FIELD

The present disclosure relates to the field of therapeutic treatment of juvenile idiopathic arthritis, such as systemic juvenile idiopathic arthritis and polyarticular-course juvenile idiopathic arthritis (which comprises polyarticular and extended oligoarticular juvenile idiopathic arthritis). Certain aspects of the invention relate to the use of interleukin-6 receptor (IL-6R) antagonists, such as anti-IL-6R antibodies, to treat systemic juvenile idiopathic arthritis and polyarticular-course juvenile idiopathic arthritis.

BACKGROUND

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease of childhood. JIA is defined by the International League of Associations for Rheumatology (ILAR) as arthritis of unknown etiology with onset before 16 years of age and persists for at least 6 weeks with other known conditions excluded (Petty, R. E. et al., 2001. J Rheumatol. 2004; 31(2):390-2; Giannini, E. H. et al., 1997 Arthritis Rheum. 40(7):1202-9; and Macaubas, C. et al., 2009 Nat Rev Rheumatol. 5(11):616-26). The condition comprises seven subtypes as defined by the ILAR including polyarticular-course JIA and systemic JIA. See Petty, R. E. et al., 2001. J Rheumatol. 2004; 31(2):390-2, incorporated by reference herein in its entirety.

There is no known cure for JIA. While conventional treatments may be utilized for the treatment of affected individuals, more effective treatments for treating persistent types of JIA are needed.

SUMMARY

This disclosure provides, inter alia, methods for treating JIA in a subject in need thereof comprising administering an effective amount of an antibody that specifically binds IL-6R.

In an embodiment, the JIA is systemic JIA (sJA).

In an embodiment, the antibody that specifically binds to the IL-6R comprises a heavy chain variable region of sequence SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO: 2.

In various embodiments, the antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the three complementarity determining regions (CDRs) found within the sequence of SEQ ID NO:1 and wherein the VL comprises the three CDRs found within the sequence of SEQ ID NO:2. In various embodiments, the anti-IL-6R antibody or antigen-binding fragment thereof comprises three heavy chain complementarity determining regions (HCDRs; i.e., HCDR1, HCDR2 and HCDR3) and three light chain complementarity determining regions (LCDRs; i.e., LCDR1, LCDR2 and LCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; the HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; the LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 8.

In an embodiment, the antibody is sarilumab.

In various embodiments, no other disease modifying antirheumatic drug (DMARD) is administered with the antibody. In some embodiments, at least one other DMARD is administered to the subject. In an embodiment, at least one other DMARD is administered to the subject concurrently with or at the same time as the antibody.

In some embodiments, the subject is suffering from at least one symptom of sJIA such as arthritis in at least 1 joint for at least 6 weeks duration with or preceded by fever lasting at least 2 weeks; evanescent erythematous rash predominantly on the trunk and the extremities; generalized lymphadenopathy; hepatomegaly and/or splenomegaly; polyserositis; weight loss; fatigue; malaise; fever; elevated peripheral white blood cell (WBC) count (25 000 to 50 000/mL3); increased platelet count (e.g., >1×106), markedly elevated erythrocyte sedimentation rate (ESR) of >100 mm/h; anemia; and/or a high ferritin level relative to a healthy subject. In an embodiment, treating the subject comprises reducing, slowing or halting the progression of, or otherwise ameliorating any one of (or any combination of) these symptoms.

As used herein, a “symptom” associated with JIA includes any clinical or laboratory (e.g., diagnostic) manifestation associated with JIA and is not limited to what the subject can feel or observe.

In various embodiments, the subject is suffering from at least one symptom of sJIA, such as limping; stiffness when awakening; reluctance of the subject to use an arm or leg; reduced activity level; quotidian, high spiking (e.g., reaching about 40° C. or at least 40° C.) fever; joint swelling; and/or difficulty with fine motor activities. In an embodiment of the method, the at least one symptom of sJIA in the subject is improved after administering the antibody.

