to the present disclosure of those amino acid sequence variants such as N-terminal fusions to a specified sequence and to immunoadhesins and heterologous signal sequences in fusion proteins and the like.

[0076] The phrase "substantially the same" means that the relevant amino acid or nucleotide sequence (e.g., C DR (singular or plural), V H or V L domain) is the same as or has minor differences (e.g., due to conservative amino acid substitutions) compared to a particular reference sequence. Minor differences include slight amino acid changes such as one or two substitutions in the 5 amino acid sequence of a specified region. In the case of an antibody, the substituted antibody has the same specificity and has at least 50% of the affinity of the same one. Sequences substantially the same as (e.g., at least about 85 % sequence identity) the sequences disclosed herein are also part of this application. In some embodiments, the sequence identity is about 90% or greater, e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher values.

[0077] "Identity" with respect to native polypeptides and their functional derivatives, as used herein, means aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent identity. After insertion, without considering conservative substitutions as part of sequence identity, the percentage of amino acid residues in a candidate sequence that are the same as the residues of the corresponding native polypeptide is defined. N or C-terminal extensions or insertions are not to be interpreted as decreasing identity. Methods of alignment and computer programs are well known. The percent identity can be determined by standard alignment algorithms, e.g., the Basic Local Alignment Search Tool (BLAST) described by Altschul et al. ((1990) J. Mol. Biol., Vol. 215, pp. 403-410), the algorithm of Needleman et al. ((1970) J. Mol. Biol., Vol. 48, pp. 444-453) or the algorithm of Meyers et al. ((1988) Comput. Appl. Biosci., Vol. 4, pp. 11-17). A set of parameters is a Blosum 62 scoring matrix with a gap penalty of 12, a gap extension penalty of 4, and a frameshift gap penalty of 5. The percent identity between two amino acid or nucleotide sequences can also be determined using the algorithm of E. Meyers and W. Miller ((1989) CABIOS, Vol. 4, pp. 11-17) incorporated into the ALIGN program (version 2.0) with a PAM120 weighted residue table, a gap length penalty of 12, and a gap penalty of 4. "Amino acid(s)" refers to all naturally occurring L-α-amino acids and also includes, for example, D-amino acids. Amino acids are specified by well-known one-letter or three-letter designations.

[0078]

[0079] The term "amino acid sequence variant" refers to a molecule having some differences in their amino acid sequences as compared to the sequences according to the present disclosure. For example, an amino acid sequence variant of a polypeptide according to the present disclosure of a designated sequence binds to human IL-17 or still has the ability to inhibit, for example, the production of IL-6 in IL-17-induced human dermal fibroblasts. A substitution variant has at least one amino acid residue removed and has, for example, a different amino acid inserted at that position at the same position in a polypeptide according to the present disclosure of a designated sequence . These substitutions may be single, where only one amino acid in the molecule is substituted, or they may be multiple, where two or more amino acids are substituted within the same molecule. An insertion variant has one or more amino acids inserted immediately adjacent to an amino acid at a specific position in, for example, a polypeptide according to the present disclosure of a designated sequence . Immediately adjacent to an amino acid means bonded to the α-carboxy or α-amino functional group of the amino acid . A deletion variant has one or more amino acids removed, for example, from a polypeptide according to the present disclosure of a designated sequence . Usually, a deletion variant has one or two amino acids deleted in a specific region of the molecule . As used herein, a "therapeutically effective amount" is an amount of a subject (human patient) intended to treat, prevent, prevent the onset of, cure, delay the onset of, reduce the severity of, improve at least one symptom of, or extend the survival period of the subject beyond the expected survival period if such treatment is not performed, of a disorder or recurrent disorder .

[0080] IL-17 antagonists that are effective upon single or repeated administration to, for example, IL-17 binding molecules (e.g., IL-17 antibodies or antigen-binding fragments thereof, e.g., secukinumab) or IL-17 receptor binding molecules (e.g., IL-17 antibodies or antigen-binding fragments thereof). When referring to an individual active ingredient administered alone (e.g., an 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 an IL-17 receptor binding molecule (e.g., an IL-17 antibody or antigen-binding fragment thereof)), the term applies only to that ingredient. When applied to a formulation, the term refers to the total amount of the active ingredient(s) that provide a therapeutic effect, whether administered sequentially or simultaneously, as a

[0081] The terms "treatment" or "treating" refer to both prophylactic treatment or prophylaxis and treatment of patients at risk of or suspected of having a disease or condition, as well as patients with a disease or diagnosed medical condition, including curative or disease-modifying therapy, including suppression of clinical recurrence. Treatment can be carried out on subjects having a medical disorder or subjects who may ultimately be at risk of developing a disorder, in order to prevent, cure, delay the onset of, reduce the severity of, improve one or more symptoms of, or extend the survival period of a subject beyond that expected if

[0082] As used herein, the term "inflammatory arthritis" means various conditions of joints associated with the immune system and inflammation, including autoimmune disorders, Examples include seronegative spondyloarthropathies such as AS, Reiter's syndrome, PsA, and enteropathic arthritis as well as other arthritides such as RA, juvenile idiopathic arthritis, and systemic lupus erythematosus, crystalline arthritis (gout, pseudogout, apatite gout), polymyalgia rheumatica, amyloid arthritis , pigmented villonodular synovitis, synovial osteochondromatosis, hemophilic arthritis, and reactive synovitis, among others. 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" refer to inflammatory arthritis characterized by chronic inflammation that can lead to eventual fusion of the spine and joints that may include the sacroiliac in the spine and pelvis. Using the Revised New York Criteria for AS or the ASAS Axial SPA Criteria (2009), a patient can be diagnosed as having AS. In some embodiments of the disclosed methods, regimens, uses, kits, and pharmaceutical compositions, the patient has AS.

[0084] As used herein, the terms "psoriatic arthritis" and "PsA" refer to inflammatory arthritis often accompanied by psoriasis of the skin. Using various criteria such as the Moll and Wright criteria, Revised ESSG criteria, McGonagle criteria, Classification Criteria for Psoriatic Arthritis (CASPAR) criteria, etc., a patient can be diagnosed as having PsA. In some embodiments of the disclosed methods, regimens, uses, kits, and pharmaceutical compositions, the patient has PsA.

[0085] ​As used herein, "rheumatoid arthritis" or "RA" refers to a chronic systemic inflammatory arthritis that can affect many tissues and organs but primarily attacks synovial joints. Using the 2010 ACR / EULAR criteria, a patient can be diagnosed as having RA. In some embodiments of the disclosed methods, regimens, uses, kits, and pharmaceutical compositions, the patient has RA.

[0086] As used herein, the phrase "2010 ACR / EULAR criteria" refers to the 2010 American College of Rheumatology / European League Against Rheumatism classification criteria for RA found in Aletaha et al. (2010) Ann. Rheum. Dis., Vol. 69, pp. 1580-1588. The criteria used to classify a patient as having rheumatoid arthritis are shown in Table 1.

[0087] As used herein, "C-reactive protein" and "CRP" refer to serum C-reactive protein, a plasma protein commonly used as an indicator of the acute-phase response to inflammation. The level of CRP in plasma can be expressed in any concentration, e.g., mg / dl, nmol / L. The level of CRP can be measured by various well-known methods, such as radial immunodiffusion, electroimmunoassay, immunonephelometry, ELISA, turbidimetry, fluorescence polarization immunoassay, and laser nephelometric analysis. The test for CRP can use a standard CRP test or a high-sensitivity CRP (hs-CRP) test (i.e., a high-sensitivity test that can measure low levels of CRP in a sample using laser nephelometric analysis). Kits for detecting the level of CRP are available from various companies, e.g., Calbiotech, Inc. , Cayman Chemical, Roche Diagnostics Corpo ration, Abazyme, DADE Behring, Abnova Corpo ration, Aniara Corporation, Bio-Quant Inc. , Siemens Healthcare Diagnostics, etc. can be purchased .

[0088] As used herein, "high level of CRP" means exceeding the normal CRP level as defined by the 2010 ACR / EULA R criteria (Aletaha et al. (2010) Ann. Rheum. Dis., Vol. 69, pp. 1580-88). According to the 2010 ACR / EULAR criteria , normal / abnormal CRP is based on local laboratory standards. Each local laboratory uses its own rules to calculate the cut-off value for abnormal (high) CRP to calculate the normal maximum CRP . Physicians generally order CRP tests from local laboratories, and local laboratories report normal or abnormal (low or high) CRP using the rules used by individual laboratories to calculate normal CRP . Therefore, unless otherwise indicated by context, what is considered a normal CRP value varies between laboratories and assays. As used herein, "high level of CRP" does not mean a specific numerical value . In some embodiments of the present disclosure , "high level of CRP" is greater than about 10 mg / L (e.g., 10 mg / L), greater than about 20 mg / L (e.g., 20 mg / L) or greater than about 30 mg / L (e.g., 30 mg / L). When evaluating the CRP level at baseline, "baseline " does not mean a specific numerical value. In some embodiments of the present disclosure , "high level of CRP" is greater than about 10 mg / L (e.g., 10 mg / L), greater than about 20 mg / L (e.g., 20 mg / L) or greater than about 30 mg / L (e.g., 30 mg / L). The CRP level, when evaluated at baseline, is "baseline It is called "in-CRP". A high level of CRP at baseline can be called "baseline C RP elevation" or "high baseline CRP". In some embodiments of the disclosed methods, regimens, uses, kits and pharmaceutical compositions, the patient has high baseline CRP (or hsCRP) or a high level of CRP (or hsCRP). The term "hsCRP" means the level of CRP in the blood measured by a high-sensitivity CRP test.

[0089] As used herein, "erythrocyte sedimentation rate", "ESR", "sedimentation rate" and " sedrate" mean the sedimentation rate of red blood cells in a patient sample (e.g., a plasma sample). ESR reflects the viscosity of plasma and the presence of acute-phase proteins and is usually reported in units of "mm / hour". ESR is determined by measuring the distance that red blood cells sediment in a tube over time. Typical ESR test methods use the Westergren method, the zeta sedimentation rate (ZSR) method and the Wintrobe method (all of which are incorporated herein by reference in their entirety, see Moseley and Bull (1982) Clin. Lab. Haematol., Vol. 4, pp. 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). Commercially available kits for measuring ESR are available from, for example, ARKRAY USA, BD Diagnostic Sys tems and Polymedco Inc. ESR instruments are available from, for example, the United States (see references). Commercially available kits for measuring ESR are available from, for example, ARKRAY USA, BD Diagnostic Sys tems and Polymedco Inc. ESR instruments are available from, for example, the United States The invention can be found in US Patent No. 6974701 and is available from Steelex Scientific. ic, Nicesound Electronics Co., Globe Scien tific Inc., Alifax, Analysis Instrument AB, Streck Laboratories, PolyMed Co, Inc. and Qua It is provided by various companies such as ntimetrix.

[0090] As used herein, "high ESR" refers to a material that meets the 2010 ACR / EULAR criteria ( Normal E as defined by Aletaha et al. (2010) Ann. Rheum. Dis., 69, 1580-88 Means exceeding SR. According to the 2010 ACR / EULAR criteria, normal / abnormal ESR is based on local laboratory standards. Each local laboratory calculates its normal maximum ESR. In order to determine whether ESR is abnormal (high), the cutoff value for ESR based on the laboratory rules is used. Generally, ESR testing by a local laboratory is ordered, and the local laboratory uses Normal or elevated ESR is reported using the rules used by laboratories for determining whether ESR is normal or elevated. Unless otherwise indicated, what is considered a normal ESR value varies among laboratories and assays. Therefore, as used herein, "high ESR" is not meant to indicate 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" refers to a condition that is often found in RA patients. The term "autoantibody" refers to an autoantibody against the Fc portion of an IgG antibody that is present in the human body. For the crab, "RF" refers to any RF isotype, such as IgG, IgE, IgM, and IgA and includes. RF can be assayed using various well-known techniques available for determining the presence or absence of a specific antibody, such as ELISA assays, agglutination tests, nephelometry tests, etc. RF levels can be reported by laboratories in various ways, such as IU / ml, units / ml, and titer ( measuring how much a patient's blood sample can be diluted using a dilution test before RF can no longer be detected, e.g., a titer of 1:80 indicates more detectable RF than a titer of 1:20). RF kits are commercially available, for example, from IBL-Ame rica (Immuno-Biological Laboratories).

[0092] Patients who are seropositive for RF are referred to herein as "RF+". Similarly , if a sample obtained from a patient has RF, the sample is "RF+". Each local laboratory uses a cutoff value for the normal RF level based on the rules of that laboratory to calculate the normal maximum RF. As proposed by Aletaha et al. (2010) Ann. Rheum. Dis., 69, 1580 - 1588 patients are considered RF+ based on the upper limit of normal [ULN] for the tests and assays of each laboratory. If a value greater than the ULN of the tests and assays of each laboratory is measured, the patient is RF+. Thus, unless otherwise indicated by context, since the ULN varies between laboratories and assays, as used herein, "RF+" does not mean a specific numerical value . As a non-limiting example, at the time of testing, laboratory X has a normal range of RF in the blood ​​​​​The titer is shown as 14 - 60 units / mL. During the test, Laboratory Y shows the normal range of RF in the blood as 40 IU / ml or less. During the test, Laboratory Z shows the normal range of RF in the blood as 1 :20 - 1:80 titer. Therefore, if Laboratory X reports an RF level greater than 60 units / ml, if Laboratory Y reports an RF value greater than 40 IU / ml, or if Laboratory Z reports an RF titer greater than 1:80, the patient will be RF+. In some embodiments of the methods, regimens, uses, kits, and pharmaceutical compositions shown, the patient is RF+. The term "seroreactive" is used to indicate the presence of a specific substance (e.g., RF) in the patient's serum.

[0093] As used herein, "anti-citrullinated protein antibody", "ACPA", " anti-cyclic citrullinated peptide antibody", and "anti-CCP" mean autoantibodies that bind to citrullinated amino acid residues on proteins found in the joints of RA patients. Cyclic citrullinated

[0094] peptides are used in in vitro tests (e.g., ELISA assays) to confirm the presence of ACPA in the patient's blood, and as a result, ACPA is also referred to as "anti-CCP" antibodies. ACPA levels can be assayed using various well-known techniques available to determine the presence or absence of a specific antibody, such as agglutination, ELISA assays, etc. ACPA kits are commercially available, for example, the DIASTAT® anti-CCP test provided by Axis-Shield Diagnostics, Ltd. (UK) and the AxSYM Anti provided by Abbot Diagnonstics (Germany). The levels can be assayed using various well-known techniques available to determine the presence or absence of a specific antibody, such as agglutination, ELISA assays, etc. ACPA kits are commercially available, for example, the DIASTAT® anti-CCP test provided by Axis-Shield Diagnostics, Ltd. (UK) and the AxSYM Anti This is the i-CCP (registered trademark) kit.

[0095] Patients who are seropositive for ACPA are referred to herein as "ACPA+" Similarly, if a sample obtained from a patient has ACPAs, the sample is "ACPA+." Each local laboratory will use the normal ACPA based on the laboratory's rules to calculate the normal maximum ACPA. A cut-off value for CPA level is used. Aletaha et al. (2010) Ann. Rheum. Dis., 69, 1580 As suggested by p. 1588, patients should be monitored to ensure that the upper limit of normal for each laboratory test and assay is met. ACPA+ based on the ULN [ULN of each laboratory test and assay] If a threshold is measured, the patient is ACPA+. Unless otherwise specified, the ULN, as used herein, varies between laboratories and assays. "ACPA+" is not meant to indicate a specific numerical value. Laboratory A set the reference range for ACPA in blood to less than 20 EU (arbitrary ELISA units). At the time of testing, Laboratory B set the reference range for ACPA in blood at <5 U / ml. Therefore, if laboratory A reports an ACPA value greater than 20 EU or laboratory B reports an ACPA value greater than 20 EU, If B reports an ACPA value greater than 5 U / ml, the patient is ACPA+. In some embodiments of the methods, regimens, uses, kits and pharmaceutical compositions, a patient is ACPA+.

[0096] Selected normal / abnormal and reference ranges for ACPA, ESR, RF and CRP are e.g. Fischbach and Dunning (2009), "A Man "ual of Laboratory and Diagnostic Tests" (8th Edition), Wolters Kluwer / Lippincott Willia can be found in ms and Williams.

[0097] As used herein, the term "high-risk RA patient" refers to a patient who is a) RF+, AC PA+ or both RF+ and ACPA+, and b) has a high level of CRP (or hsC RP), high ESR or both high levels of CRP and high ESR. It is used to define. In some embodiments of the disclosed methods, regimens, uses, kits, and pharmaceutical compositions, the patient is a high-risk RA patient. In some embodiments, the patient has at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 small joint lesions. In some embodiments, the patient has at least 1, 2, 3, 4 , 5, 6, 7, 8, 9, or 10 large joint lesions. In some embodiments , the patient shows more than 10 joint lesions, and at least 1 of the joints is a small joint . In some embodiments, the patient has a symptom duration of at least 6 weeks .

[0098] "Joint lesion" means any swollen or tender joint upon examination that can be confirmed by imaging evidence of synovitis. The category of joint distribution is classified according to the location and number of affected joints, and the positioning into the highest category is based on the pattern of joint lesions. "Large joint" refers to the shoulder , elbow, hip, knee, and ankle. "Small joint" refers to the middle interphalangeal joint, proximal interphalangeal joint, 2nd - 5th middle phalangeal joints of the foot, thumb interphalangeal joint, and radiocarpal joint. In the disclosed methods, regimens, ​​In some embodiments of the use, kit and composition, the patient has six or more of the 28 tender joints and six or more of the 28 swollen joints and hsCRP exceeding 10 mg / L and has P.

[0099] "Duration of symptoms" means, regardless of the treatment situation, the patient's self-report of the duration of signs or symptoms of synovitis (e.g., pain, swelling, tenderness) of the joints clinically affected at the time of evaluation of.

[0100] As used herein, "selecting a high-risk RA patient for treatment" and "selecting a patient for treatment based on the patient being a high-risk RA patient" and "selected for treatment" are used to mean that a particular RA patient is selected from a larger group or RA patients based on the particular patient meeting the high-risk 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 ).

[0101] As used herein, the phrase "previously treated for RA" is used to refer to patients who have previously received RA treatment with anti-rheumatic drugs, e.g., patients who have had previous unsuccessful cases, inadequate responders or intolerance to RA therapy, anti-rheumatic drugs or treatment regimens. Such patients include patients who have previously received treatment with biologics such as MTX, DMARD and / or TNF alpha antagonists . In some embodiments of the disclosed methods, regimens, uses, kits and pharmaceutical compositions, the patient has previously been treated for RA .

[0102] As used herein, the phrase "previously untreated for RA" is used to refer to patients who have not previously received RA treatment with anti-rheumatic drugs, i.e., the patient is "treatment-naive." In some embodiments of the disclosed methods, regimens, uses, kits and pharmaceutical compositions, the patient has not previously received treatment for RA.

[0103] As used herein, "treatment failure" for previous RA therapy means (1) patients who do not have a meaningful clinical benefit (lack of major efficacy), (2) patients who have a measurable and meaningful response but the response could have been better, e.g., patients in whom RA disease activity is low or remission of RA is not achieved ("inadequate response" also called), (3) patients who deteriorate after an initial good response ("secondary loss of efficacy") and (4) patients who have a good response but discontinue due to side effects ("intolerance" also called). Patients showing TNF inadequate response (TNF-IR) or intolerance to TNF will be considered TNF treatment failures. Patients showing methotrexate inadequate response (MTX-IR) or intolerance to MTX will be considered MTX treatment failures. Patients showing DMARD inadequate response (DMARD-IR) or intolerance to DMARD will be considered DMARD treatment failures. In some embodiments of the disclosed methods, regimens, uses, kits and pharmaceutical compositions, the patient is a TNF treatment failure, an MTX treatment failure or a DMARD treatment failure.

[0104] A "treatment regimen" refers to the pattern of treatment of a disease, e.g., the dosing used during the treatment of RA ​​means a pattern with. The treatment regimen may include an induction regimen and a maintenance regimen. Examples of treatment regimens for the treatment of RA are shown in Table 2, but none of them provide treatment for high-risk RA patients.

[0105]

Table 2

[0106] The term "induction regimen" or "induction period" refers to the treatment regimen (or part of the treatment regimen) used for the initial treatment of the disease. In some embodiments, the disclosed methods , uses, kits, processes and regimens (e.g., for treating inflammatory arthritis, e.g., RA such as high-risk RA patients) use an induction regimen. A common goal of the induction regimen is to supply the patient with a high level of drug during the initial period of the treatment regimen. The induction regimen may use (in part or as a whole) a larger dose of drug than that used by the physician during the maintenance regimen, administer the drug more frequently than the physician administers the drug during the maintenance regimen , or both. In some embodiments of the disclosed methods, uses, kits, processes and regimens, the induction dose can be delivered in the induction regimen as a single, high-dose infusion (e.g., about 30 mg / kg) . Alternatively, the induction dose can be delivered as several (e.g., 2 or 3) infusions (e.g., about 10 mg / kg). Alternatively, the induction dose can be delivered as several (e.g., 1, 2, 3, 4, 5, 6 times or more) subcutaneous injections ( e.g., about 75 - 300 mg). Delivery of the drug in the induction regimen can be via the subcutaneous (s.c.) route, e.g., about 75 mg to about 300 mg, s.c. (e.g., about 75 mg, s.c., about 150 mg, s.c., about 300 mg, s.c.) delivery of the dosage, or those via the intravenous (i.v.) route, e.g., about 1 mg / kg to about 3 0 mg / kg, i.v. (e.g., about 1 mg / kg, about 3 mg / kg, about 10 mg / kg , about 30 mg / kg) of the dosage delivery or any other administration route (e.g., intramuscular, i.m.) can be. In some embodiments of the disclosed methods, compositions, kits, uses, and regimens , the IL-17 antagonist (e.g., secukinumab) is delivered by i.v. administration during at least a portion of the induction regimen . In some embodiments , the induction regimen comprises administering an IL-17 antagonist (e.g., secukinumab) at a dosage of about 1 mg / kg to about 30 mg / kg, about 1 mg / kg to about 10 mg / kg, preferably about 10 mg / kg. In further embodiments, the induction dose is delivered once a week, twice a week, every other week, or once a month, preferably every other week. In further embodiments , the induction regimen uses 1 to 10 doses of the IL-17 antagonist (e.g., secukinumab), preferably 3 doses of the IL-17 antagonist (e.g., secukinumab). The induction regimen for the delivery of an IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., any IL-17 antibody such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody

[0107] ) can also be designed using PK information (see Table 10) rather than a specific dosage. For the disclosed uses, regimens, and methods (e.g., for treating inflammatory arthritis , e.g., a method for treating RA such as in high-risk RA patients), those skilled in the art will appreciate the induction ​​​​In the regimen, an IL-17 antagonist, such as an IL-17 binding molecule (e.g., secukinumab or any IL-17 antibody) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody), can be delivered to result in an average C of about 360 μg / mL to about 401 μg / mL. max to result in In the induction regimen, an IL-17 antagonist, such as an IL-17 binding molecule (e.g., secukinumab or any IL-17 antibody) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody), can be delivered to result in an average C of about 401 μg / mL with up to about 30% to 40% [±] inter-patient variability for an average 90 kg human. In the induction regimen, an IL-17 antagonist, such as an IL-17 binding molecule (e.g., secukinumab or any IL-17 antibody) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody), can be delivered to result in an average C of about 401 μg / mL with up to about 30% to 40% [±] inter-patient variability for an average 90 kg human. Alternatively, one of ordinary skill in the art can deliver an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody), in the induction regimen to result in an average C of about 360 μg / mL for an average 75 kg human. In the induction regimen, an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody), can be delivered to result in an average C of about 401 μg / mL with up to about 30% to 40% [±] inter-patient variability for an average 90 kg human. max to result in In the induction regimen, an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody), can be delivered to result in an average C of about 401 μg / mL with up to about 30% to 40% [±] inter-patient variability for an average 90 kg human. In the induction regimen, an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody), can be delivered to result in an average C of about 401 μg / mL with up to about 30% to 40% [±] inter-patient variability for an average 90 kg human. Alternatively, one of ordinary skill in the art can deliver an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody), in the induction regimen to result in an average C of about 360 μg / mL for an average 75 kg human. In the induction regimen, an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody), can be delivered to result in an average C of about 360 μg / mL for an average 75 kg human. max to result in In the induction regimen, an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody), can be delivered to result in an average C of about 360 μg / mL for an average 75 kg human. In the induction regimen, an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody), can be delivered to result in an average C of about 360 μg / mL for an average 75 kg human. Alternatively, one of ordinary skill in the art can deliver an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody), in the induction regimen to result in a trough level above 80 μg / mL over a 10-week period for an average 75 kg human. In the induction regimen, an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody), can be delivered to result in a trough level above 80 μg / mL over a 10-week period for an average 75 kg human. In the induction regimen, an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody), can be delivered to result in a trough level above 80 μg / mL over a 10-week period for an average 75 kg human. In the induction regimen, an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody), can be delivered to result in a trough level above 80 μg / mL over a 10-week period for an average 75 kg human. In some embodiments, an IL-17 antagonist is delivered i.v. at weeks 0, 2, and 4 in the induction regimen to result in an average C of about 401 μg / mL with up to about 30% to 40% [±] inter-patient variability for an average 90 kg human. In some embodiments, an IL-17 antagonist is delivered i.v. at weeks 0, 2, and 4 in the induction regimen to result in an average C of about 401 μg / mL with up to about 30% to 40% [±] inter-patient variability for an average 90 kg human. max to result in In some embodiments, an IL-17 antagonist is delivered i.v. at weeks 0, 2, and 4 in the induction regimen to result in an average C of about 401 μg / mL with up to about 30% to 40% [±] inter-patient variability for an average 90 kg human. In some embodiments, an IL-17 antagonist is delivered i.v. at weeks 0, 2, and 4 in an induction regimen to achieve an average C of about 360 μg / mL for a human of average 75 kg. ma x In other embodiments, an IL-17 antagonist is delivered i.v. at weeks 0, 2, and 4 in an induction regimen to achieve trough levels greater than 80 μg / mL over a 10-week period for a human of average 75 kg. The terms "maintenance regimen" or "maintenance period" refer to a treatment regimen (or a portion of a treatment regimen) used, for example, to maintain a patient in a remission state during treatment of a disease over a long period (months or years). In some embodiments, the disclosed methods, uses, and regimens (e.g., methods of treating inflammatory arthritis, e.g., RA in high-risk RA patients) employ a maintenance regimen. The maintenance regimen can use continuous therapy (e.g., administering the drug regularly, e.g., once a week, once a month, once a year, etc.) or intermittent therapy (e.g., intermittent treatment, intermittent therapy, treatment at recurrence, or treatment after achieving predefined criteria [e.g., pain, disease symptoms, etc.]).

[0108] Delivery of an IL-17 antagonist in the maintenance regimen, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof), can be via a subcutaneous route, e.g., delivery of a dose of about 75 mg to about 300 mg, s.c. (e.g., about 75 mg, s.c., about 150 mg, s.c., about 300 mg, s.c.), or via an intravenous route, e.g., about 1 mg / kg For example, in some embodiments, the disclosed methods, uses, and regimens (e.g., methods of treating inflammatory arthritis, e.g., RA in high-risk RA patients) employ a maintenance regimen. The maintenance regimen can use continuous therapy (e.g., administering the drug regularly, e.g., once a week, once a month, once a year, etc.) or intermittent therapy (e.g., intermittent treatment, intermittent therapy, treatment at recurrence, or treatment after achieving predefined criteria [e.g., pain, disease symptoms, etc.]). Delivery of an IL-17 antagonist in the maintenance regimen, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof), can be via a subcutaneous route, e.g., delivery of a dose of about 75 mg to about 300 mg, s.c. (e.g., about 75 mg, s.c., about 150 mg, s.c., about 300 mg, s.c.), or via an intravenous route, e.g., about 1 mg / kg In some embodiments, the disclosed methods, uses, and regimens (e.g., methods of treating inflammatory arthritis, e.g., RA in high-risk RA patients) employ a maintenance regimen. The maintenance regimen can use continuous therapy (e.g., administering the drug regularly, e.g., once a week, once a month, once a year, etc.) or intermittent therapy (e.g., intermittent treatment, intermittent therapy, treatment at recurrence, or treatment after achieving predefined criteria [e.g., pain, disease symptoms, etc.]). Delivery of an IL-17 antagonist in the maintenance regimen, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof), can be via a subcutaneous route, e.g., delivery of a dose of about 75 mg to about 300 mg, s.c. (e.g., about 75 mg, s.c., about 150 mg, s.c., about 300 mg, s.c.), or via an intravenous route, e.g., about 1 mg / kg For example, in some embodiments, the disclosed methods, uses, and regimens (e.g., methods of treating inflammatory arthritis, e.g., RA in high-risk RA patients) employ a maintenance regimen. The maintenance regimen can use continuous therapy (e.g., administering the drug regularly, e.g., once a week, once a month, once a year, etc.) or intermittent therapy (e.g., intermittent treatment, intermittent therapy, treatment at recurrence, or treatment after achieving predefined criteria [e.g., pain, disease symptoms, etc.]). Delivery of an IL-17 antagonist in the maintenance regimen, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof), can be via a subcutaneous route, e.g., delivery of a dose of about 75 mg to about 300 mg, s.c. (e.g., about 75 mg, s.c., about 150 mg, s.c., about 300 mg, s.c.), or via an intravenous route, e.g., about 1 mg / kg In some embodiments, the disclosed methods, uses, and regimens (e.g., methods of treating inflammatory arthritis, e.g., RA in high-risk RA patients) employ a maintenance regimen. The maintenance regimen can use continuous therapy (e.g., administering the drug regularly, e.g., once a week, once a month, once a year, etc.) or intermittent therapy (e.g., intermittent treatment, intermittent therapy, treatment at recurrence, or treatment after achieving predefined criteria [e.g., pain, disease symptoms, etc.]). Delivery of an IL-17 antagonist in the maintenance regimen, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof), can be via a subcutaneous route, e.g., delivery of a dose of about 75 mg to about 300 mg, s.c. (e.g., about 75 mg, s.c., about 150 mg, s.c., about 300 mg, s.c.), or via an intravenous route, e.g., about 1 mg / kg In some embodiments, the disclosed methods, uses, and regimens (e.g., methods of treating inflammatory arthritis, e.g., RA in high-risk RA patients) employ a maintenance regimen. The maintenance regimen can use continuous therapy (e.g., administering the drug regularly, e.g., once a week, once a month, once a year, etc.) or intermittent therapy (e.g., intermittent treatment, intermittent therapy, treatment at recurrence, or treatment after achieving predefined criteria [e.g., pain, disease symptoms, etc.]). Delivery of an IL-17 antagonist in the maintenance regimen, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof), can be via a subcutaneous route, e.g., delivery of a dose of about 75 mg to about 300 mg, s.c. (e.g., about 75 mg, s.c., about 150 mg, s.c., about 300 mg, s.c.), or via an intravenous route, e.g., about 1 mg / kg For example, in some embodiments, the disclosed methods, uses, and regimens (e.g., methods of treating inflammatory arthritis, e.g., RA in high-risk RA patients) employ a maintenance regimen. The maintenance regimen can use continuous therapy (e.g., administering the drug regularly, e.g., once a week, once a month, once a year, etc.) or intermittent therapy (e.g., intermittent treatment, intermittent therapy, treatment at recurrence, or treatment after achieving predefined criteria [e.g., pain, disease symptoms, etc.]). Delivery of an IL-17 antagonist in the maintenance regimen, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof), can be via a subcutaneous route, e.g., delivery of a dose of about 75 mg to about 300 mg, s.c. (e.g., about 75 mg, s.c., about 150 mg, s.c., about 300 mg, s.c.), or via an intravenous route, e.g., about 1 mg / kg g~about 30 mg / kg, i.v. (e.g., about 1 mg / kg, about 3 mg / kg, about 10 m g / kg, about 30 mg / kg) or can be via any other route of administration (e.g., intramuscular, i.m.). In some embodiments of the disclosed methods, uses and regimens, an IL-17 antagonist (e.g., secukinumab) is delivered by s .c. administration in the maintenance regimen. In some embodiments, the maintenance regimen comprises administering an amount of an IL-17 antagonist (e.g., secukinumab) of about 75 mg .c. administration in the maintenance regimen. In some embodiments, the maintenance regimen comprises administering an amount of an IL-17 antagonist (e.g., secukinumab) of about 75 mg ~about 300 mg, about 75 mg~about 150 mg, preferably about 75 mg or about 150 mg of the IL-17 antagonist (e.g., secukinumab). In some embodiments, the maintenance regimen comprises administering a dose of an IL-17 antagonist (e.g ., secukinumab) once a month. For delivery of an IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., any IL-17 antibody such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody

[0109] ), the maintenance regimen can also be designed using PK information (see Table 9) rather than a specific dose. For the disclosed uses, regimens and methods (e.g., for treating inflammatory arthritis, e.g., a method of treating RA such as in high-risk RA patients), one of ordinary skill in the art can maintain an average steady-state trough level of about 9.4 μg / mL~about 31 μg / mL (e.g., about 9.4 μg / mL, about 17.3 μg / mL, about 31 μg / mL) with up to about 30% [+ or -] inter-patient variability for humans of average 75 kg (e.g., 71~79 kg) by administering an IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., secukinumab ), in the maintenance regimen. kg (e.g., 71~79 kg) with up to about 30% [+ or -] inter-patient variability for humans of average 75 kg (e.g., 71~79 kg) and bring about an average steady-state trough level of about 9.4 μg / mL~about 31 μg / mL (e.g., about 9.4 μg / mL, about 17.3 μg / mL, about 31 μg / mL) in the maintenance regimen by administering an IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., secukinumab ), e.g., any IL-17 antibody) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody an IL-17 antibody such as a mab) or an IL-17 receptor-binding molecule (e.g., an IL-17 receptor antibody) can be delivered. Alternatively, one of ordinary skill in the art can maintain a regimen that provides an average steady-state trough level of about 8.0 μg / mL to about 30.0 μg / mL (e.g., about 8.0 μg / mL, about 17 μg / mL, about 30 μg / mL) for a human of about 75 kg. an IL-17 antagonist, such as an IL-17-binding molecule (e.g., an IL-17 antibody such as secukinumab) or an IL-17 receptor-binding molecule (e.g., an IL-17 receptor antibody), can be delivered. In some embodiments, an IL-17 antagonist is delivered once a month in a maintenance regimen that provides an average steady-state trough level of about 9.4 μg / mL to about 31 μg / mL (e.g., about 9.4 μg / mL, about 17.3 μg / mL, about 31 μg / mL) with a maximum of about 30% [+ or -] patient-to-patient variability for a human of about 70 kg. .0 μg / mL to about 30.0 μg / mL (e.g., about 8.0 μg / mL, about 17 μg / m L, about 30 μg / mL) for a human of about 75 kg. In other embodiments, an IL-17 antagonist is delivered once a month in a maintenance regimen that provides an average steady-state trough level of about 8.0 μg / mL to about 30. 0 μg / mL (e.g., about 8.0 μg / mL, about 17 μg / mL, about 30 μg / mL) for a human of about 75 kg. Alternatively, one of ordinary skill in the art can maintain a regimen that provides an average AUC tau in the steady state of about 314 mg*day / L to about 1323 mg*day / L (e.g., about 314 mg*day / L to about 1256 mg*day / L, e.g., about 331 mg*day / L to about 1323 mg*day / L) and deliver an IL-17 antagonist, such as an IL-17-binding molecule (e.g., an IL-17 antibody such as secukinumab) or an IL-17 receptor-binding molecule (e.g., an IL-17 receptor antibody). about 30% [+ or -] patient-to-patient variability, for a human of about 70 kg, an average steady-state trough level of about 9.4 μg / mL to about 31 μg / mL (e.g., about 9.4 μg / mL, about 17.3 μg / mL, about 31 μg / mL) is provided by delivering an IL-17 antagonist once a month in a maintenance regimen. In other embodiments, an IL-17 antagonist is delivered once a month in a maintenance regimen that provides an average steady-state trough level of about 8.0 μg / mL to about 30. 0 μg / mL (e.g., about 8.0 μg / mL, about 17 μg / mL, about 30 μg / mL) for a human of about 75 kg. Alternatively, one of ordinary skill in the art can maintain a regimen that provides an average AUC tau in the steady state of about 314 mg*day / L to about 1323 mg*day / L and deliver an IL-17 antagonist, such as an IL-17-binding molecule (e.g., an IL-17 antibody such as secukinumab) or an IL-17 receptor-binding molecule (e.g., an IL-17 receptor antibody). 0 μg / mL (e.g., about 8.0 μg / mL, about 17 μg / mL, about 30 μg / mL) for a human of about 75 kg. In other embodiments, an IL-17 antagonist is delivered once a month in a maintenance regimen that provides an average steady-state trough level of about 8.0 μg / mL to about 30. 0 μg / mL (e.g., about 8.0 μg / mL, about 17 μg / mL, about 30 μg / mL) for a human of about 75 kg. Alternatively, one of ordinary skill in the art can maintain a regimen that provides an average AUC tau in the steady state of about 314 mg*day / L to about 1323 mg*day / L and deliver an IL-17 antagonist, such as an IL-17-binding molecule (e.g., an IL-17 antibody such as secukinumab) or an IL-17 receptor-binding molecule (e.g., an IL-17 receptor antibody). (e.g., about 314 mg*day / L to about 1256 mg*day / L, e.g., about 331 mg*day / L to about 1323 mg*day / L) and deliver an IL-17 antagonist, such as an IL-17-binding molecule (e.g., an IL-17 antibody such as secukinumab) or an IL-17 receptor-binding molecule (e.g., an IL-17 receptor antibody). an IL-17 antagonist, such as an IL-17-binding molecule (e.g., an IL-17 antibody such as secukinumab) or an IL-17 receptor-binding molecule (e.g., an IL-17 receptor antibody), can be delivered. an IL-17 antibody such as secukinumab) or an IL-17 receptor-binding molecule (e.g., an IL-1 7 receptor antibody) can be delivered.

[0110] The timing of administration is generally measured from the day of the first administration of secukinumab (also known as the "baseline"). However, different healthcare providers use different nomenclatures as shown in Table 3 below. Specifically, week 0 may be referred to as week 1 in some nomenclatures, while day 0 may be referred to as day 1 in some nomenclatures. Thus, different physicians may refer to the same dosing schedule, for example, specifying doses to be administered at week 3 / day 21, week 3 / day 22, week 4 / day 21, week 4 / day 22. To maintain consistency, as used herein, the first week of administration shall be referred to as week 0, while the first day of administration shall be referred to as day 1. Thus, by way of example, the 4 induction doses of secukinumab administered once weekly during the induction regimen would be supplied at week 0 (e.g., approximately day 1), week 1 (e.g., approximately day 8), week 2 (e.g., approximately day 15), and week 3 (e.g., approximately day 22). The induction doses can be administered every 2 weeks (i.e., every other week), for example, at week 0, week 2, week 4, etc. The induction doses can be administered every 3 weeks, for example, at week 0, week 3, week 6, etc. The induction doses can be administered daily over a 1-week period, for example, on days 1 - 7. However, it should be noted that this nomenclature is used only for clarity and should not be construed as restrictive.

[0111]

Table 3

[0112] In particular, week 0 may be called week 1 in some nomenclatures, while day 0 may be called day 1 in some nomenclatures. Therefore, different doctors may mention the same dosing schedule, for example, specifying the doses to be administered at week 3 / day 21, week 3 / day 22, week 4 / day 21, week 4 / day 22. To maintain consistency, when used in this specification, the first week of administration shall be called week 0, while the first day of administration shall be called day 1. Therefore, for example, the 4 induction doses of secukinumab administered once a week during the induction regimen will be supplied at week 0 (e.g., about day 1), week 1 (e.g., about day 8), week 2 (e.g., about day 15), and week 3 (e.g., about day 22). The induction doses can be administered every 2 weeks (i.e., every other week), for example, at week 0, week 2, week 4, etc. The induction doses can be administered every 3 weeks, for example, at week 0, week 3, week 6, etc. The induction doses can be administered daily for 1 week, for example, on days 1 - 7. However, it should be noted that this nomenclature is used only for clarification and should not be construed as restrictive.

[0113] As used herein, the phrase "means of administration" includes prefilled syringes, vials and syringes, pen injectors, automated infusion devices, intravenous drips and bags, pumps, etc., but is not limited thereto, and is used to indicate available tools for systemic administration of biologic agents. Using such items, a patient can self-administer (i.e., administer the drug for themselves) the drug, or a physician can administer the drug.

[0114] Various aspects of the present disclosure are described in more detail in the following subsections. All patents, patent applications, references, and other publications are hereby incorporated by reference in their entirety.

[0115] IL-17 antagonists Various disclosed pharmaceutical compositions, regimens, processes, uses, methods, and kits utilize IL-17 antagonists, such as IL-17 binding molecules (e.g., IL-17 antibodies or antigen-binding fragments thereof, e.g., secukinumab) or IL-17 receptor binding molecules (e.g., IL -17 antibodies or antigen-binding fragments thereof).

[0116] In one embodiment, the IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab), comprises at least one immunoglobulin heavy chain variable domain (V ) containing the hypervariable regions CDR1, CDR2, and CDR3 in sequence, wherein said CDR1 has the amino acid sequence H SEQ ID NO: 1 (N-Y-W- M-N), said CDR2 has the amino acid sequence SEQ ID NO: 2 (A-I-N-Q-D-G- S-E-K-Y-Y-V-G-S-V-K-G), and said CDR3 has the amino acid sequence Has the sequence number 3 (D - Y - Y - D - I - L - T - D - Y - Y - I - H - Y - W - Y - F - D - L).

[0117] In one embodiment, 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) comprises at least one immunoglobulin light - chain variable domain (V ) in order containing hypervariable regions CDR1’, CDR2’ and CDR3’, wherein said CDR1’ has the amino acid sequence sequence number 4 (R - L A - S - Q - S - V - S - S - S - Y - L - A), said CDR2’ has the amino acid sequence sequence number 5 (G - A - S - S - R - A - T), and said CDR3’ has the amino acid sequence sequence number 6 (Q - Q - Y - G - S - S - P - C - T).

[0118] In one embodiment, 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) comprises at least one immunoglobulin heavy - chain variable domain (V ) in order containing hypervariable regions CDR1 - x, CDR2 - x and CDR3 - x, wherein said CDR1 - x has the amino acid sequence sequence number H 11 (G - F - T - F - S - N - Y - W - M - N), said CDR2 - x has the amino acid sequence number 12 (A - I - N - Q - D - G - S - E - K - Y - Y), and said CD R3 - x has the amino acid sequence sequence number 13 (C - V - R - D - Y - Y - D - I - L - T - D - Y - Y - I - H - Y - W - Y - F - D - L - W - G).

[0119] In one embodiment, an IL - 17 antagonist, e.g., an IL - 17 binding molecule ​​(For example, an IL-17 antibody or an antigen-binding fragment thereof, for example, secukinumab) has at least one immunoglobulin V H domain and at least one immunoglobulin V L domain, and a) the immunoglobulin V H domain comprises i) hypervariable regions CDR1, CDR2 and CDR3 (wherein CDR1 has the amino acid sequence SEQ ID NO: 1, CDR2 has the amino acid sequence SEQ ID NO: 2, and CDR3 has the amino acid sequence SEQ ID NO: 3) or ii) hypervariable regions CDR1-x, CDR2-x and CDR3-x (wherein CDR1-x has the amino acid sequence SEQ ID NO: 11, CDR2-x has the amino acid sequence SEQ ID NO: 12, and the said CDR3-x has the amino acid sequence SEQ ID NO: 13), and b) the immunoglobulin V L domain comprises hypervariable regions CDR1', CDR2' and CDR3' (wherein CDR1' has the amino acid sequence SEQ ID NO: 4, CDR2' has the amino acid sequence SEQ ID NO: 5, and the said CDR3' has the amino acid sequence SEQ ID NO: 6).

[0120] In one embodiment, an IL-17 antagonist, for example, an IL-17 binding molecule (for example, an IL-17 antibody or an antigen-binding fragment thereof, for example, secukinumab) has at least one immunoglobulin V H domain and at least one immunoglobulin V L domain, and a) at least one immunoglobulin V H domain comprises hypervariable regions CDR1, CDR2 and CDR3 in sequence, wherein CDR1 has the amino acid sequence SEQ ID NO: 1, and the said CDR2 has the amino acid sequence SEQ ID NO: 2, and said CDR3 has the amino acid sequence SEQ ID NO: having 3, and b) at least one immunoglobulin V L domain comprises, in order, the hypervariable regions CDR1′ , CDR2′ and CDR3′, wherein said CDR1′ has the amino acid sequence SEQ ID NO: 4 , said CDR2′ has the amino acid sequence SEQ ID NO: 5, and said CDR3′ has the amino acid sequence SEQ ID NO: 6.

[0121] In one embodiment, 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) comprises at least one immunoglobulin V H domain and at least one immunoglobulin V L domain, and a) at least one immunoglobulin V domain comprises, in order, the hypervariable regions CDR1- H x, CDR2-x and CDR3-x, wherein said CDR1-x has the amino acid sequence SEQ ID NO: 11, said CDR2-x has the amino acid sequence SEQ ID NO: 12, and said CDR3 -x has the amino acid sequence SEQ ID NO: 13, and b) at least one immunoglobulin V domain comprises, in order, the hypervariable regions CDR1′, CDR2′ and CDR3′, wherein said CDR1 L domain comprises, in order, the hypervariable regions CDR1′, CDR2′ and CDR3′, wherein said CDR1 ′ has the amino acid sequence SEQ ID NO: 4, said CDR2′ has the amino acid sequence SEQ ID NO: 5 , and said CDR3′ has the amino acid sequence SEQ ID NO: 6.

[0122] In one embodiment, 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) comprises the following . a) An immunoglobulin heavy chain variable domain (V H) containing the amino acid sequence shown as SEQ ID NO: 8 H) and b) an immunoglobulin light chain comprising the amino acid sequence shown as SEQ ID NO: 10 Variable domain (V L ) and c) an immunoglobulin V domain and an immunoglobulin V H domain comprising the amino acid sequence shown as SEQ ID NO: 10 L domain , d) an immunoglobulin V domain comprising the hypervariable regions shown as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 H , e) an immunoglobulin V domain comprising the hypervariable regions shown as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 L , f) an immunoglobulin V domain comprising the hypervariable regions shown as SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13 H , g) an immunoglobulin V domain comprising the hypervariable regions shown as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 H domain and an immunoglobulin V domain comprising the hypervariable regions shown as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 L , or h) an immunoglobulin V domain comprising the hypervariable regions shown as SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13 H domain and an immunoglobulin V domain comprising the hypervariable regions shown as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 L domain

[0123] For easy reference, based on Kabat's definition, the amino acid sequences of the hypervariable regions of the secukinumab monoclonal antibody determined by X-ray analysis and using the approach of Chothia and co-workers are shown in Table 4 below.

[0124]

Table 4

[0125] In a preferred embodiment, the variable domains of both the heavy and light chains are of human origin, such as, for example, SEQ ID NO: 10 (= variable domain of the light chain, i.e., amino acids 1 to 1 09) and SEQ ID NO: 8 (= variable domain of the heavy chain, i.e., amino acids 1 to 1 27) of the secukinumab antibody shown. The constant region domains are also preferably, for example, "Sequences of Proteins of Immunological Interest", Kabat E.A. et al., US Department of Health and Human Services, Public Health Service, National Institute of Heal th, including appropriate human constant region domains described therein.

[0126] In some embodiments, an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) comprises the variable light domain of SEQ ID NO: 10. In other embodiments, an IL-17 antagonist such as an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) comprises the variable heavy domain of SEQ ID NO: 8. In other embodiments, an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 anti body or an antigen-binding fragment thereof, such as secukinumab) comprises the variable light domain of SEQ ID NO: 10 and the variable heavy domain of SEQ ID NO: 8. In some embodiments, an IL-17 a ntagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment The original binding fragment, e.g., secukinumab, contains the three CDRs of SEQ ID NO: 10. In other embodiments the IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab), contains the three CDRs of SEQ ID NO: 8. In other embodiments, the IL-17 antagonist, e.g., an IL-1 7 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab ), contains the three CDRs of SEQ ID NO: 10 and the three CDRs of SEQ ID NO: 8. The CDRs of SEQ ID NO: 8 and SEQ ID NO: 10 according to both the Choth ia and Kabat definitions can be found in Table 4.