In various embodiments of the method, the antibody improves at least one score or metric such as JIA ACR (e.g., JIA ACR30, JIA ACR50, JIA ACR70, JIA ACR90, and JIA ACR100), a JIA ACR component (e.g., count of joints with active arthritis, count of joints with limited range of motion, physician global assessment of disease activity, acute phase reactant such as erythrocyte sedimentation rate or C-reactive protein (CRP), childhood health assessment questionnaire, patient (or parent) global assessment of overall well-being), and/or reduced fever (e.g., in subjects with a fever when the antibody is first administered), reduction from baseline of amount of corticosteroid use (e.g., glucocorticoids), and/or Juvenile Arthritis Disease Activity Score (such as Juvenile Arthritis Disease Activity Score-27). In various embodiments of the method, the improvement is characterized by at least one score or metric, such as JIA ACR30, JIA ACR50, JIA ACR70, JIA ACR90, and/or JIA ACR100. In various embodiments of the method, the improvement is characterized by at least one score or metric, such as physician global assessment of disease activity score, patient or parent assessment of overall well-being, childhood health assessment questionnaire, number of joints with active arthritis, number of joints with limited motion, high sensitivity C-reactive protein, and/or reduced fever (e.g., in subjects with a fever when the antibody is first administered). In various embodiments, the improvement is characterized by at least one biomarker. In various embodiments of the method, the antibody causes clinically inactive disease, as defined by Wallace criteria. Wallace criteria are defined as physician global VAS< 1/10, no active arthritis, no active uveitis, and CRP<10 mg/L. In various embodiments of the method, the antibody causes clinically inactive disease, as defined by Juvenile Arthritis Disease Activity Score-27—CRP≤1. In various embodiments of the method, the antibody causes clinically inactive disease or low disease activity, as defined by Juvenile Arthritis Disease Activity Score-27—CRP≤3.8.

In an embodiment of the method, the subject has an inadequate response to current treatment and is considered as a candidate for a biologic disease modifying antirheumatic drug.

In an embodiment of the method, the subject is between the ages of about 1 and about 17. In other embodiments, the subject is between the ages of about 4 and about 6 or between the ages of about 12 and about 18.

In an embodiment of the method, the subject has either 5 or more active joints, or 2 active joints and systemic symptoms (e.g., a fever). In an embodiment of the method, the subject has either 5 or more active joints or 2 or more active joints and sJIA fever of greater than about 37.5° C. for at least 3 out of any 7 consecutive days despite glucocorticoids at a dose stable for at least 3 days.

An “active joint” is a joint with (i) swelling within the joint not due to deformity, and/or (ii) limitation of motion with either pain or tenderness.

In an embodiment of the method, the JIA is polyarticular-course JIA (pcJIA). In certain embodiments, the pcJIA is extended oligoarticular JIA. In various embodiments, the pcJIA is Rheumatoid factor (RF)-positive polyarticular JIA. In some embodiments, the pcJIA is RF-negative polyarticular JIA. In an embodiment of the method, the subject is between the ages of about 12 and about 14 or between the ages of about 7 and about 9.

In an embodiment, the antibody that specifically binds to the IL-6R comprises a heavy chain variable region of sequence SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO: 2.

In various embodiments, the antibody comprises a VH and a VL, wherein the VH comprises the three CDRs found within the sequence of SEQ ID NO:1 and wherein the VL comprises the three CDRs found within the sequence of SEQ ID NO:2. In various embodiments, the anti-IL-6R antibody or antigen-binding fragment thereof comprises three HCDRs (i.e., HCDR1, HCDR2 and HCDR3) and three LCDRs (i.e., LCDR1, LCDR2 and LCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; the HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; the LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 8.

In an embodiment, the antibody is sarilumab.

In various embodiments, no other DMARD is administered with the antibody. In some embodiments, at least one other DMARD is administered to the subject. In an embodiment, at least one other DMARD is administered to the subject concurrently with or at the same time as the antibody.

In some embodiments, the subject is suffering from at least one symptom of RF-positive polyarticular JIA. In some embodiments, the subject is suffering from at least one symptom of RF-positive polyarticular JIA such as deforming symmetrical polyarthritis that can evolve to joint subluxation (e.g., in a wrist and/or thumb); a joint contracture (e.g., proximal and distal interphalangeals, bone overgrowth of proximal interphalangeals, and finger deformities such as swan-neck or boutonniere deformities); chronic synovial inflammation; articular cartilage loss and erosion of juxta-articular bone; normocytic chronic anemia; elevated ESR and C-reactive protein; white blood cell count; asymptomatic arthritis of the cervical spine; and/or micrognathia. In various embodiments, a subject has joint subluxation (e.g., in a wrist and/or thumb) and/or a joint contracture (e.g., proximal and distal interphalangeals, bone overgrowth of proximal interphalangeals, and finger deformities such as swan-neck or boutonniere deformities). In an embodiment, treating the subject comprises reducing, slowing or halting the progression of, or otherwise ameliorating any one of (or any combination of) these symptoms. In an embodiment of the method, the subject is between the ages of about 12 and about 14.