[0127] In some embodiments, the IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab), contains the light domain of SEQ ID NO: 15. In other embodiments, the IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g ., secukinumab), contains the heavy domain of SEQ ID NO: 17. In other embodiments, I L-17 antagonist, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody or its antigen-binding fragment, e.g., secukinumab), contains the light domain of SEQ ID NO: 15 and the sequence number 17 of the heavy domain. In some embodiments, the IL-17 antagonist , e.g., an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab), contains the three CDRs of SEQ ID NO: 15. In other embodiments , the IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody ​or an antigen-binding fragment thereof, such as secukinumab) comprises the three CDRs of SEQ ID NO: 17 In other embodiments, an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) comprises the three CDRs of SEQ ID NO: 15 and the three CDRs of SEQ ID NO: 17. The CDRs of SEQ ID NO: 15 and SEQ ID NO: 17 according to both Chothia and Kabat definitions can be found in Table 4 .

[0128] The hypervariable regions are preferably of human origin but can be associated with any kind of framework region. Suitable framework regions are described by Kabat E.A. et al., supra. Preferred heavy chain frameworks are human heavy chain frameworks, such as the heavy chain framework of the secukinumab antibody. It consists, in turn, of, for example, FR1 (amino acids 1-30 of SEQ ID NO: 8), FR2 (amino acids 36-49 of SEQ ID NO: 8), FR3 (amino acids 67-98 of SEQ ID NO: 8) and FR4 (amino acids 117-127 of SEQ ID NO: 8) regions. Taking into account the defined hypervariable regions of secukinumab by X-ray analysis, other preferred heavy chain frameworks consist, in turn, of FR1-x (amino acids 1-25 of SEQ ID NO: 8), FR2-x (amino acids 36-49 of SEQ ID NO: 8), FR3-x (amino acids 61-95 of SEQ ID NO: 8) and FR4 (amino acids 119-127 of SEQ ID NO: 8) regions. Similarly, the light chain framework consists, in turn, of FR1' (amino acids 1-23 of SEQ ID NO: 10), FR2' (amino acids 36-50 of SEQ ID NO: 1 0), FR3' (amino acids 58-89 of SEQ ID NO: 10) and FR4 ' (amino acids 99-109 of SEQ ID NO: 10) regions. ​​​​​​

[0129] In one embodiment, an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) comprises at least a) a variable domain comprising, in order, hypervariable regions CDR1, CDR2, and CDR3, and a constant region of a human heavy chain or a fragment thereof (wherein CDR1 has the amino acid sequence SEQ ID NO: 1, CDR2 has the amino acid sequence SEQ ID NO: 2, and CDR3 has the amino acid sequence SEQ ID NO: 3), and b) a variable domain comprising, in order, hypervariable regions CDR1′, CDR2′, and CDR3, and a constant region of a human light chain or a fragment thereof (wherein CDR1′ has the amino acid sequence SEQ ID NO: 4, CDR2′ has the amino acid sequence SEQ ID NO: 5, and CDR3′ has the amino acid sequence SEQ ID NO: 6), and is selected from human IL-17 antibodies comprising

[0130] In one embodiment, an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) comprises a) a first domain comprising, in order, hypervariable regions CDR1, CDR2, and CDR3 (wherein CDR1 has the amino acid sequence SEQ ID NO: 1, CDR2 has the amino acid sequence SEQ ID NO: 2, and CDR3 has the amino acid sequence SEQ ID NO: 3), and b) a second domain comprising hypervariable regions CDR1′, CDR2′, and CDR3′ (wherein CDR1′ has the amino acid sequence SEQ ID NO: 4, CDR2′ has the amino acid sequence SEQ ID NO: 5, and CDR3′ has the amino acid sequence SEQ ID NO: 6), and c) the N-terminus of the first domain and the second domain ​​​​​​​​​​​​It is selected from single-chain binding molecules containing 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 contains a peptide linker.

[0131] Alternatively, an IL-17 antagonist, for example, an IL-17 binding molecule (for example, an IL- 17 antibody or an antigen-binding fragment thereof, for example, secukinumab), in order, a) hypervariable region C DR1 (SEQ ID NO: 1), CDR2 (SEQ ID NO: 2) and CDR3 (SEQ ID NO: 3) or b) hyper variable region CDR1 i , CDR2 i , CDR3 i It may contain at least one immunoglobulin heavy chain variable domain (V H ), and may contain at least one antigen-binding site, wherein the hyper variable region CDR1 i differs from the hypervariable region of CDR1 by 3, preferably 2, more preferably 1 amino acid, as shown in SEQ ID NO: 1, and the hypervariable region CDR2 i differs from the hypervariable region of CDR2 by 3, preferably 2, more preferably 1 amino acid, as shown in SEQ ID NO: 2, and the above mentioned hypervariable region CD3 i differs from the hypervariable region of CDR3 by 3, preferably 2, more preferably 1 amino acid, as shown in SEQ ID NO: 3, and the IL-17 binding molecule has an activity of about 1 nM (= 30 ng / ml) human IL-17 at a concentration of about 5 0 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 to inhibit by 5 0%, and the inhibitory activity is measured based on the production of IL-6 induced by hu-IL-1 7 in human skin fibroblasts.

[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 (CDRs) C DR1-x (SEQ ID NO: 11), CDR2-x (SEQ ID NO: 12), and CDR3-x (SEQ ID NO: 13) or b) has at least one antigen-binding i site comprising at least one immunoglobulin heavy chain variable domain (V i ) and comprising at least one of CDR1 i -x, CDR2 -x, and CDR3 H -x, wherein said CDR1 -x differs from the CDR1-x CDR by 3, preferably 2, more preferably 1 amino acid as shown in SEQ ID NO: 11, said i CDR2 -x differs from the CDR2-x CDR by 3, preferably 2, more preferably 1 amino acid as shown in SEQ ID NO: 12, and said CDR3 -x differs from the CDR3-x CDR by 3, preferably 2, more preferably i 1 amino acid as shown in SEQ ID NO: 13, and said 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, and said 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 (CDRs) C DR1-x (SEQ ID NO: 11), CDR2-x (SEQ ID NO: 12), and CDR3-x (SEQ ID NO: 13) or b) has at least one antigen-binding site comprising at least one immunoglobulin heavy chain variable domain (V ) and comprising at least one of CDR1

[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 (CDRs) C DR’1 (SEQ ID NO: 4), CDR’2 (SEQ ID NO: 5) and CDR’3 (SEQ ID NO: 6) or b) At least one hypervariable region CDR1’ i , CDR2’ i , CDR3’ i and at least one immunoglobulin light chain variable domain (V L ) containing at least one antigen-binding site, or preferably, said hypervariable region CDR’1 i differs from the hypervariable region of CDR’1 as shown in SEQ ID NO: 4 by 3, preferably 2, more preferably 1 amino acid, said hypervariable region CDR’2 differs from the hypervariable region of CDR’2 as shown in SEQ ID NO: 5 by 3, preferably 2, more preferably i is , differs from the hypervariable region of CDR’2 as shown in SEQ ID NO: 5 by 3, preferably 2, more preferably 1 amino acid, said hypervariable region CDR’3 i differs from the hypervariable region of CDR’3 as shown in SEQ ID NO: 6 by 3, preferably 2, more preferably 1 amino acid, said IL-17 binding molecule can inhibit the activity of 1 nM (= 30 ng / ml) human IL-17 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 said molecule, and said inhibitory activity is measured based on the production of IL-6 induced by hu-IL-17 in human skin fibroblasts. Alternatively, an IL-17 antagonist, for example, an IL-17 binding molecule (for example, an IL- 17 antibody or an antigen-binding fragment thereof, for example, secukinumab) may contain both a heavy (V ) and a light chain ( V

[0134] 17 antibody or an antigen-binding fragment thereof, for example, secukinumab) may contain both a heavy (V ), and a light chain ( H ) variable domains, and said IL-17 binding molecule may, a) in order contain an immunoglobulin heavy chain variable domain (V L ) containing hypervariable regions CDR1 (SEQ ID NO: 1), CDR2 (SEQ ID NO: 2) and CDR3 (SEQ ID NO: ), and an immunoglobulin light chain variable domain (VH ) and in order, the hypervariable regions CDR1’ (sequence number 4), CDR2’ (sequence number 5) and CDR3’ (sequence number 6) of an immunoglobulin light chain variable domain (V ), or b) in order, the hypervariable regions CDR1 L , CDR2 i , CDR i and CDR 3 i of an immunoglobulin heavy chain variable domain (V H )(the hypervariable region CDR1 i is different from the hypervariable region of CDR1 by 3, preferably 2, more preferably 1 amino acid as shown in sequence number 1, the hypervariable region CDR2 is different from the hypervariable region of CDR2 by 3, preferably 2, more preferably 1 amino acid as shown in sequence number 2, the hypervariable region CDR3 i is different from the hypervariable region of CDR3 by 3, preferably 2, more preferably 1 amino i acid as shown in sequence number 3) and in order, the hypervariable regions CDR1’ , CDR2’ i , CDR3’ i , CDR3’ i of an immunoglobulin light chain variable domain (V )(the hypervariable region CDR’1 L is different from the hypervariable region of CDR’1 by 3, preferably 2, more preferably 1 amino acid as shown in sequence number 4 i , the hypervariable region CDR’2 is different from the hypervariable region of CDR’2 by 3, preferably 2, more preferably 1 amino acid as shown in sequence number 5, the hypervariable region CDR’3 i is different from the hypervariable region of CDR’3 by 3, preferably 2, more preferably 1 amino i acid as shown in sequence number 6) and having at least one antigen-binding site, said IL-17 binding molecule ​​is capable of inhibiting the activity of 1 nM (= 30 ng / ml) human IL-17 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, more preferably about 1 nM or less, and the inhibitory activity is measured based on the production of IL-6 induced by hu-IL-17 in human skin fibroblasts. Alternatively, an IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., an IL- 17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) may contain both a heavy (V

[0135] H 17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) may contain both a heavy (V H ) and a light chain ( V L ) variable domains, and the IL-17 binding molecule may comprise a) immunoglobulin heavy chain variable domains (V H ) containing hypervariable regions CDR1-x (SEQ ID NO: 11), CDR2-x (SEQ ID NO: 12), and CDR3 H ) containing hypervariable regions CDR1-x (SEQ ID NO: 11), CDR2-x (SEQ ID NO: 12), and CDR3 -x (SEQ ID NO: 13), and immunoglobulin light chain variable domains (V L ) containing hypervariable regions CDR1’ (SEQ ID NO: 4), CDR2’ (SEQ ID NO: 5), and CDR3’ (SEQ ID NO: 6) containing hypervariable regions CDR1’ (SEQ ID NO: 4), CDR2’ (SEQ ID NO: 5), and CDR3’ (SEQ ID NO: 6 i - x, CDR2 i -x, and CDR3 i -x, or b) immunoglobulin heavy chain variable domains (V H )( The hypervariable regions CDR1 i -x, CDR2 i -x, CDR3 i -x, the hypervariable region CDR1 i -x differs from the hypervariable region of CDR1-x by 3, preferably 2, more preferably 1 amino acid as shown in SEQ ID NO: 11, and the hypervariable region CDR2 i -x is the sequence number As shown in No. 12, the hypervariable region of CDR2-x differs from that of 3, preferably 2, more preferably 1 amino acid, and the hypervariable region CDR3 -x differs from the hypervariable region of CDR3-x as shown in SEQ ID NO: 13 by 3, preferably 2, more preferably 1 amino acid), and in order, the hypervariable i regions CDR1’ regions CDR1’ i , CDR2’ i , CDR3’ i An immunoglobulin light chain variable domain containing (V L )(The hypervariable region CDR’1 i differs from the hypervariable region of CDR’1 as shown in SEQ ID NO: 4 by 3, preferably 2, more preferably 1 amino acid, and the hypervariable region CDR’2 differs from the hypervariable region of CDR’2 as shown in SEQ ID NO: 5 by 3, preferably 2, more preferably is 1 amino acid different, and the hypervariable region CDR’3 i differs from the hypervariable region of CDR’3 as shown in SEQ ID NO: 6 by 3, preferably 2, more preferably 1 amino acid). It contains at least one antigen-binding site, and the IL-17 binding molecule has an activity of inhibiting 50% of 1 nM (= 30 ng / ml) human IL-17 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, and the inhibitory activity is measured based on the production of IL-6 induced by hu-IL-17 in human skin fibroblasts.

[0136] The human IL-17 antibody disclosed herein may include a heavy chain that is substantially the same as that shown as SEQ ID NO: 17 and a light chain that is substantially the same as that shown as SEQ ID NO: 15. The human IL-17 antibody disclosed herein may include a heavy chain containing SEQ ID NO: 17 and a light chain that is substantially the same as that shown as SEQ ID NO: 15. The human IL-17 antibody disclosed herein may include a heavy chain containing SEQ ID NO: 17 and a light chain that is substantially the same as that shown as SEQ ID NO: 15. The human IL-17 antibody disclosed herein may include a heavy chain containing SEQ ID NO: 17 and It may include a light chain containing SEQ ID NO: 15.

[0137] The human IL-17 antibody disclosed herein may include one heavy chain containing a variable domain having substantially the same amino acid sequence as that shown in SEQ ID NO: 8 and a constant region of a human heavy chain, and b) one light chain containing a variable domain having substantially the same amino acid sequence as that shown in SEQ ID NO: 10 and a constant region of a human light chain. It may include.

[0138] Inhibition of the binding of IL-17 to its receptor can be conveniently tested in various assays, including those described in WO 2006 / 013107. The term "to the same extent" means that the reference and equivalent molecules exhibit essentially the same IL-17 inhibitory activity based on statistical grounds in one of the assays referenced herein (see Example 1 of WO 2006 / 013107). For example, when assayed as described in Example 1 of WO 2006 / 013107, the human IL-17-binding molecule disclosed herein preferably has an IC substantially the same as that of the corresponding reference molecule, and is preferably about 10 nM, more preferably about 9, 8, 7, 6, 5, 4, 3, 2 or about 1 nM or less for inhibition of human IL-17-induced production of IL-6 in human skin fibroblasts. Alternatively, the assay used may be an assay for competitive inhibition of the binding of IL-17 by a soluble IL-17 receptor (e.g., the human IL-17R / Fc construct of Example 1 of WO 2006 / 013107) and an IL-17-binding molecule of the present disclosure. s generally for inhibition of human IL-17. 50 50 s generally for inhibition of human IL-17.

[0139] ​​​​​​​​​ The present disclosure relates to an IL-17 antagonist in which one or more, generally a small number (e.g., 1 to 4), of amino acid residues of CDR1, CDR2, CDR3, CDR1-x, CDR2-x, CDR3-x, CDR1′, CDR2′, or CDR3′ or the framework have been changed, for example, by random mutation, such as site-directed mutagenesis. The present disclosure also includes, for example, an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab). The present disclosure includes a DNA sequence encoding such a changed IL-17 binding molecule. In particular, the present disclosure includes an IL-17 binding molecule in which one or more residues of CDR1′ or CDR2′ have been changed from the residues shown in SEQ ID NO: 4 (for CDR1′) and SEQ ID NO: 5 (for CDR2′). The present disclosure also relates to an IL-17 binding molecule having binding specificity for human IL-17, particularly an IL-17 antibody capable of inhibiting the binding of IL-17 to its receptor, and an IL-17 antagonist capable of inhibiting 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 (the inhibitory activity is measured based on the production of IL-6 induced by hu-IL-17 in human dermal fibroblasts). The present disclosure includes an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab). The present disclosure includes a DNA sequence encoding such a changed IL-17 binding molecule. In particular, the present disclosure includes an IL-17 binding molecule in which one or more residues of CDR1′ or CDR2′ have been changed from the residues shown in SEQ ID NO: 4 (for CDR1′) and SEQ ID NO: 5 (for CDR2′). The present disclosure also relates to an IL-17 binding molecule having binding specificity for human IL-17, particularly an IL-17 antibody capable of inhibiting the binding of IL-17 to its receptor, and an IL-17 antagonist capable of inhibiting 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 (the inhibitory activity is measured based on the production of IL-6 induced by hu-IL-17 in human dermal fibroblasts). The present disclosure includes an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab). The present disclosure includes a DNA sequence encoding such a changed IL-17 binding molecule. In particular, the present disclosure includes an IL-17 binding molecule in which one or more residues of CDR1′ or CDR2′ have been changed from the residues shown in SEQ ID NO: 4 (for CDR1′) and SEQ ID NO: 5 (for CDR2′).

[0140] The present disclosure also relates to an IL-17 binding molecule having binding specificity for human IL-17, particularly an IL-17 antibody capable of inhibiting the binding of IL-17 to its receptor, and an IL-17 antagonist capable of inhibiting 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 (the inhibitory activity is measured based on the production of IL-6 induced by hu-IL-17 in human dermal fibroblasts). The present disclosure includes an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab). The present disclosure includes a DNA sequence encoding such a changed IL-17 binding molecule. In particular, the present disclosure includes an IL-17 binding molecule in which one or more residues of CDR1′ or CDR2′ have been changed from the residues shown in SEQ ID NO: 4 (for CDR1′) and SEQ ID NO: 5 (for CDR2′). The present disclosure also relates to an IL-17 binding molecule having binding specificity for human IL-17, particularly an IL-17 antibody capable of inhibiting the binding of IL-17 to its receptor, and an IL-17 antagonist capable of inhibiting 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 (the inhibitory activity is measured based on the production of IL-6 induced by hu-IL-17 in human dermal fibroblasts). The present disclosure includes an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab). The present disclosure includes a DNA sequence encoding such a changed IL-17 binding molecule. In particular, the present disclosure includes an IL-17 binding molecule in which one or more residues of CDR1′ or CDR2′ have been changed from the residues shown in SEQ ID NO: 4 (for CDR1′) and SEQ ID NO: 5 (for CDR2′). The present disclosure also relates to an IL-17 binding molecule having binding specificity for human IL-17, particularly an IL-17 antibody capable of inhibiting the binding of IL-17 to its receptor, and an IL-17 antagonist capable of inhibiting 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 (the inhibitory activity is measured based on the production of IL-6 induced by hu-IL-17 in human dermal fibroblasts). The present disclosure includes an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab).

[0141] The present disclosure relates to a therapeutically effective amount of an IL-17 antagonist, such as an IL-17 binding molecule (For example, an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) is administered to a subject suffering from RA, for example, a high-risk RA patient, comprising the step of treating RA. In some embodiments, the IL-17 antibody, such as secukinumab, binds to an epitope of mature human IL-17 comprising Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr 125, Pro126, Ile127, Val128, His129. In some embodiments, the IL-17 antibody, such as secukinumab, binds to an epitope of mature human IL-17 comprising Tyr43, Tyr44, Arg46, Ala79, Asp80. In some embodiments, the IL-17 antibody, such as secukinumab, binds to an epitope of an IL-17 homodimer having two mature human IL-17 chains, wherein the epitope comprises Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 on one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain. The residue numbering scheme used to define these epitopes is based on the residue that is the first amino acid of the mature protein (i.e., IL-17A lacking the 23-amino acid N-terminal signal peptide and starting with glycine). The sequence of immature IL-17A is shown in Swiss-Prot entry Q16552.

[0142] In some embodiments, the IL-17 antibody has a Kd of about 100-200 pM. D In some embodiments, the IL-17 antibody has an IC50 of about 0.67 nM for human IL-17A has an IC of about 0.4 nM with respect to in vitro neutralization of biological activity 50 . In some embodiments , the absolute bioavailability of an IL-17 antibody administered subcutaneously (s.c.) is about in the range of about 60% to about 80%, for example about 76%. In some embodiments, an IL- 17 antagonist, for example, an IL-17 binding molecule (e.g., an IL -17 antibody such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody) has a half-life of disappearance of about 4 weeks (e.g., about 23 to about 30 days, for example, about 30 days). In some embodiments, an IL-17 antagonist, for example, an IL-17 binding molecule (e.g ., an IL-17 antibody such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody) has a T of about 7 to 8 days max .

[0143] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, kits, assays and treatment regimens, the IL-17 antagonist is a) an IL-17 binding molecule or an IL-1 7 receptor binding molecule, b) secukinumab, c) an IL-17 antibody that binds to an epitope of IL-17 comprising Leu74, Tyr85, His86, M et87, Asn88, Val124, Thr125, Pro126, Ile127, V al128, His129, d ) an IL-17 antibody that binds to an epitope of IL-17 comprising Tyr43, Tyr44, Arg46, Ala79, Asp80, e ) an IL-17 antibody that binds to an epitope of an IL-17 homodimer having two mature IL-17 protein chains (said epitope being Leu74, Tyr85, His86, Met87, Asn88, Val124 on one chain, and the epitope on the other chain is as defined above), or f) an IL-17 antibody that binds to an epitope of IL-17 comprising Tyr43, Tyr44, Arg46, Ala79, Asp80, or g) an IL-17 antibody that binds to an epitope of an IL-17 homodimer having two mature IL-17 protein chains (said epitope being Leu74, Tyr85, His86, Met87, Asn88, Val124 on one chain, Thr125, Pro126, Ile127, Val128, His129 and on other chains including Tyr43, Tyr44, Arg46, Ala79, Asp80 of ), f) two IL-17 antibodies that bind to the epitope of an IL-17 homodimer having two mature IL-17 protein chains (the epitope includes Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 on one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain, and the IL-17 binding molecule has a K of about 100 - 200 pM ), and the IL-17 binding molecule has an in vivo half-life of about 4 weeks), and g) i) an immunoglobulin heavy chain variable domain (V ) containing the amino acid sequence shown as SEQ ID NO: 8, ii i) an immunoglobulin light chain variable domain (V D ) containing the amino acid sequence shown as SEQ ID NO: 10, iii) an immunoglobulin V domain containing the amino acid sequence shown as SEQ ID NO: 8 and an immunoglobulin V domain containing the amino acid sequence shown as SEQ ID NO: 10, iv) an immunoglobulin V H domain containing the hypervariable regions shown as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, v) an immunoglobulin V domain containing the hypervariable regions shown as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, vi) an immunoglobulin V domain containing the hypervariable regions shown as SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: L 13, vii) an immunoglobulin V H domain containing the hypervariable regions shown as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 and an immunoglobulin V L domain containing the amino acid sequence shown as SEQ ID NO: 10, iv v) an immunoglobulin V domain containing the hypervariable regions shown as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, v) an immunoglobulin V H domain containing the hypervariable regions shown as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, vi) an immunoglobulin V domain containing the hypervariable regions shown as SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: L 13, vii) an immunoglobulin V domain containing the hypervariable regions shown as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 H and an immunoglobulin V domain containing the hypervariable regions shown as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 H domain An immunoglobulin V containing hypervariable regions shown as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 domain, and viii) an immunoglobulin V containing hypervariable regions shown as SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13 L domain, and an immunoglobulin V containing hypervariable regions shown as SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, and is selected from the group consisting of IL-17 antibodies containing antibodies selected from the group H consisting of immunoglobulin V domains. An IL-17 antagonist particularly preferred for use in the disclosed methods, uses, kits, etc., for example, an IL-17 binding molecule (for example, an IL-17 antibody or its antigen-binding fragment, for example, secukinumab) or an IL-17 receptor binding molecule (for example, an IL-17 antibody L or its antigen-binding fragment) is a human antibody, particularly, secukinumab described in Examples 1 and 2 of WO 2006 / 013107. Secukinumab (AIN457) is an IgG1 / kappa isotype recombinant high-affinity fully human monoclonal anti-human interleukin-17A (IL-17A, IL-17) antibody. Secukinumab (see, for example, WO 2006 / 013107 and WO 2007 / 117749) has a very high affinity for IL

[0144] -17, that is, a K of about 100 - 200 pM and an IC of about 0.67 nM in vitro neutralization of the biological activity of about 0.4 nM of human IL-17A. Thus, secukinumab inhibits the antigen at a molar ratio of about 1:1. Due to this high binding affinity, the secukinumab antibody is particularly suitable for therapeutic applications. Furthermore, sec ukinumab is an IgG1 / kappa isotype recombinant high-affinity fully human monoclonal anti-human interleukin-17A (IL-17A, IL-17) antibody. Secukinumab (see, for example, WO 2006 / 013107 and WO 2007 / 117749) has a very high affinity for IL -17, that is, a K of about 100 - 200 pM and an IC of about 0.67 nM in vitro neutralization of the biological activity of about 0.4 nM of human IL-17A. Thus, secukinumab inhibits the antigen at a molar ratio of about 1:1. Due to this high binding affinity, the secukinumab antibody is particularly suitable for therapeutic applications. Furthermore, sec ukinumab (see, for example, WO 2006 / 013107 and WO 2007 / 117749) has a very high affinity for IL -17, that is, a K of about 100 - 200 pM D and an IC of about 0.67 nM in vitro neutralization of the biological activity of about 0.4 nM of human IL-17A. Thus, secukinumab inhibits the antigen at a molar ratio of about 1:1. Due to this high binding affinity, the secukinumab antibody is particularly suitable for therapeutic applications. Furthermore, sec 50 ukinumab has. Therefore, secukinumab inhibits the antigen at a molar ratio of about 1:1. Due to this high binding affinity, the secukinumab antibody is particularly suitable for therapeutic applications. Furthermore, sec ukinumab has. Therefore, secukinumab inhibits the antigen at a molar ratio of about 1:1. Due to this high binding affinity, the secukinumab antibody is particularly suitable for therapeutic applications. Furthermore, sec ukinumab antibody is particularly suitable for therapeutic applications due to this high binding affinity. Furthermore, sec Kineret has a very long half-life, namely, a half-life of about 4 weeks, which allows for a long period between each dose and has been confirmed to be an exceptional property when treating lifelong chronic diseases such as rheumatoid arthritis (RA).

[0145] Treatment regimen, method of treatment, pharmaceutical composition and use The disclosed IL-17 antagonists, for example, IL-17 binding molecules (e.g., IL- 17 antibodies or antigen-binding fragments thereof, e.g., secukinumab) or IL-17 receptor binding molecules (e.g., IL-17 antibodies or antigen-binding fragments thereof) are useful for the treatment, prevention or improvement of inflammatory arthritis (e.g., rheumatoid arthritis (RA), spondyloarthritis, ankylosing spondylitis and psoriatic arthritis). Thus, such molecules are useful for causing changes in the signs and symptoms of arthritis and structural changes, preventing further joint erosion, and improving the structure of joints, etc. In some embodiments, patients with inflammatory arthritis are RA patients, e.g., high-risk RA patients.

[0146] IL-17 antagonists, for example, IL-17 binding molecules (e.g., IL-17 antibodies or antigen-binding fragments thereof, e.g., secukinumab) or IL-17 receptor binding molecules ( e.g., IL-17 antibodies or antigen-binding fragments thereof) can be used in vitro, ex vivo, or incorporated into a pharmaceutical composition and administered to an individual (e.g., a human subject) to treat, improve or prevent RA in vivo, e.g., in high-risk RA patients. The pharmaceutical composition shall be formulated to be compatible with its intended route of administration (e.g., oral compositions generally contain an inert diluent or an edible carrier). Other non- parenteral routes of administration...​​​​ As limiting examples, there are parenteral (e.g., intravenous), intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administrations, etc. Pharmaceutical compositions suitable for each intended route are

[0147] IL-17 antagonists, e.g., IL-17 binding molecules (e.g., IL-17 antibodies or antigen-binding fragments thereof, e.g., secukinumab) or IL-17 receptor binding molecules ( e.g., IL-17 antibodies or antigen-binding fragments thereof), when mixed with a pharmaceutically acceptable carrier, can be used as a pharmaceutical composition. Such compositions may, in addition to the IL-17 an tagonist (e.g., secukinumab), contain carriers, various diluents, fillers, salts, buffers , stabilizers, solubilizers, and other substances well-known in the art. The characteristics of the carrier depend on the route of administration.

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

[0149] The pharmaceutical compositions of the present disclosure include 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), where the IL-17 antagonist In addition to a pharmaceutically acceptable carrier, it may be in the form of liposomes that are bound to amphiphilic substances such as lipids that aggregate in the form of micelles, insoluble monolayers, liquid crystals or lamellar layers in an aqueous solution. It may be in the form of liposomes that are bound to amphiphilic substances such as lipids that aggregate in the form of micelles, insoluble monolayers, liquid crystals or lamellar layers in an aqueous solution. Suitable lipids for liposome formulations include, without limitation, monoglycerides, diglycerides, sulfatides, lysophosphatidylcholine, phospholipids, saponins, bile acids and the like. Suitable lipids for liposome formulations include, without limitation, monoglycerides, diglycerides, sulfatides, lysophosphatidylcholine, phospholipids, saponins, bile acids and the like.

[0150] In practicing the methods, regimens, uses, etc. of the present disclosure, a therapeutically effective amount of an IL-17 antagonist, for example, 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) is administered to a subject, for example, a mammal (e.g., a human). In practicing the methods, regimens, uses, etc. of the present disclosure, a therapeutically effective amount of an IL-17 antagonist, for example, 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) is administered to a subject, for example, a mammal (e.g., a human). In practicing the methods, regimens, uses, etc. of the present disclosure, a therapeutically effective amount of an IL-17 antagonist, for example, 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) is administered to a subject, for example, a mammal (e.g., a human). In practicing the methods, regimens, uses, etc. of the present disclosure, a therapeutically effective amount of an IL-17 antagonist, for example, 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) is administered to a subject, for example, a mammal (e.g., a human). The IL-17 antagonist (e.g., secukinumab) can be administered alone or in combination with other therapies, such as in combination with an additional therapy for inflammation, by the methods of the present disclosure. The IL-17 antagonist (e.g., secukinumab) can be administered alone or in combination with other therapies, such as in combination with an additional therapy for inflammation, by the methods of the present disclosure. When administered in combination with one or more drugs, the IL-17 antagonist (e.g., secukinumab) can be administered simultaneously or sequentially with the other drugs. When administered sequentially, the attending physician determines the appropriate order for administering the IL-17 antagonist (e.g., secukinumab) in combination with the other drugs. When administered sequentially, the attending physician determines the appropriate order for administering the IL-17 antagonist (e.g., secukinumab) in combination with the other drugs. When administered sequentially, the attending physician determines the appropriate order for administering the IL-17 antagonist (e.g., secukinumab) in combination with the other drugs.

[0151] When a therapeutically effective amount of an IL-17 antagonist, for example, 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) is administered orally, the binder is in the form of tablets, capsules, powders, solutions or elixirs. When administered in the form of tablets When a therapeutically effective amount of an IL-17 antagonist, for example, 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) is administered orally, the binder is in the form of tablets, capsules, powders, solutions or elixirs. When administered in the form of tablets When a therapeutically effective amount of an IL-17 antagonist, for example, 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) is administered orally, the binder is in the form of tablets, capsules, powders, solutions or elixirs. When administered in the form of tablets When a therapeutically effective amount of an IL-17 antagonist, for example, 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) is administered orally, the binder is in the form of tablets, capsules, powders, solutions or elixirs. When administered in the form of tablets When used, the pharmaceutical composition of the present disclosure may further contain a solid carrier or adjuvant such as gelatin. When administered in liquid form, animal or plant-derived oils such as water, petroleum, peanut oil (caution regarding peanut allergy), mineral oil, soybean oil or sesame oil or synthetic oils, etc., can be added as liquid carriers. The pharmaceutical composition in liquid form may further contain components such as physiological saline solution, dextrose or other sugar solutions or glycols such as ethylene glycol, propylene glycol or polyethylene glycol.

[0152] When a therapeutically effective amount of an IL-17 antagonist, for example, an IL-17 binding molecule (for example, an IL-17 antibody or an antigen-binding fragment thereof, for example, secukinumab) or an IL-17 receptor binding molecule (for example, an IL-17 antibody or an antigen-binding fragment thereof) is administered by intravenous, cutaneous or subcutaneous injection, the IL-17 binding molecule is in a pyrogen-free, parenterally acceptable solution form. The pharmaceutical composition for intravenous, cutaneous or subcutaneous injection may, in addition to the IL-17 antag onist (for example, secukinumab), contain isotonic excipients such as sodium chloride, Ringer's, dextrose, dextrose sodium chloride, lactated Ringer's, etc., or other excipients known in the art.

[0153] The pharmaceutical composition used in the disclosed method can be manufactured by conventional methods. In one embodiment, the pharmaceutical composition is preferably provided as a lyophilized product. For immediate administration, it is dissolved in a suitable aqueous carrier, for example, sterile water for injection or sterile buffered physiological saline. For administration by infusion rather than bolus injection, it is desirable to prepare a larger volume of solution. When it is considered appropriate, it may be convenient to incorporate human serum albumin or the patient's own heparinized blood into the physiological saline at the time of formulation. The presence of excessive amounts of such physiologically inert proteins prevents loss of the antibody due to adsorption onto the walls of the containers and tubes used with the infusion solution. When using albumin, a suitable concentration is from 0.5 to 4.5% by weight of the physiological saline solution. Other formulations include liquid or lyophilized formulations. The appropriate dose will of course vary depending on, for example, the particular IL-17 antagonist used, such as, for example, an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as, for example, secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof), the host, the method of administration, and the nature and severity of the condition being treated and the nature of any previous treatment the patient has received. Ultimately, the attending healthcare provider will determine the amount of IL-17 antagonist (e.g., secukinumab) for treating an individual subject. In some embodiments, the attending healthcare provider can administer a low dose of the IL-17 binding molecule and observe the subject's response. In other embodiments, the initial dose(s) of the IL-17 antagonist (e.g., secukinumab) administered to the subject is high and then the dose is titrated down until signs of recurrence occur. Higher doses of the IL-17 antagonist (e.g., secukinumab) can be administered until an optimal therapeutic effect is obtained for the subject, at which point the dose is generally not further increased.

[0154] An IL-17 antagonist, for example, an IL-17 binding molecule (e.g., an IL-17 antibody

[0155] ​​​​​​​​​​​​or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor binding molecule ( For example, the IL-17 antibody or antigen-binding fragment thereof may be administered parenterally, e.g., into the antebrachium or The pharmaceutical compositions of the present disclosure are conveniently administered intravenously into a peripheral vein, intramuscularly, or subcutaneously. The duration of intravenous (iv) therapy with the composition will depend on the severity of the disease being treated and on the individual The administration of the pharmaceutical composition of the present disclosure subcutaneously (sc .) therapy is also contemplated. Healthcare providers may administer IV or s.v. therapy using the pharmaceutical compositions of the present disclosure. c. Determine the appropriate duration and timing of therapy.

[0156] A satisfactory outcome (treatment, prevention, delay in onset of symptoms) is achieved at a cost of approximately 0. 0.05 mg to about 30 mg per kilogram of body weight, more usually about 0.1 mg to about 20 mg per kilogram of body weight It is generally believed that a dose of 1 g is sufficient to achieve this. The frequency of administration ranges from approximately once a day to approximately once every three months. in the range of once every 2 weeks to once every 12 weeks, e.g. or once every 4 to 8 weeks. The frequency of administration will depend, among other things, on the phase of the treatment regimen. do.

[0157] HERCEPTIN™ (trastuzumab), RITUXAN™ (rituximab) The efficacy and safety of antibody drugs, including products such as SYNAGIS (palivizumab), Their use as components is now widespread. The technology for purifying antibodies to pharmaceutical grade is currently Antibodies, such as antibodies against IL-17, are typically administered parenterally. in ready-to-use aqueous dosage form or lyophilized for reconstitution with a suitable diluent prior to administration; In some embodiments of the disclosed methods and uses, the IL-17 antagonist is A tagonist, for example, an IL-17 antibody, for example, secukinumab, is formulated as a lyophilizate. Suitable lyophilizate formulations can be reconstituted with a small volume of liquid (e.g., 2 ml or less) to enable subcutaneous administration and can provide a solution with low levels of antibody aggregation. The composition shall be at least sterile at the time of its formation. The composition shall be non-pyrogenic by nature, for example, less than 1 EU (endotoxin unit, a standard measure) per dose, preferably or less than 0.1 EU per dose. The composition shall preferably be gluten-free. In the formulations disclosed herein, the antibody preferably constitutes at least 80% by weight of the total protein in the formulation (e.g., at least 90%, 95%, 97%, 98%, 99% or more). Thus, the antibody is in a purified form.

[0158] Lyophilizate Techniques for lyophilizing antibodies are well known in the art. For example, Rey & May (2004) Freez e-Drying / Lyophilization Of Pharmaceutical & Biological Products ISBN 0824748689 , WO 92 / 15331, US Patent Application No. 2008 / 0286280, WO 03 / 041637, WO 2008 / 116103, WO 2008 / 029908, WO 2007 / 074880, WO 03 / 00981 7 and WO 98 / 022136 may be referred to. For example, the antibody products SYNAGI S (trademark), REMICADE (trademark), RAPTIVA (trademark), SIMULECT ( trademark), XOLAIR (trademark) and HERCEPTIN (trademark) are available as lyophilizates. are provided. These antibodies are reconstituted to various final concentrations. For example, SIMULECT( trademark) is reconstituted to a concentration of 4 mg / ml antibody, REMICADE(trademark) is 10 m g / ml, HERCEPTIN(trademark) is 21 mg / ml, SYNAGIS (trademark) and RAPTIVA(trademark) are 100 mg / ml, and XOLAIR(trademark) is , 125 mg / ml.

[0159] The lyophilizates of the present disclosure can be reconstituted to an aqueous composition having an anti-IL-17 antibody concentration of at least about 15 mg / ml. The antibody concentration can be higher than about 15 mg / ml, for example, > about 15 mg / ml, > about 20 mg / ml, > about 25 mg / ml, > about 50 mg / ml, > about 75 mg / ml, > about 100 mg / ml, > about 125 mg / m l, > about 150 mg / ml, > about 300 mg / ml, or even higher. The lyophilizates can contain, in addition to the anti-IL-17 antibody, for example, one or more additional components such as (i) sugars, (ii) buffers, (i

[0160] ii) surfactants, and (iv) stabilizers. The inclusion of each of such additional components (i), (ii), and (iii) is typical and can result in a composition having low aggregation of the anti-IL-17 antibody. The inclusion of component (iv) has been shown to further reduce aggregation after storage and is thus advantageous.

[0161] When present, components (i)-(iv) are present at a pre-lyophilization concentration sufficient to maintain the anti-IL-17 antibody in an active and soluble form after storage (under normal conditions) and reconstitution. The components are to be present after reconstitution.

[0162] ​​​​​ Suitable sugars for use with the present invention include, but are not limited to, monosaccharides, disaccharides, and trisaccharides. For example, the sugar can be sucrose, trehalose, raffinose, maltose, sorbitol or mannitol. The sugar can be a sugar alcohol or an amino sugar. Sucrose and trehalose (e.g., at a concentration of about 175 mM to about 300 mM, such as about 175 mM, about 1 80 mM, about 185 mM, about 190 mM, about 195 mM, about 200 mM, about 225 mM, about 250 mM, about 275 mM, about 300 mM) are particularly useful.

[0163] Suitable buffers for use with the present invention include, but are not limited to, histidine buffers, citrate buffers, phosphate buffers, succinate buffers, acetate buffers, or tris buffers. Histidine buffers (e.g., at a concentration of about 5 mM to about 50 mM, such as about 5 mM, about 10 m M, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 4 5 mM, about 50 mM) are particularly useful.

[0164] Suitable surfactants for use with the present invention include, but are not limited to, nonionic surfactants, ionic surfactants, and zwitterionic surfactants. Typical surfactants for use with the present invention are sorbitan fatty acid esters (e.g., sorbitan monocaprylate, sorbitan monolaurate, sorbitan monopalmitate), sorbitan trioleate, glycerin fatty acid esters (e.g., glycerin monocaprylate, mono myristate glycerin, glycerin monostearate), polyglycerin fatty acid esters (e.g., decaglyceryl monostearate, decaglyceryl distearate, mono lauroyl decaglyceryl ether), (e.g., decaglyceryl monostearate, decaglyceryl distearate, monolauroyl decaglyceryl ether), Decaglyceryl oleate), polyoxyethylene sorbitan fatty acid esters (e.g., mono Polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan trioleate, polyoxyethylene sorbitan tristearate), polyoxyethylene sorbitol fatty acid esters (e.g., polyoxyethylene sorbitol tetrastearate, polyoxyethylene sorbitol tetraoleate), polyoxyethylene glycerol fatty acid esters (e.g., polyoxyethylene glyceryl monostearate), polyethylene glycol fatty acid esters (e.g., polyethylene glycol distearate), polyoxyethylene alkyl ethers (e.g., polyoxyethylene lauryl ether), polyoxyethylene polyoxy propylene alkyl ethers (e.g., polyoxyethylene polyoxypropylene glycol, polyoxyethylene polyoxypropylene propyl ether, polyoxyethylene polyoxy propylene cetyl ether), polyoxyethylene alkyl phenyl ethers (e.g., polyoxy ethylene nonyl phenyl 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 poly oxyethylene fatty acid amides (e.g., polyoxyethylene stearic acid amide), C10 ~C18 alkyl sulfates (e.g., sodium cetyl sulfate, sodium lauryl sulfate, o ), etc. Sodium lauryl sulfate), polyoxyethylene having an average addition of 2 to 4 moles of ethylene oxide units Xylene C10-C18 alkyl ether sulfate (e.g., polyoxyethylene lauryl Sodium sulfate) and C1-C18 alkyl sulfosuccinate salts (e.g., lauryl Sodium sulfosuccinate) and natural surfactants such as lecithin, glycerophospholipids, sphingo Myelin lipids (e.g., sphingomyelin) and sucrose esters of C12-C1 8 fatty acids, including but not limited to these. The composition may contain one or more of these surfactants. Preferred surfactants are polyoxyethylene sorbitan Fatty acid esters, e.g., polysorbate 20, 40, 60 or 80. Polysorbate 80 (Tween80) (e.g., at a concentration of about 0.01% to about 0.1%, e.g., about 0. 02%, about 0.04%, about 0.06%, about 0.08%, about 0.1%) is particularly useful.

[0165] The lyophilized product may contain an active ingredient in addition to the antibody. For example, it may contain substances having further pharmacological effects such as chemotherapeutic compounds. For example, it may contain methotrexate, and it is known to include sodium methotrexate in the lyophilized product.

[0166] The pH of the aqueous antibody formulation before lyophilization may be in the range of 4.0 to 8.0, within the range of about 5.5 to about 7.4, e.g., pH values of about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6, about 6.2, about 6.4, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3 and about 7.4 are common.

[0167] An anti-IL-17 antibody of about 25 mg, 50 mg, 75 mg, 150 mg or 300 mg, preferably an anti-IL-17 antibody of 75 mg to 150 mg (e.g., 75 mg or 150 mg) A lyophilized antibody product containing the same is disclosed. Also disclosed is a lyophilized product containing an IL-17 antibody, such as secukinumab, sugar, buffer and surfactant. The composition may also contain a stabilizer.

[0168] (i) preparing an aqueous solution containing an IL-17 antibody, such as secukinumab, sugar, buffer, surfactant and optionally a stabilizer; and (ii) lyophilizing the aqueous solution A method for preparing a lyophilized product is also disclosed.

[0169] Reconstitution product Before the lyophilized product can be administered to a patient, it should be reconstituted with a liquid reconstituting agent (e.g., an aqueous liquid) to obtain a liquid composition (hereinafter "reconstitution product"). The lyophilized product can be reconstituted with reconstituting agents of various volumes (e.g., 0.25 ml, 0.5 ml, 1.0 ml, 1.5

[0170] ml, etc.) (e.g., an aqueous reconstituting agent, e.g., water). This step redissolves the antibody and other components in the lyophilized product to obtain a solution suitable for injection into a patient. The volume of the aqueous substance used for reconstitution may determine the concentration of the antibody in the resulting pharmaceutical composition and may also determine the route of administration. Reconstitution with a volume of reconstituting agent less than the volume before lyophilization gives a more concentrated composition than before lyophilization. As described above, the lyophilized product of the present invention can be reconstituted so as to obtain an aqueous composition containing an anti-IL-17 antibody at a concentration of at least about 75 mg / ml (or higher), and the volume of the reconstituting agent shall be selected accordingly. The volume of the aqueous substance used for reconstitution may determine the concentration of the antibody in the resulting pharmaceutical composition and may also determine the route of administration. Reconstitution with a volume of reconstituting agent less than the volume before lyophilization gives a more concentrated composition than before lyophilization. The volume of the aqueous substance used for reconstitution may determine the concentration of the antibody in the resulting pharmaceutical composition and may also determine the route of administration. Reconstitution with a volume of reconstituting agent less than the volume before lyophilization gives a more concentrated composition than before lyophilization. Reconstitution with a volume of reconstituting agent less than the volume before lyophilization gives a more concentrated composition than before lyophilization. As described above, the lyophilized product of the present invention can be reconstituted so as to obtain an aqueous composition containing an anti-IL-17 antibody at a concentration of at least about 75 mg / ml (or higher), and the volume of the reconstituting agent shall be selected accordingly. The lyophilized product of the present invention can be reconstituted so as to obtain an aqueous composition containing an anti-IL-17 antibody at a concentration of at least about 75 mg / ml (or higher), and the volume of the reconstituting agent shall be selected accordingly. The volume of the reconstituting agent shall be selected accordingly.

[0171] Disclosed herein is a composition comprising an anti-IL-17 antibody, the composition having at least about 25 mg / ml, 50 mg / ml, 75 mg / ml, 150 mg / ml or 30 0 mg / ml, preferably having an antibody concentration of from 75 mg / ml to 150 mg / ml (e.g., 75 mg / ml or 150 mg / ml). Ideally, the volume of the composition is small, e.g., 0.25 to 2.0 ml, to facilitate subcutaneous administration of the IL-17 antagonist.

[0172] Common reconstitution agents for lyophilized antibodies are sterile water or buffer solutions, optionally containing preservatives. If the lyophilized product contains a buffer, the reconstitution agent may contain additional buffer (which may be the same as or different from the buffer in the lyophilized product), or rather may not contain buffer (e.g., WFI, saline). The composition may contain pharmacologically active substances such as chemotherapeutic compounds that promote co-delivery

[0173] with the antibody. When present, the above components (i)-(iv) are pharmaceutically acceptable at the time of use and, simultaneously, maintain the anti-IL-17 antibody in an active and soluble form at a concentration sufficient to maintain it under normal storage conditions after

[0174] reconstitution. In addition to the antibody and water, the composition may contain additional components derived from the lyophilized product and / or the reconstitution agent. Such components include, but are not limited to, buffers, salts, stabilizers, glycerol, alcohol, ​The discussion can be found in Gennaro (2000) Remington: The Science and Practice of Pharmacy, 20th edition, ISBN: 0683306472.

[0175] A recombinant pharmaceutical composition comprising an IL-17 antibody, such as secukinumab, a sugar, a buffer and a surfactant is disclosed. The composition may contain a stabilizer. A method for preparing a reconstitute is also disclosed, which includes the step of mixing a lyophilized product with an aqueous reconstituting agent, wherein the lyophilized product contains an IL-17 antibody, such as secukinumab, a sugar, a buffer, a surfactant and optionally a stabilizer. A method for treating rheumatoid arthritis (RA) is also disclosed, which includes the step of administering a therapeutically effective amount of an IL-17 antagonist to a high-risk RA patient. .

[0176] Disclosed herein is a method for treating rheumatoid arthritis (RA) that includes administering a therapeutically effective amount of an IL-17 antagonist to a high-risk RA patient.

[0177] Also disclosed herein is a method for treating rheumatoid arthritis (RA) that includes a) selecting a patient for treatment based on the patient being a high-risk RA patient, and b) administering a therapeutically effective amount of an IL-17 antagonist to the patient.

[0178] Disclosed herein is a method for treating rheumatoid arthritis (RA) that includes a) assaying a sample from a patient for 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, and b) thereafter treating the patient if the patient is RF+, ACPA+, or RF+ and ACPA+ and the patient has a high level of CRP, high ESR, or high levels of both CRP and high ESR. When having, the step of administering an IL-17 antagonist to a patient, and the method for treating rheumatoid arthritis (RA). It is a method for treating equine rheumatosis (RA).

[0179] Disclosed herein is a method for treating rheumatoid arthritis (RA) that includes the step of administering to a patient a therapeutically effective amount of an IL-17 antagonist, under the condition of selecting a patient for treatment based on a) being RF+, ACPA+, or both RF+ and ACPA+ and b) having a high level of CRP, a high ESR, or both a high level of CRP and a high ESR. In some embodiments, the administering step includes a) administering the IL-17 antagonist to the patient in an induction regimen and b) subsequently administering the IL-17 antagonist to the patient in a maintenance regimen. Disclosed herein is a method for treating rheumatoid arthritis (RA) that includes the step of administering to a patient a therapeutically effective amount of an IL-17 antagonist, under the condition of selecting a patient for treatment based on a) being RF+, ACPA+, or both RF+ and ACPA+ and b) having a high level of CRP, a high ESR, or both a high level of CRP and a high ESR. In some embodiments, the administering step includes a) administering the IL-17 antagonist to the patient in an induction regimen and b) subsequently administering the IL-17 antagonist to the patient in a maintenance regimen. In some embodiments, the administering step includes a) administering the IL-17 antagonist to the patient in an induction regimen and b) subsequently administering the IL-17 antagonist to the patient in a maintenance regimen. In some embodiments, the administering step includes a) administering the IL-17 antagonist to the patient in an induction regimen and b) subsequently administering the IL-17 antagonist to the patient in a maintenance regimen. In some embodiments, the administering step includes a) administering the IL-17 antagonist to the patient in an induction regimen and b) subsequently administering the IL-17 antagonist to the patient in a maintenance regimen.

[0180] Disclosed herein is a method for treating rheumatoid arthritis (RA) that includes the step of administering to a patient a therapeutically effective amount of an IL-17 antagonist, under the condition of selecting a patient for treatment based on a) being RF+, ACPA+, or both RF+ and ACPA+ and b) having a high level of CRP, a high ESR, or both a high level of CRP and a high ESR. In some embodiments, the administering step includes a) administering the IL-17 antagonist to the patient in an induction regimen and b) subsequently administering the IL-17 antagonist to the patient in a maintenance regimen. In some embodiments, the administering step includes a) administering the IL-17 antagonist to the patient in an induction regimen and b) subsequently administering the IL-17 antagonist to the patient in a maintenance regimen. In some embodiments, the administering step includes a) administering the IL-17 antagonist to the patient in an induction regimen and b) subsequently administering the IL-17 antagonist to the patient in a maintenance regimen. In some embodiments, the administering step includes a) administering the IL-17 antagonist to the patient in an induction regimen and b) subsequently administering the IL-17 antagonist to the patient in a maintenance regimen.

[0181] Disclosed herein is a method for treating rheumatoid arthritis (RA) that includes the step of administering to a patient a therapeutically effective amount of an IL-17 antagonist, under the condition of selecting a patient for treatment based on a) being RF+, ACPA+, or both RF+ and ACPA+ and b) having a high level of CRP, a high ESR, or both a high level of CRP and a high ESR. In some embodiments, the administering step includes a) administering the IL-17 antagonist to the patient in an induction regimen and b) subsequently administering the IL-17 antagonist to the patient in a maintenance regimen. In some embodiments, the administering step includes a) administering the IL-17 antagonist to the patient in an induction regimen and b) subsequently administering the IL-17 antagonist to the patient in a maintenance regimen. In some embodiments, the administering step includes a) administering the IL-17 antagonist to the patient in an induction regimen and b) subsequently administering the IL-17 antagonist to the patient in a maintenance regimen. Step (delivering the first dose at week 0, the second dose at week 2, and the third dose at week 4 weeks), and c) then, starting at week 8, administering to the patient the IL-17 antagonist at about 75 mg to about 150 mg twice monthly, monthly, every two months, or every three months, which is a treatment regimen for treating rheumatoid arthritis (RA). Disclosed herein is an IL-17 antagonist for use in treating rheumatoid arthritis (RA),

[0182] characterized by administering the IL-17 antagonist to a patient selected for treatment based on the patient being a high-risk RA patient. Disclosed herein is an IL-17 antagonist for use in treating rheumatoid arthritis (RA), characterized by administering the IL-17 antagonist to a patient selected for treatment based on the patient being a high-risk RA patient. Disclosed herein is an IL-17 antagonist for use in treating rheumatoid arthritis (RA), characterized by administering the IL-17 antagonist to a patient selected for treatment based on the patient being a high-risk RA patient.

[0183] Disclosed herein is an IL-17 antagonist for use in treating high-risk RA patients. In some embodiments, the high-risk RA patient is a) seropositive for rheumatoid factor ( RF+), anti-citrullinated protein antibody (ACPA+), or both RF+ and ACPA+, and b) has a high level of C-reactive protein (CRP), high erythrocyte sedimentation rate (ESR), or both a high level of CRP and a high ESR. In some embodiments, when measured by hsCRP, a high level of CRP is 10 mg / L or higher. In some embodiments, a high ESR is 28 mm / hour or higher. Disclosed herein is a) RF+, ACPA+, or both RF+ and ACPA+

[0184] Disclosed herein is an IL-17 antagonist for use in treating high-risk RA patients, and b) selecting a patient for treatment based on having high levels of CRP, high ESR, or both high levels of CRP and high ESR administering an IL-17 antagonist to the patient, characterized in that it is used for treating rheumatoid arthritis (RA).

[0185] Disclosed herein is an IL-17 antagonist for treating rheumatoid arthritis (RA), which comprises administering the IL-17 antagonist to a high-risk RA patient at a dose of about 10 mg / kg three times (each of the three doses is delivered every other week), and then starting from the first month after the delivery of the third intravenous dose, administering to the patient at a dose of about 75 mg to about 150 mg per month

[0186] Disclosed herein is a method for treating rheumatoid arthritis (RA), which comprises: a) assaying a sample from a patient for i) rheumatoid factor (RF), anti-citrullinated protein antibody (ACPA), or both RF and ACPA, and ii) C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), or both CRP and ESR; b) administering an IL-17 antagonist to the patient when 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

[0187] Disclosed herein is the use of an IL-17 antagonist for the manufacture of a medicament for treating RA, characterized by administering the IL-17 antagonist to a high-risk RA patient

[0188] ​​​​​​​​​​​​ Disclosed herein is the use of an IL-17 antagonist for the manufacture of a medicament for treating RA, which is characterized by administering to a high-risk RA patient during an induction regimen and a subsequent maintenance regimen.

[0189] Disclosed herein is a pharmaceutical composition for treating RA, which contains an IL-17 antagonist as an active ingredient and is administered to a high-risk RA patient.

[0190] Disclosed herein is a pharmaceutical composition for treating RA, which contains an IL-17 antagonist as an active ingredient and is administered to a high-risk RA patient during an induction regimen and a subsequent maintenance regimen.

[0191] Disclosed herein is a treatment regimen for treating RA, which includes a) the step of selecting a high-risk RA patient; b) the step of administering an IL-17 antagonist to the patient at about 10 mg / kg at 0, 2, and 4 weeks; and c) thereafter, starting from the 8th week, administering the IL-17 antagonist to the patient at about 75 mg to about 150 mg once a month.

[0192] Disclosed herein is a) administering an IL-17 binding molecule to a patient in need thereof during an induction regimen to provide an average maximum plasma concentration (C) of the IL-17 binding molecule of about 360 μg / ml; and b) thereafter, administering the IL-17 binding molecule to the patient during a maintenance regimen to i) provide an average steady-state trough level of the IL-17 binding molecule of about 8 μg / ml to about 30 μg / ml and / or ii) provide about 331 mg*day / L to about 1323 mg*day / L. C max ) ​​​​​​​​​​​A method of treating a patient with rheumatoid arthritis (RA) or at high risk of RA, the method including steps that result in an average AUC tau in the steady state. It is a method of treating a patient with RA.

[0193] Disclosed herein is an IL-17 binding molecule, which is administered to a patient in an a) induction regimen to provide an average maximum plasma concentration (C ) of the IL-17 binding molecule of about 360 μg / ml, and then b) administered to the patient in a maintenance regimen to provide i) an average steady state trough level of the IL-17 binding molecule of about 8 μg / ml to about 30 μg / max ml and / or ii) an average AUC tau in the steady state of about 331 mg*day / L to about 1323 mg*day / L. The IL-17 binding molecule is used for treating a patient with RA or at high risk of RA. ml and / or ii) an average AUC tau in the steady state of about 331 mg*day / L to about 1323 mg*day / L. The IL-17 binding molecule is used for treating a patient with RA or at high risk of RA. ml and / or ii) an average AUC tau in the steady state of about 331 mg*day / L to about 1323 mg*day / L. The IL-17 binding molecule is used for treating a patient with RA or at high risk of RA. ml and / or ii) an average AUC tau in the steady state of about 331 mg*day / L to about 1323 mg*day / L. The IL-17 binding molecule is used for treating a patient with RA or at high risk of RA. ml and / or ii) an average AUC tau in the steady state of about 331 mg*day / L to about 1323 mg*day / L. The IL-17 binding molecule is used for treating a patient with RA or at high risk of RA. ml and / or ii) an average AUC tau in the steady state of about 331 mg*day / L to about 1323 mg*day / L. The IL-17 binding molecule is used for treating a patient with RA or at high risk of RA.

[0194] Disclosed herein is a method of treating a patient at high risk of RA, the method including a) administering an IL-17 binding molecule to a patient in an induction regimen to provide an average maximum plasma concentration ( C ) of the IL-17 binding molecule of about 401 μg / ml, and then b) administering the IL-17 binding molecule to the patient in a maintenance regimen to provide i) an average steady state trough level of the IL-17 binding molecule of about 9.4 μg / ml to about 31 μg / ml and / or ii) an average AUC tau in the steady state of about 314 mg*day / L to about 1256 mg*day max ) of the IL-17 binding molecule of about 401 μg / ml, and then b) administering the IL-17 binding molecule to the patient in a maintenance regimen to provide i) an average steady state trough level of the IL-17 binding molecule of about 9.4 μg / ml to about 31 μg / ml and / or ii) an average AUC tau in the steady state of about 314 mg*day / L to about 1256 mg*day / L. / L. / L. / L.

[0195] Disclosed herein is an IL-17 binding molecule, which is administered to a patient in an a) induction regimen to provide an average maximum plasma concentration (C ) of the IL-17 binding molecule of about 401 μg / ml. max ) of the IL-17 binding molecule of about 401 μg / ml. and b) then administered to the patient during the maintenance regimen to provide i) an average steady-state trough level of the IL-17 binding molecule of from about 9.4 μg / ml to about 31 μg / ml and / or ii) an average AUC tau in the steady state of from about 314 mg*day / L to about 1256 mg*day / L, an IL-17 binding molecule for use in treating psoriasis, characterized in that. In some embodiments, the maintenance regimen provides an average steady-state trough level of the IL-17 binding molecule of from about 9.4 μg / ml to about 17.3 μg / ml. In some embodiments, the maintenance provides an average steady-state trough level of the IL-17 binding molecule of about 9.4 μg / ml or about 17.3 μg / ml. In some embodiments, the induction regimen comprises intravenous administration of the IL-17 binding molecule every other week. In some embodiments, the maintenance regimen comprises once-monthly subcutaneous administration of the IL-17 binding molecule. The present disclosure relates to an IL-17 antagonist for use in the preparation of a medicament for treating RA, under the condition of selecting a patient for treatment for the purpose of a) being 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 present disclosure relates to an IL-17 antagonist for use in the manufacture of a medicament for the treatment of RA in a patient characterized by a) being 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 medicament comprising a container, each container containing at least about

[0196] In some embodiments, the maintenance regimen provides an average steady-state trough level of the IL-17 binding molecule of from about 9.4 μg / ml to about 17.3 μg / ml. In some embodiments, the maintenance provides an average steady-state trough level of the IL-17 binding molecule of from about 9.4 μg / ml to about 17.3 μg / ml. In some embodiments, the maintenance provides an average steady-state trough level of the IL-17 binding molecule of about 9.4 μg / ml or about 17.3 μg / ml. In some embodiments, the induction regimen comprises intravenous administration of the IL-17 binding molecule every other week. In some embodiments, the maintenance regimen comprises once-monthly subcutaneous administration of the IL-17 binding molecule. In some embodiments, the maintenance regimen provides an average steady-state trough level of the IL-17 binding molecule of from about 9.4 μg / ml to about 17.3 μg / ml. In some embodiments, the maintenance provides an average steady-state trough level of the IL-17 binding molecule of about 9.4 μg / ml or about 17.3 μg / ml. In some embodiments, the induction regimen comprises intravenous administration of the IL-17 binding molecule every other week. In some embodiments, the maintenance regimen comprises once-monthly subcutaneous administration of the IL-17 binding molecule. In some embodiments, the induction regimen comprises intravenous administration of the IL-17 binding molecule every other week. In some embodiments, the maintenance regimen comprises once-monthly subcutaneous administration of the IL-17 binding molecule. In some embodiments, the induction regimen comprises intravenous administration of the IL-17 binding molecule every other week. In some embodiments, the maintenance regimen comprises once-monthly subcutaneous administration of the IL-17 binding molecule. In some embodiments, the maintenance regimen comprises once-monthly subcutaneous administration of the IL-17 binding molecule.

[0197] The present disclosure relates to an IL-17 antagonist for use in the preparation of a medicament for treating RA, under the condition of selecting a patient for treatment for the purpose of a) being 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 present disclosure relates to an IL-17 antagonist for use in the preparation of a medicament for treating RA, under the condition of selecting a patient for treatment for the purpose of a) being 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 present disclosure relates to an IL-17 antagonist for use in the preparation of a medicament for treating RA, under the condition of selecting a patient for treatment for the purpose of a) being 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 present disclosure relates to an IL-17 antagonist for use in the preparation of a medicament for treating RA, under the condition of selecting a patient for treatment for the purpose of a) being 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.

[0198] The present disclosure relates to an IL-17 antagonist for use in the preparation of a medicament for treating RA, under the condition of selecting a patient for treatment for the purpose of a) being 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 present disclosure relates to an IL-17 antagonist for use in the preparation of a medicament for treating RA, under the condition of selecting a patient for treatment for the purpose of a) being 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 present disclosure relates to an IL-17 antagonist for use in the preparation of a medicament for treating RA, under the condition of selecting a patient for treatment for the purpose of a) being 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. 17 antagonist, the medicament comprising a container, each container containing at least about An amount sufficient to enable delivery of 75 mg to about 150 mg of an IL-17 antagonist is formulated to have an IL-17 antagonist.

[0199] Disclosed herein is an IL-17 antagonist for the manufacture of a medicament for the treatment of RA in a patient who is a) RF+, ACPA+, or both RF+ and ACPA+ and b) characterized as having high levels of CRP, high ESR, or both high levels of CRP and high ESR, wherein the medicament comprises a container, each container being formulated to have an amount of IL-17 antagonist sufficient to enable delivery of at least about 10 mg / kg per unit dose. 10 mg / kg of an IL-17 antagonist per unit dose. is formulated to have an IL-17 antagonist.

[0200] Disclosed herein is an IL-17 antagonist for the manufacture of a medicament for the treatment of RA in a patient who is a) RF+, ACPA+, or both RF+ and ACPA+ and b) characterized as having high levels of CRP, high ESR, or both high levels of CRP and high ESR, wherein the medicament is formulated in a dose that enables intravenous delivery of about 10 mg / kg per unit dose. 17 antagonist, and the medicament is formulated in a dose that enables intravenous delivery of about 10 mg / kg per unit dose. is formulated in a dose that enables intravenous delivery of about 10 mg / kg per unit dose.

[0201] Disclosed herein is an IL-17 antagonist for the manufacture of a medicament for the treatment of RA in a patient who is a) RF+, ACPA+, or both RF+ and ACPA+ and b) characterized as having high levels of CRP, high ESR, or both high levels of CRP and high ESR, wherein the medicament is formulated in a dose that enables subcutaneous delivery of about 75 mg to about 150 mg of an IL-17 antagonist per unit dose. 17 antagonist per unit dose. is formulated in a dose that enables subcutaneous delivery of about 75 mg to about 150 mg of an IL-17 antagonist per unit dose.

[0202] Disclosed herein is an in vitro test method for selecting a patient for the treatment of RA, comprising the step of determining whether the patient is i. RF+, ACPA+, or both RF+ and ACPA+ and ii. has either a high level of CRP, a high ESR, or both a high level of CRP and a high ESR. In some embodiments of the disclosed in vitro test method, the patient is administered an IL-17 antagonist at a dose of about 10 mg / kg three times, with the first dose delivered at week 0, the second dose delivered at week 2, and the third dose delivered at week 4, and then, starting at week 8, an IL-17 agonist is administered to the patient at about 75 mg to about 150 mg twice monthly, monthly, every two months, or every three months, and has an improved treatment response to the following regimen: a) administering an IL-17 antagonist to the patient three times at a dose of about 10 mg / kg, delivering the first dose at week 0, the second dose at week 2, and the third dose at week 4; and a) thereafter, starting at week 8, administering an IL-17 agonist to the patient at about 75 mg to about 150 mg twice monthly, monthly, every two months, or every three months. has an improved treatment response.

[0203] In some embodiments of the disclosed method, kit, use, pharmaceutical composition, and regimen, a high-risk RA patient is a) seropositive for rheumatoid factor (RF+), anti-citrullinated protein antibody ( ACPA+), or both RF+ and ACPA+, and b) has either a high level of C-reactive protein (CRP), a high erythrocyte sedimentation rate (ESR), or both a high level of CRP and a high ESR. In some embodiments, when measured by hsCRP, a high level of CRP is 10 mg / L or greater. In some embodiments, a high ESR is 28 mm / hour or greater. In some embodiments of the disclosed method, kit, use, pharmaceutical composition, and regimen, the administering step comprises administering an IL-17 antagonist to the patient at a dose of about 10 mg / kg and a high level of CRP and a high ESR. In some embodiments, when measured by hsCRP, a high level of CRP is 10 mg / L or greater. In some embodiments, a high ESR is 28 mm / hour or greater. In some embodiments, when measured by hsCRP, a high level of CRP is 10 mg / L or greater. In some embodiments, a high ESR is 28 mm / hour or greater. In some embodiments, a high ESR is 28 mm / hour or greater.

[0204] In some embodiments of the disclosed method, kit, use, pharmaceutical composition, and regimen, the administering step comprises administering an IL-17 antagonist to the patient at a dose of about 10 mg / kg and then, starting at week 8, an IL-17 agonist is administered to the patient at about 75 mg to about 150 mg It includes the step of intravenous administration three times, and each of the said dosages is administered every other week. How many In some embodiments, the step of administration includes subcutaneously administering an IL-17 antagonist to the said patient at a dosage of about 75 mg to about 150 mg, and each of the said dosages is administered once a month. In some embodiments, the step of administration includes: a) administering an IL-17 antagonist to high-risk RA patients in an induction regimen; and b) then administering an IL-17 antagonist to the patients in a maintenance regimen.

[0205] In some embodiments of the disclosed methods, kits, uses, pharmaceutical compositions and regimens the induction regimen includes administering an IL-17 antagonist to the patient three times at a dosage of about 10 mg / kg. In some embodiments, the first dosage of about 10 mg / kg is delivered at week 0, the second dosage of about 10 mg / kg is delivered at week 2, and the third dosage of about 10 mg / kg is delivered at week 4.

[0206] In some embodiments of the disclosed methods, kits, uses, pharmaceutical compositions and regimens the maintenance regimen includes administering an IL-17 antagonist to the patient at about 75 mg to about 300 mg. In some embodiments, the maintenance regimen includes subcutaneously administering an IL-17 antagonist to the patient at about 75 mg to about 300 mg twice a month, once a month, every two months or every three months. In some embodiments, the maintenance regimen begins at week 8 and subcutaneously administers an IL-17 antagonist to the patient at about 75 mg to about 150 mg twice a month, once a month, every two months or every three months. In some embodiments In this case, the maintenance regimen starts only at the 8th week and includes the step of subcutaneously administering an IL-17 antagonist to the patient once a month at about 7 5 mg or about 150 mg.

[0207] In some embodiments of the disclosed methods, kits, uses, pharmaceutical compositions, and regimens before administering the IL-17 antagonist, the patient has received previous RA treatment including the step of administering at least one antirheumatic drug selected from the group consisting of immunosuppressive drugs, disease-modifying antirheumatic drugs (DMARDs), pain management drugs, steroids, non-steroidal anti-inflammatory drugs (NSAIDs), cytokine antagonists, bone anabolic agents, bone antiresorptive agents, and combinations thereof. In some embodiments, before administering the IL-17 antagonist, the patient has shown an insufficient response, has shown failure, or has been intolerant to treatment with a DMARD, a TNF-alpha antagonist, or methotrexate.

[0208] In some embodiments of the disclosed methods, kits, uses, pharmaceutical compositions, and regimens an effective amount of at least one antirheumatic drug selected from the group consisting of immunosuppressive drugs, DMARDs, pain management drugs, steroids, NSAIDs, cytokine antago nists, bone anabolic agents, bone antiresorptive agents, and combinations thereof is further administered to the patient.

[0209] In some embodiments of the disclosed methods, kits, uses, pharmaceutical compositions, and regimens the IL-17 antagonist is administered 3 times at a dose of about 10 mg / kg, and each of said doses is administered every other week. In some embodiments, the IL-17 antagonist is administered at a dose of about 75 mg to about 300 mg, and each of said doses is administered once a month.

[0210] In some embodiments of the disclosed methods, kits, uses, pharmaceutical compositions and regimens , an IL-17 antagonist is administered to a patient in an induction regimen and then in a maintenance regimen to the patient. In some embodiments, the induction regimen comprises administering the IL-17 antagonist to the patient three times at a dose of about 10 mg / kg. In some embodiments , a first dose of about 10 mg / kg is delivered at week zero, a second dose of about 10 mg / kg is delivered at week two, and a third dose of about 10 mg / kg is delivered at week four.

[0211] In some embodiments of the disclosed methods, kits, uses, pharmaceutical compositions and regimens , the maintenance regimen comprises administering the IL-17 antagonist to the patient at about 75 mg to about 300 mg . In some embodiments, the maintenance regimen is administered subcutaneously to the patient at about 75 mg to about 300 mg of the IL-17 antagonist twice monthly, once monthly, every two months or every three months. In some embodiments , the maintenance regimen begins at week eight and comprises administering subcutaneously to the patient at about 75 mg to about 150 mg of the IL-17 antagonist twice monthly, once monthly, every two months or every three months. In some embodiments , the maintenance regimen begins at week eight and comprises administering subcutaneously to the patient at about 75 mg to about 150 mg of the IL-17 antagonist . In some embodiments, the maintenance regimen begins at week eight and comprises administering subcutaneously to the patient once monthly at about 7 5 mg or about 150 mg of the IL-17 antagonist.

[0212] In some embodiments of the disclosed methods, kits, uses, pharmaceutical compositions and regimens , high-risk RA patients are a) seropositive for rheumatoid factor (RF+), anti-citrullinated protein antibody ( ACPA+), or both RF+ and ACPA+, and b) have high levels of C-reactive protein (CRP), high erythrocyte sedimentation rate (ESR), or both high CRP and high ESR.

[0213] In some embodiments of the disclosed methods, kits, uses, pharmaceutical compositions, and regimens the induction regimen maintains trough levels of an IL-17 binding moiety above 80 μg / ml over a 10-week period. In some embodiments, the maintenance regimen results in an average steady-state trough level of the IL-17 binding molecule of from about 8 μg / ml to about 17 μg / ml. In some embodiments, maintenance results in an average steady-state trough level of the IL -17 binding molecule of about 8 μg / ml or about 17 μg / ml.

[0214] In some embodiments of the disclosed methods, kits, uses, pharmaceutical compositions, and regimens the IL-17 antagonist is an IL-17 binding molecule or an IL-17 receptor binding molecule . In some embodiments, the IL-17 binding molecule or IL-17 receptor binding molecule is a) secukinumab, b) an IL-17 antibody that binds to an epitope of IL-17 comprising Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128 , His129, c) an IL-17 antibody that binds to an epitope of IL-17 comprising Tyr4 3, 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 (said epitope being Leu u74, Tyr85, His86, Met87, Asn88, Val124, Thr12 on one chain 5, Pro126, Ile127, Val128, His129, and Tyr4 on the other chain 3, including Tyr44, Arg46, Ala79, Asp80), e) two mature IL- An IL-17 antibody that binds to the 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, and Tyr43, Tyr44, Arg46, Ala79, As p80 on the other chain, and the IL-17 binding molecule has a K of about 100 - 200 pM D and 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: 10 ), iii) an immunoglobulin V L ) domain containing the amino acid sequence shown as SEQ ID NO: 8 and an immunoglobulin V domain containing the amino acid sequence shown as SEQ ID NO: 10, iv) an immunoglobulin V H domain containing the hypervariable regions shown as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 ), v) an immunoglobulin V L domain containing the hypervariable regions shown as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 ), vi) an immunoglobulin V H domain containing the hypervariable regions shown as SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13 ), vii) an immunoglobulin V L domain containing the hypervariable regions shown as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 and an immunoglobulin V domain containing the hypervariable regions shown as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 H ), viii) an immunoglobulin V domain containing the hypervariable regions shown as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 H domain and an immunoglobulin V An immunoglobulin V domain containing hypervariable regions shown as column number 4, sequence number 5, and sequence number 6, and viii) an immunoglobulin V domain containing hypervariable regions shown as sequence number 11, sequence number 12, and sequence number 13, and an immunoglobulin V domain containing hypervariable regions shown as column number 4, sequence number 5, and sequence number 6 L selected from the group consisting of an IL-17 binding molecule (such as an IL-17 antibody) selected from the group consisting of IL-17 antibodies comprising an antibody H In preferred embodiments of the disclosed methods, kits, uses, pharmaceutical compositions, and regimens, the IL-17 binding molecule is a human antibody. In more preferred embodiments of the disclosed methods, kits, uses, pharmaceutical compositions, and regimens, the IL-17 binding molecule is secukinumab As used herein, the phrase "a container having an amount of an IL-17 antagonist sufficient to enable delivery of [designated dose]" refers to a volume of an IL-17 antagonist (such as, as part of a pharmaceutical composition) distributed therein such that a given container (e.g., vial, pen, syringe) can be used to supply the desired dose. By way of example, if the desired dose is 75 mg, a clinician could use 2 ml from a container containing an IL-17 antibody formulation having a concentration of 37.5 mg / ml, 1 ml from a container containing an IL-17 antibody formulation having a concentration of 75 mg / ml, 0.5 ml from a container containing an IL-17 antibody formulation having a concentration of 150 mg / ml, etc. Such L selected from the group consisting of IL-17 antibodies comprising an antibody selected from the group consisting of an immunoglobulin V domain containing hypervariable regions shown as column number 4, sequence number 5, and sequence number 6, and viii) an immunoglobulin V domain containing hypervariable regions shown as sequence number 11, sequence number 12, and sequence number 13, and an immunoglobulin V domain containing hypervariable regions shown as column number 4, sequence number 5, and sequence number 6

[0215] In preferred embodiments of the disclosed methods, kits, uses, pharmaceutical compositions, and regimens, the IL-17 binding molecule is a human antibody. In more preferred embodiments of the disclosed methods, kits, uses, pharmaceutical compositions, and regimens, the IL-17 binding molecule is secukinumab As used herein, the phrase "a container having an amount of an IL-17 antagonist sufficient to enable delivery of [designated dose]" refers to a volume of an IL-17 antagonist (such as, as part of a pharmaceutical composition) distributed therein such that a given container (e.g., vial, pen, syringe) can be used to supply the desired dose. By way of example, if the desired dose is 75 mg, a clinician could use 2 ml from a container containing an IL-17 antibody formulation having a concentration of 37.5 mg / ml, 1 ml from a container containing an IL-17 antibody formulation having a concentration of 75 mg / ml, 0.5 ml from a container containing an IL-17 antibody formulation having a concentration of 150 mg / ml, etc. Such from the group consisting of IL-17 antibodies comprising an antibody selected from the group consisting of an immunoglobulin V domain containing hypervariable regions shown as column number 4, sequence number 5, and sequence number 6, and viii) an immunoglobulin V domain containing hypervariable regions shown as sequence number 11, sequence number 12, and sequence number 13, and an immunoglobulin V domain containing hypervariable regions shown as column number 4, sequence number 5, and sequence number 6

[0216] As used herein, the phrase "a container having an amount of an IL-17 antagonist sufficient to enable delivery of [designated dose]" refers to a volume of an IL-17 antagonist (such as, as part of a pharmaceutical composition) distributed therein such that a given container (e.g., vial, pen, syringe) can be used to supply the desired dose. By way of example, if the desired dose is 75 mg, a clinician could use 2 ml from a container containing an IL-17 antibody formulation having a concentration of 37.5 mg / ml, 1 ml from a container containing an IL-17 antibody formulation having a concentration of 75 mg / ml, 0.5 ml from a container containing an IL-17 antibody formulation having a concentration of 150 mg / ml, etc. Such selected from the group consisting of an immunoglobulin V domain containing hypervariable regions shown as column number 4, sequence number 5, and sequence number 6, and viii) an immunoglobulin V domain containing hypervariable regions shown as sequence number 11, sequence number 12, and sequence number 13, and an immunoglobulin V domain containing hypervariable regions shown as column number 4, sequence number 5, and sequence number 6 selected from the group consisting of IL-17 antibodies comprising an antibody selected from the group consisting of an immunoglobulin V domain containing hypervariable regions shown as column number 4, sequence number 5, and sequence number 6, and viii) an immunoglobulin V domain containing hypervariable regions shown as sequence number 11, sequence number 12, and sequence number 13, and an immunoglobulin V domain containing hypervariable regions shown as column number 4, sequence number 5, and sequence number 6 In preferred embodiments of the disclosed methods, kits, uses, pharmaceutical compositions, and regimens, the IL-17 binding molecule is a human antibody. In more preferred embodiments of the disclosed methods, kits, uses, pharmaceutical compositions, and regimens, the IL-17 binding molecule is secukinumab As used herein, the phrase "a container having an amount of an IL-17 antagonist sufficient to enable delivery of [designated dose]" refers to a volume of an IL-17 antagonist (such as, as part of a pharmaceutical composition) distributed therein such that a given container (e.g., vial, pen, syringe) can be used to supply the desired dose. By way of example, if the desired dose is 75 mg, a clinician could use 2 ml from a container containing an IL-17 antibody formulation having a concentration of 37.5 mg / ml, 1 ml from a container containing an IL-17 antibody formulation having a concentration of 75 mg / ml, 0.5 ml from a container containing an IL-17 antibody formulation having a concentration of 150 mg / ml, etc. Such selected from the group consisting of IL-17 antibodies comprising an antibody selected from the group consisting of an immunoglobulin V domain containing hypervariable regions shown as column number 4, sequence number 5, and sequence number 6, and viii) an immunoglobulin V domain containing hypervariable regions shown as sequence number 11, sequence number 12, and sequence number 13, and an immunoglobulin V domain containing hypervariable regions shown as column number 4, sequence number 5, and sequence number 6 In each such case, these containers have an amount of IL-17 antagonist sufficient to enable delivery of the desired 75 mg dose.

[0217] As used herein, the phrase "dose formulated to enable delivery of [designated dose] by [route of administration]" is used to indicate that a predetermined pharmaceutical composition can be used to supply the desired dose of IL-17 antagonist, e.g., an IL-17 antibody, e.g., secukinumab, by the designated route of administration (e.g., s.c. or i.v.). For example, if the desired subcutaneous dose is 75 mg, the clinician can use 2 ml of an IL-17 antibody formulation having a concentration of 37.5 mg / ml, 1 ml of an IL-17 antibody formulation having a concentration of 75 mg / ml, 0.5 ml of an IL-17 antibody formulation having a concentration of 150 mg / ml, etc. In each such case, these IL-17 antibody formulations are at a sufficiently high concentration to enable subcutaneous delivery of the IL-17 antibody. Subcutaneous delivery typically requires delivery of a volume of less than about 2 ml, preferably a volume of about 1 ml or less.

[0218] In some embodiments, the induction regimen includes administration of 1, 2, 3, 4, 5, 6 or more i.v. doses of an IL-17 antagonist (e.g., secukinumab), e.g., secukinumab, preferably delivered weekly, biweekly, every three weeks or every four weeks (monthly), of 1, 2 or 3 (most preferably 3) doses of secukinumab. In some embodiments, the induction regimen includes administration of 10 mg / kg, i.v. of an IL-17 antagonist (e.g., secukinumab).

[0219] ​​​​​In some embodiments, the loading dose of the IL-17 antagonist (e.g., secukinumab) is administered as three i.v. infusions (e.g., 10 mg / kg) at bi-weekly intervals, i.e., at week 0 (e.g., day 1), week 2 (e.g., about day 15 ) and week 4 (e.g., about day 29). In some embodiments, the loading dose is administered as three i.v. infusions (e.g., 10 mg / kg) at three-week intervals, i.e., at week 0 (e.g., about day 1), week 3 (e.g., about day 22 ) and week 6 (e.g., about day 43). In some embodiments, the loading dose is administered as three i.v. infusions (e.g., 10 mg / kg) at four-week intervals (monthly), i.e., at week 0 (e.g., about day 1), week 4 (e.g., about day 29)

[0220] and week 8 (e.g., about day 57). In some embodiments, the loading dose of the IL-17 antagonist (e.g., secukinumab) is administered as two i.v. infusions (e.g., 10 mg / kg) at bi-weekly intervals, i.e., at week 0 (about day 1) and week 2 (e.g., about day 15). In some embodiments, the loading dose is administered as two i.v. infusions (e.g., 10 mg / kg) at three-week intervals, i.e., at week 0 (e.g., about day 1) and week 3 (e.g., about day 22). In some embodiments, the loading dose is administered as two i.v. infusions (e.g., 10 mg / kg) at four-week intervals (monthly), i.e., at

[0221] week 0 (e.g., about day 1) and week 4 (e.g., about day 29). In some The induction dose can be administered as a single, high-dose injection (e.g., 30 mg / kg). .

[0222] In further embodiments, the induction regimen is daily or weekly for 1, 2, 3, 4, 5, 6 or more s.c. doses of an IL-17 antagonist (e.g., secukinumab), preferably including weekly administration of 3-5 (e.g., 4) doses of secukinumab. In some embodiments, the induction dose that can be administered daily or weekly is about 75 mg to about 300 mg of an IL-17 antagonist (e.g., secukinumab) delivered s.c. ( e.g., about 75 mg to about 150 mg, e.g., about 75 mg or about 150 mg).

[0223] In some embodiments, the induction regimen includes daily s.c. doses of an IL-17 antagonist (e.g., secukinumab) delivered on days 1-7, e.g., daily s.c. doses of secukinumab ( e.g., about 75 mg to about 300 mg, e.g., about 75 mg to about 15 0 mg, e.g., about 75 mg or about 150 mg). In some embodiments, the induction regimen includes weekly s.c. doses of an IL-17 antagonist (e.g., secukinumab) delivered at weeks 0, 1, 2 and 3, e.g., weekly s.c . doses of secukinumab. (e.g., secukinumab), e.g., weekly s.c . doses of secukinumab.

[0224] In other embodiments, the dose(s) of secukinumab administered to the subject in the induction regimen may be higher and more frequent (i.e., weekly for the first month of treatment) and then the patient can be maintained at a lower dose.

[0225] ​​​​In some embodiments, the maintenance regimen is when the patient's weight is less than 90 kg , comprising the step of subcutaneously administering to the patient an IL-17 binding molecule of about 75 mg or about 150 mg . In some embodiments, the maintenance regimen is when the patient's weight is 90 kg or more , comprising the step of subcutaneously administering to the patient an IL-17 binding molecule of about 150 mg or about 300 mg .

[0226] For the maintenance regimen, the dose of the IL-17 antagonist (e.g., secukinumab) can be supplied twice a month (i.e., every two weeks, every half month or every other week, i.e., about every 14 days), monthly (i.e., every four weeks, i.e., about every 28 days), every two months (i.e., every other month or every eight weeks, i.e., about every 56 days) or every three months (i.e., every 12 weeks, i.e., about every 84 days). As used herein, the date of the first dose of the maintenance regimen is measured from the last dose of the induction regimen. Thus, for example , if the last dose of the induction regimen is supplied at week 4, the first dose as part of the maintenance regimen every half month can be delivered at week 6 (about day 43), the first dose as part of the monthly maintenance regimen can be delivered at week 8 (about day 57), the first dose as part of the maintenance regimen every two months can be delivered at week 12 (about day 85), and the first dose as part of the maintenance regimen every three months can be delivered at week 16 (about day 113), etc. In some embodiments, the first dose of the maintenance regimen begins at least one month (i.e., about 4 weeks) after the delivery of the final induction (e.g., s.c. or i.v. induction) dose and is delivered monthly (once a month, about every 4 weeks). In some embodiments ... The first dose of the maintenance regimen is the first dose starting at least one month (i.e., about 4 weeks) after the delivery of the final induction (e.g., s.c. or i.v. induction) dose and is delivered monthly (once a month, about every 4 weeks). In some embodiments In some embodiments, the first dose of the maintenance regimen begins at 1 month (i.e., about 4 weeks) from the delivery of the third i.v. induction dose and is delivered monthly (once a month, about every 4 weeks). In some embodiments, the maintenance regimen is delivered every two weeks, monthly, every two months, or every three months, e.g., about 75 mg to about 300 mg (e.g., about 75 mg to about 150 mg, e.g., about 75 mg or about 150 mg) of an IL-17 antagonist (e.g., secukinumab). In some embodiments, the IL-17 antagonist (e.g., secukinumab) is delivered s.c. during the maintenance regimen. In a preferred embodiment, the maintenance dose is delivered once a month. In some embodiments, the first maintenance dose is delivered at week 6 (e.g., about day 43), week 7 (e.g., about day 50), week 8 (e.g., about day 57), week 9 (e.g., about day 64), week 10 (e.g., about day 71), week 11 (e.g., about day 78), week 12 (e.g., about day 85), or week 13 (e.g., about day 92) of the treatment regimen and then once a month (e.g., about every 4 weeks or about every 28 days).

[0227] In some embodiments, the maintenance regimen begins at week 4, 5, 6, 7, 8, 9, 10, 11, or 12, preferably week 8, and comprises the step of subcutaneously administering to the patient about 75 mg to about 300 mg (e.g., about 75 mg to about 150 mg, e.g., about 75 mg or about 150 mg) of an IL-17 antagonist (e.g., secukinumab) twice a month, once a month, every two months, or every three months. For example, about 75 mg to about 300 mg (e.g., about 75 mg to about 150 mg, e.g., about 75 mg or about 150 mg) of an IL-17 antagonist (e.g., secukinumab). mg, for example, about 75 mg or about 150 mg) of an IL-17 antagonist (e.g., secukinumab). In some embodiments, the IL-17 antagonist (e.g., secukinumab) is included in the maintenance regimen. For example, secukinumab) is delivered s.c. during the maintenance regimen. In a preferred embodiment, the maintenance dose is delivered once a month. In some embodiments, the first maintenance dose is delivered at week 6 (e.g., about day 43), week 7 (e.g., about day 50), week 8 (e.g., about day 57), week 9 (e.g., about day 64), week 10 (e.g., about day 71), week 11 (e.g., about day 78), week 12 (e.g., about day 85), or week 13 (e.g., about day 92) of the treatment regimen and then once a month (e.g., about every 4 weeks or about every 28 days). In some embodiments, the first maintenance dose is delivered at week 6 (e.g., about day 43), week 7 (e.g., about day 50), week 8 (e.g., about day 57), week 9 (e.g., about day 64), week 10 (e.g., about day 71), week 11 (e.g., about day 78), week 12 (e.g., about day 85), or week 13 (e.g., about day 92) of the treatment regimen and then once a month (e.g., about every 4 weeks or about every 28 days). For example, about 43 days), week 7 (e.g., about day 50), week 8 (e.g., about day 57), week 9 (e.g., about day 64), week 10 (e.g., about day 71), week 11 (e.g., about day 78), week 12 (e.g., about day 85), or week 13 (e.g., about day 92) of the treatment regimen and then once a month (e.g., about every 4 weeks or about every 28 days). For example, about 57 days), week 9 (e.g., about day 64), week 10 (e.g., about day 71), week 11 (e.g., about day 78), week 12 (e.g., about day 85), or week 13 (e.g., about day 92) of the treatment regimen and then once a month (e.g., about every 4 weeks or about every 28 days). For example, about 78 days), week 12 (e.g., about day 85), or week 13 (e.g., about day 92) of the treatment regimen and then once a month (e.g., about every 4 weeks or about every 28 days). For example, about 92 days) of the treatment regimen and then once a month (e.g., about every 4 weeks or about every 28 days). In some embodiments, the maintenance regimen begins at week 4, 5, 6, 7, 8, 9, 10, 11, or 12, preferably week 8, and comprises the step of subcutaneously administering to the patient about 75 mg to about 300 mg (e.g., about 75 mg to about 150 mg, e.g., about 75 mg or about 150 mg) of an IL-17 antagonist (e.g., secukinumab) twice a month, once a month, every two months, or every three months. In some embodiments, the maintenance regimen begins at week 4, 5, 6, 7, 8, 9, 10, 11, or 12, preferably week 8, and comprises the step of subcutaneously administering to the patient about 75 mg to about 300 mg (e.g., about 75 mg to about 150 mg, e.g., about 75 mg or about 150 mg) of an IL-17 antagonist (e.g., secukinumab) twice a month, once a month, every two months, or every three months. For example, about 75 mg to about 300 mg (e.g., about 75 mg to about 150 mg, e.g., about 75 mg or about 150 mg) of an IL-17 antagonist (e.g., secukinumab). For example, about 75 mg to about 150 mg, e.g., about 75 mg or about 150 mg) of an IL-17 antagonist (e.g., secukinumab). For example, secukinumab) is delivered s.c. during the maintenance regimen. In a preferred embodiment, the maintenance dose is delivered once a month. In some embodiments, the first maintenance dose is delivered at week 6 (e.g., about day 43), week 7 (e.g., about day 50), week 8 (e.g., about day 57), week 9 (e.g., about day 64), week 10 (e.g., about day 71), week 11 (e.g., about day 78), week 12 (e.g., about day 85), or week 13 (e.g., about day 92) of the treatment regimen and then once a month (e.g., about every 4 weeks or about every 28 days).

[0228] RA patients (e.g., high-risk RA patients) as well as other inflammatory arthritides, e.g., spondyloarthritis , Preferred treatment regimens for treating patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are shown in Table 5. It is understood that administration need not be at an exact time point; for example, the scheduled dose on day 29 can be administered, for example, on days 24

[0229] [Table 5]

[0230] to 34. It will be understood that it can be done.

[0231] In some embodiments, the dose of the IL-17 antagonist (e.g., secukinumab) used in the disclosed induction and / or maintenance regimens (where applicable) is based on the patient's body weight (e.g., if the patient is less than or greater than 75 kg, 80 kg, 85 kg, 90 kg, 95 kg, 10 0 kg, 105 kg, etc., the dose of the IL-17 antagonist, e.g., secukinumab, for delivery to the patient can be determined). In one embodiment where the patient's body weight is about 80 kg or less, about 75 mg or about 150 mg (e.g., s.c. delivery) is administered to the patient. In one embodiment, where the patient's body weight is about 90 k g or less, about 75 mg or about 150 mg (e.g., s.c. delivery) is administered to the patient . In one embodiment, where the patient's body weight is about 100 kg or less, about 7 5 mg or about 150 mg (e.g., s.c. delivery) is administered to the patient. In other embodiments, where the patient's body weight exceeds about 80 kg, about 150 mg or about 300 mg (e.g., s.c. delivery) is administered to the patient. In other embodiments, where the patient's body weight exceeds about 90 kg , about 150 mg or about 300 mg (e.g., s.c. delivery) is administered to the patient. In other embodiments where the patient's body weight exceeds about 90 kg, about 150 mg or about 300 mg (e.g., s.c. delivery) is administered to the patient. In other embodiments where the patient's body weight exceeds about 90 kg, about 150 mg or about 300 mg (e.g., s.c. delivery) is administered to the patient. In an embodiment, if the patient's weight exceeds about 100 kg, about 150 mg or about 3 00 mg (e.g., s.c. delivery) is administered to the patient.

[0232] For certain patients, e.g., patients showing an inadequate response to treatment with an IL-17 antagonist (e.g., secukinumab), an increase in dose may be required (e.g., at the introduction and / or maintenance phase). Thus, the s.c. dose of the IL-17 antagonist (e.g., secukinumab) can be from about 75 mg to about 300 mg, more than s.c., e.g., about 80 mg, about 100 mg, about 125 mg, about 175 mg, about 2 50 mg, about 350 mg, about 400 mg, etc., and similarly, the i.v. dose can be more than about 10 m g / kg, e.g., about 11 mg / kg, 12 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, etc. For certain patients, e.g., patients showing an adverse event or an adverse reaction to treatment with an IL-17 antagonist (e.g., secukinumab), a decrease in dose may also be required (e.g., at the introduction and / or maintenance phase). Thus, the dose of the IL-17 antagonist (e.g., secukinumab) can be from about 75 mg to about 300 mg, less than s.c., e.g., about 25 mg, about 50 mg, about 80 mg, about 100 mg, about 125 mg, about 175 mg, about 2 00 mg, 250 mg, etc., and similarly, the i.v. dose can be less than about 10 mg / kg, e.g., about 9 mg / kg, 8 mg / kg, 5 mg / kg, 4 mg / kg, 3 mg / k

[0233] In some embodiments of the methods, uses, pharmaceutical compositions, kits, and treatment regimens described above CRP levels of about 3 mg / L or greater (e.g., 3 mg / L), about 5 mg / L or greater (e.g., 5 mg / L ), about 10 mg / L or greater (e.g., 10 mg / L), about 15 mg / L or greater (e.g., 15 mg / L) are considered high levels of CRP. In some embodiments CRP levels of 200 nmol / L or greater or 240 nmol / L or greater are considered high CRP levels. In preferred embodiments, for example, when measured by a high-sensitivity CRP assay CRP levels of about 10 mg / L or greater (e.g., 10 mg / L) are considered high C RP levels. In some embodiments, high levels of CRP are greater than about 10 m g / L, greater than about 20 mg / L, or greater than about 30 mg / L.

[0234] In some embodiments of the methods, uses, pharmaceutical compositions, kits, and treatment regimens described above "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 females)) / 2. As a result, "high ESR" > (age (years) + 5 (for females)) / 2. In some embodiments, an ESR of 20 mm / hour or greater is high ESR in females. In some embodiments, an ESR of 15 mm / hour or greater is high ESR in males. In preferred embodiments, an ESR of 28 m m / hour or greater is high ESR.

[0235] In some embodiments of the methods, uses, pharmaceutical compositions, kits, and treatment regimens described above wherein the patient's RF value is greater than 20 IU / ml or greater than 30 IU / ml, the patient is RF+. In some embodiments, when measured by nephelometry, if the patient's R F value is greater than 40 units / ml or greater than 60 units / ml, the patient is RF+ . In some embodiments, when measured by dilution test, if the patient's RF titer is 1: greater than 20 or greater than 1:80, the patient is RF+. In a preferred embodiment , for example, when measured by nephelometry, if the patient's RF value is 12 kU / L (kilo units / liter) or more, the patient is RF+.

[0236] In some embodiments of the methods, uses, pharmaceutical compositions, kits, and treatment regimens described above wherein, for example, when measured by anti-CCP ELISA test, if the patient's ACPA value is 1 U / ml or greater, 3 U / ml or greater, or 5 U / ml or greater, the patient is ACPA +. In a preferred embodiment, if the patient's ACPA value is greater than 20 units / ml (20 U) , the patient is ACPA+.

[0237] Also disclosed herein is a) administering to a high-risk RA patient from about 75 mg to about 300 mg (e.g., from about 75 mg to about 150 mg, e.g., about 75 mg or about 150 mg) of 4 or 5 doses of an IL-17 antagonist, such as an IL-17-binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) or an IL-17 receptor-binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof) (e.g., by subcutaneous administration) (Step of administering subcutaneously) (administering each of 4 or 5 doses once a week) and, b) then, I from about 75 mg to about 300 mg (e.g., from about 75 mg to about 150 mg, e.g., about 75 mg or about 150 mg) of an IL-17 antagonist (e.g., secukinumab) twice a month, once every month, once every two months or once every three months to a patient, and a method for treating rheumatoid arthritis (R A).

[0238] Also disclosed herein is a) i.) a patient who is RF+, ACPA+, or both RF+ and ACPA+, and ii.) based on the criteria that the patient has high levels of CRP, high ESR, or both high levels of CRP and high ESR, selecting a patient having rheumatoid arthritis, b) from about 75 mg to about 300 mg (e.g., from about 75 mg to about 150 mg, e.g., about 75 mg or about 1 50 mg) of 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) administered to the patient once a week for 4 or 5 weeks (e.g., by subcutaneous administration step), and c) then, from about 75 mg to about 300 mg (e.g., from about 75 mg to about 150 mg, e.g., about 75 mg or about 150 mg) of an IL-17 binding molecule administered to the patient twice a month, once every month, once every two months or once every three months (e.g., by subcutaneous administration step), and a treatment regimen for treating RA. For example, from about 75 mg to about 150 mg, e.g., about 75 mg or about 150 mg) of an IL-17 binding molecule administered to the patient twice a month, once every month, once every two months or once every three months (e.g., by subcutaneous administration step), and a treatment regimen for treating RA.

[0239] Disclosed herein is a therapeutically effective amount of an IL-17 antagonist, e.g., an IL- IL-17 binding molecule (e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab mab) or an IL-17 receptor binding molecule (e.g., an IL-17 antibody or its antigen-binding fragment) as an elevation in baseline CRP level (e.g., greater than about 10 mg / L, about 20 mg / L, RA patients exhibiting a serum creatinine concentration of about 100 mg / L or greater, about 30 mg / L or greater, A method for treating rheumatoid arthritis (RA).

[0240] Also disclosed herein are methods for treating a patient suffering from a) an elevated baseline CRP level (e.g., For example, higher than about 10 mg / L, higher than about 20 mg / L, higher than about 30 mg / L) b) selecting a patient with rheumatoid arthritis based on the criterion that the patient has IL-17 antagonists, e.g., IL-17 binding molecules (e.g., IL-17 antibodies or or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor binding molecule (e.g., For example, about 75 mg to about 300 mg (e.g., IL-17 antibody or antigen-binding fragment thereof) , about 75 mg to about 150 mg, for example, about 75 mg or about 150 mg) in 4 or 5 doses or ii) administering to the patient once a week (e.g., subcutaneously) IL-17 antagonists, e.g., IL-17 binding molecules (e.g., IL-17 antibodies or or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor binding molecule (e.g., For example, about 10 mg / kg of IL-17 antibody or its antigen-binding fragment) is administered every three doses. and c) administering to the patient weekly (e.g., iv); and About 75 mg to about 300 mg (e.g., secukinumab) of an L-17 antagonist , about 75 mg to about 150 mg, for example, about 75 mg or about 150 mg) twice a month for one month administering to the patient every, every two months or every three months, preferably once a month (e.g., administering subcutaneously), which is a treatment regimen for treating RA.

[0241] As used herein, an induction regimen, e.g., 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) of about 10 mg / kg of 2 or 3 induction doses (preferably 3 induction doses) to a patient having an arthritis selected from the group consisting of rheumatoid arthritis (RA), spondyloarthritis, ankylosing spondylitis (AS) and psoriatic arthritis (PsA) (e.g., administering intravenously), which is also provided as a method for treating inflammatory arthritis. In some embodiments, the first dose is delivered at week 0, the second dose is delivered at week 2, and the third dose is delivered at week 4. In some embodiments, the first dose is delivered at week 0, the second dose is delivered at week 3, and the third dose is delivered at week 6. In some embodiments, the method further comprises a maintenance regimen, e.g., about 75 mg to about 300 mg (e.g., about 75 mg to about 150 mg, e.g., about 75 mg or about 150 mg) of an IL-17 antagonist (e.g., secukinumab) to the patient (e.g., administering subcutaneously) (administering an IL-17 binding molecule to the patient every two months, once a month, every two months or every three months). In some embodiments, the patient is a high-risk RA patient, e.g., seropositive for rheumatoid factor (RF+ ), anti-cyclic citrullinated peptide antibody (ACPA+), or RF positive, or ​​​both + and ACPA+, and having a high level of C-reactive protein (CRP), high erythrocyte sedimentation rate (ESR) or both a high level of CRP and a high ESR. In some embodiments, the high level of CRP is 10 mg / dL or more. In some embodiments, the high ESR is 28 mm / hour or more. In further embodiments, the inflammatory arthritis is selected from rheumatoid arthritis (RA), spondyloarthritis, ankylosing spondylitis, and psoriatic arthritis. In some embodiments, the patient has RA. In further embodiments, the RA patient is a high-risk RA patient. In further embodiments, the high-risk RA patient is a) seropositive for rheumatoid factor (RF+), anti-citrullinated protein antibody (ACPA+), or both RF+ and ACPA+, and b) has a high level of C-reactive protein (CRP), high erythrocyte sedimentation rate (ESR) or both a high level of CRP and a high ESR.

[0242] In some embodiments, for the treatment of adult patients with moderate to severe active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies, an IL-17 antagonist, such as an IL-17-binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor-binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof) is used in combination with methotrexate. In some embodiments, to reduce signs and symptoms (e.g., swelling, limited movement) in adult patients with moderate to severe active disease, induce a major clinical response, suppress the For example, secukinumab is used alone or in combination with methotrexate or other disease-modifying anti-rheumatic drugs (DMARDs). In some embodiments, to reduce signs and symptoms in patients with moderate to severe active rheumatoid arthritis (RA), induce a major clinical response, suppress the progression of structural damage, and improve physical function, an IL-17 antagonist (e.g., secukinumab) is used alone or in combination with methotrexate. In some embodiments, to reduce signs and symptoms and suppress the progression of structural damage and improve physical function in patients with moderate to severe active rheumatoid arthritis, an IL-17 antagonist (e.g., secukinumab) is used in combination with methotrexate. In some embodiments, an IL-17 antagonist (e.g., secukinumab) is used for the treatment of adults with moderate to severe active rheumatoid arthritis (RA). In some embodiments, an IL-17 antagonist (e.g., secukinumab) is used in combination with methotrexate for the treatment of moderate to severe active rheumatoid arthritis (RA) in adults. In some embodiments, an IL-17 antagonist (e.g., secukinumab) is used to reduce signs and symptoms in moderate to severe active rheumatoid arthritis in patients who were unsuccessful with one or more disease-modifying anti-rheumatic drugs (DMARDs) and to slow the progression of structural damage. In some embodiments, to reduce signs and symptoms, induce a major clinical response, suppress the progression of structural damage, and improve physical function in adult patients with moderate to severe active rheumatoid arthritis, an IL-17 antagonist (e.g., secukinumab) is used as monotherapy or in combination with a disease-modifying anti-rheumatic drug (DMARD). For example, secukinumab is used alone or in combination with methotrexate or other disease-modifying anti-rheumatic drugs (DMARDs). is used. In some embodiments, one or more TNF antagonist therapies are used alone or in combination with methotrexate or other DMARDs to treat adult patients with moderate to severe active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies.

[0243] Combination therapies for the treatment of arthritis In practicing the methods or uses of the present disclosure, a therapeutically effective amount of 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) is administered to a subject, e.g., a mammal (e.g., a human). An IL-17 binding antagonist (e.g., secukinumab) can be administered alone by the methods of the present disclosure or in combination with other agents and therapies for treating, e.g., RA, such as immunosuppressive agents, disease-modifying anti-rheumatic drugs (DMARDs), pain management agents, steroids, non-steroidal anti-inflammatory drugs (NSAIDs), cytokine antagonists, bone anabolic agents, bone antiresorptive agents, and combinations thereof (two-drug and three-drug combination therapies). When administered in combination with one or more additional agents, the IL-17 antagonist (e.g., secukinumab) can be administered simultaneously or sequentially with the other agents. When administered sequentially, the attending physician determines the appropriate order for co-administering the IL-17 antagonist (e.g., secukinumab) with the other agents.

[0244] IL-17 antagonists, such as, for example, secukinumab, useful in combination with non-steroidal anti-inflammatory drugs and pain management drugs for the treatment of patients with RA, such as high-risk RA patients include propionic acid derivatives, acetic acid derivatives, enolic acid derivatives, fenamic acid derivatives, Cox inhibitors, such as lumiracoxib, ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, indomethacin, sulindac, etodolac, ketorolac nabumetone, aspirin, naproxen, valdecoxib, etoricoxib, MK0966, rofecoxib, acetaminophen, celecoxib, diclofenac, tramadol piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic, valdecoxib parecoxib, etodolac, indomethacin, aspirin, ibuprofen filocoxib, and the like.

[0245] IL-17 antagonists, such as, for example, secukinumab, useful in combination with disease-modifying anti-rheumatic drugs (DMARDs) for the treatment of patients with RA, such as high-risk RA patients include methotrexate (MTX), anti-malarial drugs (e.g., hydroxychloroquine and chloroquine) sulfasalazine, leflunomide, azathioprine, cyclosporine, gold salts, minocycline cyclophosphamide, D-penicillamine, minocycline, auranofin, tacrolimus mycophenolate, chlorambucil, and the like.

[0246] IL-17 antagonists, such as, for example, secukinumab, useful in combination with... for the treatment of patients with RA, such as high-risk RA patients If so, biological agents useful in combination with secukinumab) include adalimumab (Humira (registered trademark)), etanercept (Enbrel (registered trademark)), infliximab (Remicade (registered trademark); TA-650), certolizumab pegol (Cimzia (registered trademark); CDP870), golimumab (Simponi (registered trademark); CNTO148 )), anakinra (Kineret (registered trademark)), rituximab (Rituxan (registered trademark); MabThera (registered trademark)), abatacept (Orencia (registered trademark) ), tocilizumab (RoActemra / Actemra (registered trademark)), and the like. Biological agents useful in combination with an IL-17 antagonist (e.g., secukinumab) for the treatment of RA patients, such as high-risk RA patients, include, for example, integrin antagonists (TYSABRI (registered trademark) (natalizumab)), IL-1 antagonists (ACZ885 (ilaris)), anakinra (Kineret (registered trademark)), CD4 antagonists, IL-17 antagonists (LY2439821, RG4934, AMG8 27, SCH900117, R05310074, MEDI-571, CAT-2200

[0247] ), IL-23 antagonists, IL-20 antagonists, IL-6 antagonists, TNF alpha antagonists (e.g., TNF alpha antagonists or TNF alpha receptor antagonists, such as pegsunercept, etc.), BLyS antagonists (e.g., atacicept, Benlysta (registered trademark) / LymphoStat-B (registered trademark) (belimumab)), P38 inhibitors, CD20 antagonists (ocrelizumab, anakinra (Kineret (registered trademark)), CD4 antagonists, IL-17 antagonists (LY2439821, RG4934, AMG8 27, SCH900117, R05310074, MEDI-571, CAT-2200 ), IL-23 antagonists, IL-20 antagonists, IL-6 antagonists, TNF alpha antagonists (e.g., TNF alpha antagonists or TNF alpha receptor antagonists, such as pegsunercept, etc.), BLyS antagonists (e.g., atacicept, Benlysta (registered trademark) / LymphoStat-B (registered trademark) (belimumab)), P38 inhibitors, CD20 antagonists (ocrelizumab, TNF alpha antagonists (e.g., TNF alpha antagonists or TNF alpha receptor antagonists, such as pegsunercept, etc.), BLyS antagonists (e.g., atacicept, Benlysta (registered trademark) / LymphoStat-B (registered trademark) (belimumab)), P38 inhibitors, CD20 antagonists (ocrelizumab, ), etc. Ofatumumab (Arzerra®), interferon gamma antagonist (Fontolizumab), and the like.

[0248] Steroids (e.g., glucocorticoids) useful in combination with an IL-17 antagonist (e.g., secukinumab) for the treatment of RA patients, such as high-risk RA patients, include prednisolone, prednisone, dexamethasone, cortisol, cortisone, hydrocortisone, methylprednisolone, betamethasone, triamcinolone, beclomethasone, fludrocortisone, deoxycorticosterone, aldosterone, and the like.

[0249] Other agents useful in combination with an IL-17 antagonist (e.g., secukinumab) for the treatment of RA patients, such as high-risk RA patients, include SB-681323, Rob803, AZD5672, AD452, SMP114, HZT-501, CP-195,543, doxycycline, vancomycin, CRx-102, AMG108, pioglitazone, SBI-087, SCIO-469, Cura-100, onconxin + bivucide, 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 (registered trademark)), RAD 001, Rapamune, Rapamycin, Hostamatinib, Fentanyl, XOMA052 , CNTO136, JNJ38518168, Imatinib, ATN-103, ISIS1 04838, Folic Acid, Folate, TNFa Quinoid, MM-093, Type II Collagen, VX -509, AMG82770, Masitinib (AB1010), LY2127399, Cycl osporin, SB-681323, MK0663, NNC0151-0000-0000 , ATN-103, CCX354-C, CAM3001, LX3305, Setrorelix , 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, Rosiglit zone, CH-4051, CE-224,535, GSK1827771, GW27415 0, BG9924, PLX3397, TAK-783, INCB028050, LY21 27399, LY3009104, R788, Curcumin (Longvida (trademark)) , Rosuvastatin, PRO283698, AMG714, MTRX1011A, Maraviro c, MEDI-522, MK0663, STA5326 Mesylate, CE-224,53 5, AMG108, BG00012, Ramipril, VX - 702, CRx - 102, LY 2189102, SBI - 087, SB - 681323, CDP870, Milnacipran , PD0360324, PH - 797804, AK106 - 001616, PG - 760 564, PLA - 695, MK0812, ALD518, Coliprostone, Somatropin , tgAAC94 gene therapy vector, MK0359, GW856553, Esomeprazole l, Everolimus, Trastuzumab, bone anabolic agents and bone anti - resorptive agents (e.g., PTH, bisphosphonates (e.g., Zoledronic acid)), JAK1 and JAK2 inhibitors, pan JA K inhibitors, e.g., tetracyclic pyridone 6 (P6), 325, PF - 956980, sclero stin antagonists (e.g., those the contents of which are incorporated herein by reference in their entirety, International Publication No. 09047356, International Publication No. 2000 / 32773, International Publication No. 2006102070, US Patent Application Publication No. 20080227138, US Patent Applica tion Publication No. 20100028335, US Patent Application Publication No. 20030229041, Interna tional Publication No. 2005003158, International Publication No. 2009039175, International Publication No. 20 09079471, International Publication No. 03106657, International Publication No. 2006119062 , International Publication No. 08115732, International Publication No. 2005 / 014650, International Publication No. 2005 / 003158, International Publication No. 2006 / 119107, International Publication No. 2008 / 061013, International Publication No. 2008 / 133722, International Publication No. 2008 / 115 732, US Patent No. 7592429, US Patent No. 7879322, US Patent No. 77 The preferred anti-sclerostin antibodies and antigen-binding fragments thereof disclosed in [the disclosed method, pharmaceutical composition, kit and use are found in International Publication No. 0904735 No. 6 (equivalent to US Patent No. 7879322), International Publication No. 06119107 (equivalent to US Patent No. 7872106 and US Patent No. 7592429) and International Publication No. 0811 No. 5732 (equivalent to US Patent No. 7744874]), denosumab, I L-6 antagonist, CD20 antagonist, CTLA4 antagonist, IL-1 7 antagonist, IL-8 antagonist, IL-21 antagonist, IL-22 a ntagonist, integrin antagonist (Tysarbri® (natalizumab)), scleronstin antagonist ), VGEF antagonist ), CXCL antagonist, MMP antagonist, defensin antagonist, IL -1 antagonist (including IL-1 beta antagonist) and IL-23 antag onist (e.g., receptor decoy, antagonist antibody, etc.), etc. In some embodiments, an IL-17 antagonist (e.g., secukinumab) is

[0250] co-administered with at least one anti-rheumatic drug selected from the group consisting of immunosuppressive drugs, DMARDs, pain management drugs, steroids, NSAIDs, cytokine antag onists, bone anabolic agents, bone antiresorptive agents and combinations thereof. In some embodiments, an IL-17 a ntagonist (e.g., secukinumab) is co-administered with a TNF antagonist, DMARD (e.g. ., MTX, e.g., once-weekly administration of 7.5 - 30 mg), steroid or a combination thereof ).

[0251] One of ordinary skill in the art can recognize the appropriate dosage of the above-mentioned agents for co-delivery with an IL-17 antagonist (e.g., secukinumab).

[0252] Kits and Products Disclosed herein are kits (i.e., products) useful for providing an 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 an IL-17 receptor binding molecule (e.g., an IL-17 antibody or antigen-binding fragment thereof), for the treatment of RA. Such kits may contain an IL-17 antagonist (e.g., secukinumab) (e.g., as a liquid or lyophilized form) or a pharmaceutical composition comprising an IL-17 antagonist (e.g., secukinumab). Further, such kits may contain means for administering an IL-17 antagonist (e.g., secukinumab) (e.g., a syringe or pre-filled pen) and instructions for use. These kits may contain, for example, a further therapeutic agent (described above) for the treatment of RA for co-delivery in combination with the included IL-17 antagonist (e.g., secukinumab).

[0253] Disclosed herein are: a) an 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 an IL-17 receptor binding molecule (e.g., an IL-17 antibody or antigen-binding fragment thereof), and b) instructions regarding administering an IL-17 antagonist (e.g., secukinumab) to a high-risk RA patient, and c) instructions for a patient to take an IL-17 antagonist (e.g., secukinumab). ​​​​​​​​​​​means for administration, and d) optionally, an immunosuppressive agent, a disease-modifying anti-rheumatic drug (DMARD ), a pain management drug, a steroid, a non-steroidal anti-inflammatory drug (NSAID), a cytokine an tagonist, an osteoanabolic agent, an antiresorptive agent, and a kit comprising at least one anti-rheumatic drug in a therapeutically effective amount selected from the group consisting of combinations thereof. In some embodiments , the high-risk RA patient is a) RF+, ACPA+, or both RF+ and ACPA+ and b) has a high level of CRP, a high ESR, or both a high level of CRP and a high ESR .

[0254] Disclosed herein is a) an IL -17 antagonist for use in the treatment of rheumatoid arthritis (RA) in a patient, such as an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor binding molecule (e.g , an IL-17 antibody or an antigen-binding fragment thereof) or a pharmaceutical composition comprising an IL-17 antagonist, and b) an instruction manual describing a method of administering the pharmaceutical composition to a patient , wherein the patient is characterized by i) being RF+, ACPA+, or both RF+ and ACPA+ and ii) having a high level of CRP, a high ESR, or both a high level of CRP and a high ESR .

[0255] Also disclosed herein is an in vitro test method for selecting a patient for the purpose of treating RA, comprising the step of determining whether i. the patient is RF+, ACPA+, or both RF+ and ACP A+ and ii. the patient has a high level of CRP, a high ESR, or both a high level of CR P and a high ESR. In some embodiments of the test method ​​In this regard, the patient is expected to have an improved treatment response to the following regimen. That is, a) i) 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) or an IL-17 receptor binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof) is administered to the patient 3 times at a dose of about 10 mg / kg (the first dose is delivered at week 0, the second dose is delivered at week 2 , and the third dose is delivered at week 4), or ii) 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) or an IL-17 receptor binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof) is administered to the patient once a week for 4 or 5 (preferably 5) doses at a dose of about 75 mg or about 150 mg, and b) thereafter, starting at week 8, once every two months, once a month, every two months or every three months (preferably once a month), an IL-17 antagonist is administered to the patient at a dose of about 75 mg to about 300 mg. These in vitro methods can be carried out on biological samples (e.g., blood, cartilage, bone, serum, etc.) withdrawn from the patient and can be used to determine the mode or course of treatment for an individual patient, e.g., whether to administer an IL-17 antagonist to the patient (alone or in combination with other compounds such as methotrexate, for example) or whether to select an alternative therapy ( e.g., anti-TNF therapy).

[0256] Diagnostic methods and methods for generating information in a transmissible form Disclosed herein is that RA patients have 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 ) or a method of determining (predicting) the likelihood of a favorable response (e.g., reduction of symptoms and signs, reduction of joint damage, improvement of quality of life, etc.) to treatment with an IL-17 receptor-binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof ). Such a method helps a physician determine the course of treatment for an individual RA patient. Also disclosed herein is a sample from a patient for 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

[0257] including the step of assaying. The method for determining the likelihood that an RA patient will respond to treatment with an IL-17 antagonist, e.g., an IL-17-binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor-binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof), wherein the patient is RF+, ACPA+ or RF+ and ACPA+, and the patient has a high level of CRP, high ESR, or a high level of CRP and high ESR, the patient is likely to respond to treatment of RA with an IL-17 antagonist (e.g., secukinumab). In some embodiments before the assay step, the sample is first obtained from the patient (e.g., by withdrawing blood or other biological tissue from the patient). Also disclosed herein is a step of determining whether a patient is a) RF+ and / or ACPA and 2) has a high level of CRP and / or high ESR, including the step of determining whether the patient has a high level of CRP and / or high ESR. biological tissue from the patient).

[0258] Also disclosed herein is a step of determining whether a patient is a) RF+ and / or ACPA and 2) has a high level of CRP and / or high ESR, including the step of determining whether the patient has a high level of CRP and / or high ESR. The patient is administered an IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., IL-17 An antibody or antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor-binding molecule The likelihood of responding to treatment with a IL-17 antibody or antigen-binding fragment thereof A method for predicting whether a patient is RF+, ACPA+, or RF+ and ACPA+. and high levels of CRP, high ESR, or high levels of CRP and high ESR If so, the patient has a high likelihood of or responds to treatment with an IL-17 antagonist. In some embodiments, prior to the determining step, a sample is first obtained from the patient. (e.g., by withdrawing blood or other biological tissue from the patient).

[0259] Also disclosed herein is a method for detecting C-reactive protein (CRP)-based antibodies against a patient sample. The method includes assaying for IL-17 antagonist levels in RA patients. For example, an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof) fragment, e.g., secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof), If the patient has an elevated baseline CRP, the patient is treated with an IL-17 antagonist ( In some embodiments, the patient may respond to treatment of RA with secukinumab. In the method, prior to the assay step, a sample is first obtained from a patient (e.g., blood from a patient). or by extracting other living tissue).

[0260] In these diagnostic and prognostic methods, samples from patients are analyzed using factors (RF, ACPA, CR any conventional means for detecting the level of a factor (e.g., P, ESR), such as radioimmuno-diffusion, electroimmunoassay, immunoturbidimetry, Western blot, Northern blot, ELISA, turbidimetry, fluorescence polarization immunoassay, laser nephelometry analysis, agglutination test, turbidimetric test, measurement of the distance that red blood cells settle over time in a tube (e.g., in the case of ESR), etc., can be assayed. The terms "assay" and "determine" refer to the conversion of a substance from one state to another by subjecting the sample to a physical test, e.g., the conversion of a biological sample, such as a blood sample or other tissue sample. Further, as used herein, the terms "assay" and "determine" are used to refer to testing and / or measuring. Phrases such as "assay a sample from a patient for..." are used to refer to the ability to test a sample (directly or indirectly) for the presence or absence of a given factor or for the level of a specific factor. It is understood that in situations where the presence of a substance represents one possibility and the absence of the substance represents a different possibility, the presence or absence of such a substance can be used as a guide for a therapeutic decision. In some embodiments, prior to treatment with an IL-17 antagonist, a skilled clinician determines whether the patient is a high-risk RA patient. Typically, if the presence or absence of a particular factor or the level of a particular factor has been confirmed, the results can be communicated to a physician or genetic counselor or patient or other researcher. Specifically, the results are communicated to other researchers or a physician or genetic counselor or patient. In some embodiments, prior to treatment with an IL-17 antagonist, a skilled clinician determines whether the patient is a high-risk RA patient.

[0261] Typically, if the presence or absence of a particular factor or the level of a particular factor has been confirmed, the results can be communicated to a physician or genetic counselor or patient or other researcher. Specifically, the results are communicated to other researchers It can be converted into information in a transmissible form that can be transmitted. Such forms can be variable and can be tangible or intangible. Results regarding the presence or absence of RF and / or ACPA, and / or the levels of CRP and / or ESR in the tested individual can be embodied in a descriptive representation, drawing, photograph, chart, image, or any other visual form. For example, an image of a gel electrophoresis of a PCR product can be used to illustrate the results. The descriptive representation and visual forms can be recorded on a tangible medium such as a computer-readable medium such as paper, floppy disk, compact disk, etc., or on an intangible medium, for example, in the form of an electronic medium such as an e-mail or website on the Internet or an intranet. Furthermore, the results regarding the presence or absence of RF and / or ACPA, and / or the levels of CRP and / or ESR in the tested individual can also be recorded in the form of sound and transmitted via any suitable medium, such as an analog or digital cable line, fiber optic cable, etc., by means of a telephone, fax machine, wireless mobile phone, Internet phone, and the like. All such forms (tangible and intangible) constitute "information in a transmissible form". Therefore, information and data regarding test results can be created anywhere in the world and transmitted to different locations. For example, when performing a genotyping assay overseas, the information and data regarding the test results can be generated as described above and converted into a transmissible form. The test results in such a transmissible form can be imported into the United States. Therefore, the present disclosure relates to the presence or absence of RF and / or ACPA, and / or the levels of CRP and / or ESR in an individual Also included is a method of creating information in a form that can be communicated regarding the loop.

[0262] Disclosed herein is a method for creating information in a form that can be communicated regarding a patient having RA, the method comprising: a) assaying a sample from the patient for 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; and b) embodying the results of the assaying step in information in a form that can be communicated. In some embodiments, after the embodying step, a healthcare provider (e.g., a physician) uses the information in a form that can be communicated when making a decision to prescribe one of the treatment regimens disclosed herein using an IL-17 antagonist disclosed herein. In some embodiments, after the embodyi...

Claims

1. A method for treating rheumatoid arthritis (RA) comprising the step of administering a therapeutically effective amount of an IL-17 antagonist to a high-risk RA patient.

2. A method for treating rheumatoid arthritis (RA) comprising: a) selecting a patient for treatment based on the patient being a high-risk RA patient; and b) administering to the patient a therapeutically effective amount of an IL-17 antagonist.

3. The method according to claim 1 or 2, wherein the administering step comprises intravenously administering the IL-17 antagonist to the patient three times at a dose of about 10 mg / kg, each dose being administered every other week.

4. The method according to claim 1 or 2, wherein the administering step comprises subcutaneously administering the IL-17 antagonist to the patient at a dose of about 75 mg to about 150 mg, each dose being administered once a month.

5. The method according to claim 1 or 2, wherein the administering step comprises: a) administering an IL-17 antagonist to a high-risk RA patient in an induction regimen; and b) subsequently administering the IL-17 antagonist to the patient in a maintenance regimen.

6. The method according to claim 5, wherein the induction regimen comprises intravenously administering the IL-17 antagonist to the patient three times at a dose of about 10 mg / kg.

7. The method according to claim 6, wherein a first dose of about 10 mg / kg is delivered at week 0, a second dose of about 10 mg / kg is delivered at week 2, and a third dose of about 10 mg / kg is delivered at week 4.

8. The method according to claim 5, wherein the maintenance regimen comprises subcutaneously administering the IL-17 antagonist to the patient at a dose of about 75 mg to about 300 mg.

9. The method according to claim 8, wherein the maintenance regimen comprises subcutaneously administering the IL-17 antagonist to the patient at a dose of about 75 mg to about 300 mg twice a month, once a month, every two months, or every three months.

10. The method according to claim 9, wherein the maintenance regimen begins at week 8 and comprises subcutaneously administering the IL-17 antagonist to the patient at a dose of about 75 mg to about 150 mg twice a month, once a month, every two months, or every three months.

11. The method according to claim 10, wherein the maintenance regimen begins at week 8 and comprises subcutaneously administering the IL-17 antagonist to the patient at a dose of about 75 mg or about 150 mg once a month.

12. The high-risk RA patient is ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ a) for rheumatoid factor (RF+), anti-citrullinated protein antibody (ACPA+) serum reaction positive, or both RF+ and ACPA+, and b) having a high level of C-reactive protein (CRP), a high erythrocyte sedimentation rate (ESR), or both a high level of CRP and a high ESR, The method according to any one of claims 1 to 11.

13. When measured by hsCRP, the high level of CRP is 10 mg / L or more, as claimed in The method according to claim 12.

14. The method according to claim 12, wherein the high ESR is 28 mm / hour or more.

15. a) RF+, ACPA+, or both RF+ and ACPA+, and b) having a high level of CRP, a high ESR, or both a high level of CRP and a high ESR that selecting a patient for treatment on the condition that a therapeutically effective amount of an IL-17 an tagonist is administered to the patient, a method for treating rheumatoid arthritis (RA) comprising the step of administering.

16. The step of administering comprises a) administering an IL-17 antagonist to the patient in an induction regimen; and b) then administering an IL-17 antagonist to the patient in a maintenance regimen The method according to claim 15.

17. The induction regimen comprises administering the IL-17 antagonist to the patient 3 times at a dose of about 10 mg / kg, as claimed in The method according to claim 16.

18. delivering a first dose of about 10 mg / kg at week 0, a second dose of about 10 mg / kg at week 2, and a third dose of about 10 mg / kg at week 4, as claimed in The method according to claim 17.

19. The maintenance regimen comprises administering the IL-17 antagonist to the patient at about 75 mg to about 300 mg, as claimed in The method according to claim 16.

20. The maintenance regimen comprises subcutaneously administering the IL-17 antagonist to the patient at about 75 mg to about 300 mg twice a month, once a month, every two months, or every three months, as claimed in The method according to claim 19. The method according to claim 19.

21. The maintenance regimen begins at week 8 and subcutaneously administers the IL-17 antagonist to the patient at about 75 mg to about 150 mg twice a month, once a month, every two months, or every three months, as claimed in The method according to claim 20. The method according to claim 20.

22. The maintenance regimen begins at week 8 and administers the IL-17 antagonist to the patient once a month at about 75 mg or The method according to claim 21, comprising the step of subcutaneously administering to a patient at about 150 mg.

23. Prior to administering the IL-17 antagonist, the patient has received previous RA treatment comprising the step of administering at least one anti-rheumatic drug selected from the group consisting of immunosuppressive drugs, disease-modifying anti-rheumatic drugs (DMARDs), pain management drugs, steroids, non-steroidal anti-inflammatory drugs (NSAIDs), cytokine antagonists, bone anabolic agents, bone antiresorptive agents, and combinations thereof. The method according to any one of claims 1 to 22.

24. Prior to administering the IL-17 antagonist, the patient has shown an inadequate response, has shown failure, or has been intolerant to treatment with a DMARD, TNF alpha antagonist, or methotrexate. The method according to claim 23.

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 anti-rheumatic drug selected from the group consisting of immunosuppressive drugs, DMARDs, pain management drugs, steroids, NSAIDs, cytokine antagonists, bone anabolic agents, bone antiresorptive agents, and combinations thereof.

26. A method of treating rheumatoid arthritis (RA) comprising: a) administering an IL-17 antagonist to a high-risk RA patient three times at a dose of about 10 mg / kg (each of the three doses is delivered every other week); b) thereafter, administering the IL-17 antagonist to the patient monthly starting at the first month after the delivery of the third intravenous dose at about 75 mg to about 150 mg.

27. a) i. Selecting a patient having RA based on the criteria that the patient is RF+, ACPA+, or both RF+ and ACPA+ and ii. The patient has a high level of CRP, a high ESR, or both a high level of CRP and a high ESR; b) administering an IL-17 antagonist to the patient three times at a dose of about 10 mg / kg (the first dose is delivered at week 0, the second dose is delivered at week 2, and the third dose is delivered at week 4); c) thereafter, starting at week 8, administering the IL-17 antagonist to the patient at about 75 mg to about 150 mg twice monthly, monthly, every two months, or every three months.

28. a) a sample from the patient ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ i. Rheumatoid factor (RF), anti-citrullinated protein antibody (ACPA), or both RF and ACPA, and ii. C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), or both CRP and ES R assaying steps, and b) Then, when 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, administering an IL-17 antagonist to the patient A method for treating rheumatoid arthritis (RA) comprising.

29. a) Rheumatoid factor (RF), anti-citrullinated protein antibody (ACPA), or both RF and ACPA, and b) C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), or both CRP and ES R including the step of assaying a sample from the patient for, when the patient is RF+, ACPA+, or both RF+ and ACPA+, and the patient has high levels of CR P, high ESR, or both high levels of CRP and high ESR, the patient may respond to treatment of RA with an IL-17 an tagonist, A method for determining the likelihood that an RA patient will respond to treatment with an IL-17 antagonist.

30. An IL-17 antagonist for use in treating rheumatoid arthritis (RA), characterized by administering the IL-17 antagonist to a high-risk RA patient.

31. An IL-17 antagonist for use in treating rheumatoid arthritis (RA), characterized by administering the IL-17 antagonist to a patient selected for treatment based on the patient being a high-risk RA patient.

32. The IL-17 antagonist according to claim 30 or 31, administered three times at a dose of about 10 mg / kg, each of said doses being administered every other week.

33. The IL-17 antagonist according to claim 30 or 31, administered at a dose of about 75 mg to about 300 mg, each of said doses being administered once a month.

34. The IL-17 antagonist according to claim 30 or 31, administered to a patient who requires it during an induction regimen and a subsequent maintenance regimen.

35. The IL-17 antagonist according to claim 34, wherein the induction regimen comprises intravenously administering the IL-17 antagonist to the patient three times at a dose of about 10 mg / kg.

36.

37.

38. ​ ​ ​ ​ ​ Deliver a first dose of about 10 mg / kg at week 0, a second dose of about 10 mg / kg at week 2, and a third dose of about 10 mg / kg at week 4, as claimed in claim 35 The IL-17 antagonist used.

37. The maintenance regimen comprises subcutaneously administering to the patient an IL-17 antagonist at about 75 mg to about 300 mg, as claimed in claim 34 The IL-17 antagonist used.

38. The maintenance regimen comprises, starting at week 8, subcutaneously administering to the patient an IL-17 antagonist at about 75 mg to about 300 mg twice monthly, monthly, every two months, or every three months, as claimed in claim 37 The IL-17 antagonist used.

39. The maintenance regimen comprises, starting at week 8, subcutaneously administering to the patient an IL-17 antagonist at about 75 mg to about 150 mg twice monthly, monthly, every two months, or every three months, as claimed in claim 38 The IL-17 antagonist used.

40. The maintenance regimen comprises, starting at week 8, subcutaneously administering to the patient an IL-17 antagonist at about 75 mg or about 150 mg monthly, as claimed in claim 39.

41. The high-risk RA patient is a) Seropositive for rheumatoid factor (RF+), 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 IL-17 antagonist used according to any one of claims 30 to 40.

42. When measured by hsCRP, a high level of CRP is 10 mg / L or more, as claimed in claim 41 The IL-17 antagonist used.

43. A high ESR is 28 mm / h or more, as claimed in claim 41. The IL-17 antagonist used

44.

44. The IL-17 antagonist used according to claim 41.

45. 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 On the condition that the patient is selected for treatment based on Administering an IL-17 antagonist to a patient, characterized in that it is used for treating rheumatoid arthritis (RA). IL-17 antagonist.

45. ​ Administering an IL-17 antagonist to a patient during an induction regimen and then to the patient during a maintenance regimen The IL-17 antagonist for use according to claim 44, characterized in that it is administered to the patient during a maintenance regimen .

46. The IL-17 antagonist for use according to claim 45, wherein the induction regimen comprises the step of administering the IL-17 antagonist to the patient three times at a dose of about 10 mg / kg .

47. The IL-17 antagonist for use according to claim 46, wherein a first dose of about 10 mg / kg is delivered at week 0, a second dose of about 10 mg / kg is delivered at week 2, and a third dose of about 10 mg / kg is delivered at week 4 . .

48. The IL-17 antagonist for use according to claim 45, wherein the maintenance regimen comprises the step of administering the IL-17 antagonist to the patient at about 75 mg to about 300 mg .

49. The IL-17 antagonist for use according to claim 48, wherein the maintenance regimen comprises the step of subcutaneously administering the IL-17 antagonist to the patient at about 75 mg to about 300 mg twice monthly, monthly, every two months or every three months . .

50. The IL-17 antagonist for use according to claim 49, wherein the maintenance regimen comprises the step of subcutaneously administering the IL-17 antagonist to the patient at about 75 mg to about 150 mg twice monthly, monthly, every two months or every three months, starting at week 8 . .

51. The use according to claim 50, wherein the maintenance regimen comprises the step of subcutaneously administering the IL-17 antagonist to the patient at about 75 mg or about 150 mg monthly, starting at week 8 .

52. Before administering the IL-17 antagonist, the patient has received previous RA treatment comprising administering at least one antirheumatic drug selected from the group consisting of immunosuppressive drugs, disease-modifying antirheumatic drugs (DMARDs), pain management drugs, steroids, non-steroidal anti-inflammatory drugs (NSAIDs), cytokine antagonists, bone anabolic agents, bone antiresorptive agents and combinations thereof . . . The IL-17 antagonist for use according to any one of claims 30 to 51 。

53. Before administering the IL-17 antagonist, the patient has shown an insufficient response, has shown failure or has been intolerant to treatment with a DMARD, a TNF alpha antagonist or methotrexate . The IL-17 antagonist for use according to claim 53

54. Immunosuppressive drugs, DMARDs, pain management drugs, steroids, NSAIDs, cytokine antagonists Therapy selected from the group consisting of bone anabolic agents, bone antiresorptive agents, and combinations thereof Further comprising administering to a patient an effective amount of at least one anti-rheumatic drug, the IL-17 antagonist used according to any one of claims 30 to 51.

55. The IL-17 antagonist is a) Administered to high-risk RA patients three times at a dose of about 10 mg / kg (each of the three doses is delivered every other week), b) Thereafter, starting from the first month after the delivery of the third intravenous dose, about 75 mg to about 15 0 mg per month to the patient An IL-17 antagonist used for treating rheumatoid arthritis (RA), characterized by this.

56. a) A sample from a patient is 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 ES R Assayed for, b) When 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, administer an IL-17 antagonist to the patient An IL-17 antagonist used for treating rheumatoid arthritis (RA), characterized by this.

57. Use of an IL-17 antagonist for the manufacture of a medicament for treating RA, characterized by administering the IL-17 antagonist to high-risk RA patients.

58. Use of an IL-17 antagonist for the manufacture of a medicament for treating RA, characterized by administering the IL-17 antagonist to high-risk RA patients during an induction regimen and a subsequent maintenance regimen.

59. A pharmaceutical composition for treating RA, comprising an IL-17 antagonist as an active ingredient, administered to high-risk RA patients.

60. A pharmaceutical composition for treating RA, comprising an IL-17 antagonist as an active ingredient, administered to high-risk RA patients during an induction regimen and a subsequent maintenance regimen.

61. High-risk RA patients are a) Seropositive 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 according to claim 57 or 58, or the pharmaceutical composition according to claim 59 or 60

62. 。

63. a) a step of selecting high-risk RA patients; b) a step of administering an IL-17 antagonist to the patients at about 10 mg / kg at weeks 0, 2, and 4; c) a step of then administering an IL-17 antagonist to the patients at about 75 mg to about 150 mg starting from week 8 once a month; d) a step of administering an IL-17 antagonist to the patients at about 75 mg to about 150 mg starting from week 8 once a month; e) a step of administering an IL-17 antagonist to the patients at about 75 mg to about 150 mg starting from week 8 once a month; A treatment regimen for treating RA, comprising:

64. a) administering an IL-17 binding molecule to a patient in need thereof during an induction regimen to achieve: The mean maximum plasma concentration (C max ) of the IL-17 binding molecule at 60 μg / ml that results in a step b) a step of then administering an IL-17 binding molecule to the patient during a maintenance regimen to achieve: i) an average steady-state trough level of the IL-17 binding molecule of about 8 μg / ml to about 30 μg / ml and / or ii) an average AUCτ in the steady state of about 331 mg*day / L to about 1323 mg*day / L; A method for treating RA patients or high-risk RA patients, comprising:

65. An IL-17 binding molecule for use in treating RA patients or high-risk RA patients, characterized in that: a) the IL-17 binding molecule is administered to the patient during an induction regimen to achieve an IL-17 binding molecule trough level of about 360 μg / ml; b) the IL-17 binding molecule is then administered to the patient during a maintenance regimen to achieve: i) an average steady-state trough level of the IL-17 binding molecule of about 8 μg / ml to about 30 μg / ml and / or ii) an average AUCτ in the steady state of about 331 mg*day / L to about 1323 mg*day / L.

66. Average maximum plasma concentration (C max ) resulting in The method or use according to claim 63, wherein the induction regimen maintains a trough level of the IL-17 binding molecule above 80 μg / ml over a 10-week period.

67. The method or use according to claim 63, wherein the maintenance regimen results in an average steady-state trough level of the IL-17 binding molecule of about 8 μg / ml to about 17 μg / ml.

68. The method or use according to claim 67, wherein the maintenance results in an average steady-state trough level of the IL-17 binding molecule of about 8 μg / ml or about 17 μg / ml.

69. a) administering an IL-17 binding molecule to a patient in need thereof during an induction regimen to achieve: b) a step of then administering an IL-17 binding molecule to the patient during a maintenance regimen to achieve: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ The average maximum plasma concentration (C max ) that results in a step of 01 μg / ml of the IL-17 binding molecule ​ ​ i) An average steady-state trough level of the IL-17 binding molecule of about 9.4 μg / ml to about 31 μg / ml and / or ii) An average AUCτ in the steady state of about 314 mg*day / L to about 1256 mg*day / L resulting in a step of tau and a method of treating a high-risk RA patient.

69. The IL-17 binding molecule is administered to a patient in an a) induction regimen to achieve an IL-17 binding molecule of about 401 μg / ml, and then administered to the patient in a b) maintenance regimen to Resulting in the average maximum plasma concentration (C max ), and i) an average steady-state trough level of the IL-17 binding molecule of about 9.4 μg / ml to about 31 μg / ml and / or ii) an average AUCτ in the steady state of about 314 mg*day / L to about 1256 mg*day / L resulting in an IL-17 binding molecule for use in treating psoriasis.

70. The method or use according to claim 68 or claim 69, wherein the maintenance regimen results in an average steady-state trough level of the IL-17 binding molecule of about 9.4 μg / ml to about 17.3 μg / ml.

71. The method or use according to claim 70, wherein the maintenance results in an average steady-state trough level of the IL-17 binding molecule of about 9.4 μg / ml or about 17.3 μg / ml.

72. The method or use according to claim 63 or 68, or claim 64 or 69, wherein the induction regimen comprises bi-weekly i.v. administration of the IL-17 binding molecule.

73. The method or use according to claim 63 or 68, or claim 64 or 69, wherein the maintenance regimen comprises monthly s.c. administration of the IL-17 binding molecule.

74. A kit comprising a) a pharmaceutical composition comprising an IL-17 antagonist for use in treating rheumatoid arthritis (RA) in a patient, and b) an instruction manual describing a method of administering the pharmaceutical composition to the patient, wherein the patient is characterized by i) being RF+, AC-PA+, or both RF+ and AC-PA+, and ii) having high levels of CRP, high ESR, or both high levels of CRP and high ESR.

75. Use of an IL-17 antagonist in the preparation of a medicament for treating RA, on the condition that a patient is selected for treatment based on a) being RF+, AC-PA+, or both RF+ and AC-PA+, and b) having high levels of CRP, high ESR, or both high levels of CRP and high ESR.

76. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ a) RF+, ACPA+, or both RF+ and ACPA+, and b) having a high level of CRP, high ESR, or both a high level of CRP and high ESR Use of an IL-17 antagonist for the manufacture of a medicament for the treatment of RA in a patient characterized by wherein the medicament comprises a container, each container containing an amount of IL-17 antagonist sufficient to enable delivery of at least about 75 mg to about 150 mg of IL-17 antagonist per unit dose, and is formulated to have an IL -17 antagonist. **Claim 77** a) RF+, ACPA+, or both RF+ and ACPA+, and b) having a high level of CRP, high ESR, or both a high level of CRP and high ESR Use of an IL-17 antagonist for the manufacture of a medicament for the treatment of RA in a patient characterized by wherein the medicament comprises a container, each container containing an amount of IL-17 antagonist sufficient to enable delivery of at least about 10 mg / kg, and is formulated to have an IL-17 antagonist. Use of an IL-17 antagonist. **Claim 78** a) RF+, ACPA+, or both RF+ and ACPA+, and b) having a high level of CRP, high ESR, or both a high level of CRP and high ESR Use of an IL-17 antagonist for the manufacture of a medicament for the treatment of RA in a patient characterized by wherein the medicament is formulated at a dose that enables intravenous delivery of about 10 mg / kg per unit dose Use of an IL-17 antagonist. **Claim 79** a) RF+, ACPA+, or both RF+ and ACPA+, and b) having a high level of CRP, high ESR, or both a high level of CRP and high ESR Use of an IL-17 antagonist for the manufacture of a medicament for the treatment of RA in a patient characterized by wherein the medicament is formulated at a dose that enables subcutaneous delivery of about 75 mg to about 150 mg of IL-17 antagonist per unit dose, and is formulated to have an IL-17 antagonist Use. **Claim 80** i. The patient is RF+, ACPA+, or both RF+ and ACPA+, and ii. The patient has a high level of CRP, high ESR, or both a high level of CRP and high ESR Having An in vitro test method for selecting a patient for the purpose of treating RA, comprising the step of determining whether In vitro test method. **Claim 81** The patient is on the following regimen, namely a) An IL-17 antagonist is administered to a patient three times at a dose of about 10 mg / kg, wherein the first dose is delivered at week 0, the second dose is delivered at week 2, and the third dose is delivered at week 4 and, a) Thereafter, starting at week 8, the IL-17 antagonist is administered to the patient at about 75 mg to about 150 mg, twice a month, once a month, every two months, or every three months and An in vitro test method according to claim 80, having an improved treatment response compared to. **Claim 82** a) A sample from a patient is i) Assayed for 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 in a step of assaying for, b) A step of embodying the results of step a) in information in a form that can be communicated and A method of creating information in a form that can be communicated regarding a patient having RA, comprising. **Claim 83** The IL-17 antagonist is an IL-17 binding molecule or an IL-17 receptor binding molecule in Any one of claims 1 to 29, claim 63, claims 65 to 68, claims 70 to 73, claims 80 to 82, the kit according to claim 74, claims 30 to 58, claim 61, claims 64 to 67, claims 69 to 73, claims 75 to 79 any one of the uses described in, the pharmaceutical composition according to any one of claims 59 to 61, or the regimen according to claim 62. **Claim 84** The IL-17 binding molecule or IL-17 receptor molecule is a) Secukinumab, b) An IL-17 antibody that binds to an epitope of IL-17 comprising Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129, c) An IL-17 antibody that binds to an epitope of IL-17 comprising Tyr43, 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 comprises Leu74, Tyr85, H is86, Met87, Asn88, Val124, Thr125, Pro126, Il e127, Val128, His129 on one chain and Tyr43, Tyr44, Arg 46, Ala79, Asp80 on the other chain), ​ ​ e) to an epitope of an IL-17 homodimer having two mature IL-17 protein chains An IL-17 antibody that binds (the epitope includes Leu74, Tyr85, H is86, Met87, Asn88, Val124, Thr125, Pro126, Il e127, Val128, His129 on one chain and Tyr43, Tyr44, Arg 46, Ala79, Asp80 on the other chain, and the IL-17 binding molecule has an affinity of about 100 - 200 pM K D having an IL-17 binding molecule with an in vivo half-life of about 4 weeks), and f) i) An immunoglobulin heavy chain variable domain comprising the amino acid sequence shown as SEQ ID NO: 8 (V H ) ii) An immunoglobulin light chain variable domain comprising the amino acid sequence shown as SEQ ID NO: 10 In (V L ), iii) An immunoglobulin V domain comprising the amino acid sequence shown as SEQ ID NO: 8 H domain and an immunoglobulin V domain comprising the amino acid sequence shown as SEQ ID NO: 10 L domain iv) An immunoglobulin comprising hypervariable regions shown as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 Globulin V H domain, v) An immunoglobulin comprising hypervariable regions shown as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 Roburin V L domain, vi) An immunoglobulin comprising hypervariable regions shown as SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13 Immunoglobulin V H domain, vii) An immunoglobulin comprising hypervariable regions shown as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 Immune globulin V H domains and those shown as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 Immunoglobulin V containing a hypervariable region L domain, and viii) An immunoglobulin comprising hypervariable regions shown as SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13 immunoglobulin V containing H domains and as SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6 Immunoglobulin V domain containing the variable region shown L domain An IL-17 binding molecule selected from the group consisting of, the method, use , pharmaceutical composition, kit or regimen according to claim 83. **Claim 85** The method, use, pharmaceutical composition , kit or regimen according to claim 84, wherein the IL-17 binding molecule is secukinumab.

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