In various embodiments, the subject is suffering from at least one symptom of RF-negative polyarticular JIA. In various embodiments, the subject is suffering from at least one symptom of RF-negative polyarticular JIA such as symmetrical polyarthritis with reduced motion, muscle weakness, and/or decreased physical function. In an embodiment, treating the subject comprises reducing, slowing or halting the progression of, or otherwise ameliorating any one of (or any combination of) these symptoms. In an embodiment of the method, the subject is between the ages of about 7 and about 9.

In an embodiment, the subject is suffering from at least one symptom of extended oligoarticular JIA. In various embodiments, the subject is suffering from at least one symptom of extended oligoarticular JIA such as an aseptic inflammatory synovitis that affects more than 4 joints (e.g., in larger joints, such as knees, ankles, wrists) after the first 6 months of disease; ambulating with a limp; chronic anterior uveitis; chronic arthritis in a knee or ankle leading to overgrowth of that limb with subsequent leg length discrepancy; muscle atrophy (e.g., in extensor muscles such as vastus lateralis, quadriceps when knee affected); and/or flexion contractures in the knees or wrists. In an embodiment, treating the subject comprises reducing, slowing or halting the progression of, or otherwise ameliorating any one of (or any combination of) these symptoms.

In various embodiments, the subject is suffering from at least one symptom of pcJIA, such as limping; stiffness when awakening; reluctance of the subject to use an arm or leg; reduced activity level; joint swelling; and/or difficulty with fine motor activities.

In an embodiment of the method, the at least one symptom of pcJIA in the subject is improved after administering the antibody. In various embodiments of the method, the improvement is characterized by at least one score or metric, such as JIA ACR30, JIA ACR50, JIA ACR70, JIA ACR90, and JIA ACR100 defined as improvement in ≥ 3/6 of the following core set variables with no more than ⅙ worsened: (i) a physician global assessment of disease activity (e.g., by Visual Analogue Scale (VAS)), (ii) patient or parent assessment of overall well-being, (iii) childhood health assessment questionnaire (e.g., by a Childhood Health Assessment Questionnaire Disability Index (CHAQ-DI)), (iv) number of joints with active arthritis, (v) number of joints with limited motion, and (vi) an index of inflammation (e.g., high sensitivity C-reactive protein). In an embodiment, a JIA ACR30 response is when the ≥ 3/6 core set variables improve ≥30% from baseline with no more than ⅙ worsened by ≥30%.

In various embodiments of the method, the improvement in disease activity is characterized by at least one Juvenile Arthritis Disease Activity Score (such as the Juvenile Arthritis Disease Activity Score-27 that includes 4 measures: Physician global assessment of disease activity, Parent/patient global assessment of well-being, Count of joints with active disease, and Index of inflammation (hs-CRP or ESR level)).

In various embodiments of the method, the improvement is characterized by at least one score or metric, such as physician global assessment of disease activity, patient or parent assessment of overall well-being, childhood health assessment questionnaire, number of joints with active arthritis, number of joints with limited motion, high sensitivity C-reactive protein, and/or Juvenile Arthritis Disease Activity Score (such as Juvenile Arthritis Disease Activity Score-27).

In various embodiments of the method, the antibody causes clinically inactive disease, as defined by Wallace criteria. Wallace criteria are defined as physician global VAS< 1/10, no active arthritis, no active uveitis, and CRP<10 mg/L. In various embodiments of the method, the antibody causes clinically inactive disease, as defined by Juvenile Arthritis Disease Activity Score-27—CRP≤1. In various embodiments of the method, the antibody causes clinically inactive disease or low disease activity, as defined by Juvenile Arthritis Disease Activity Score-27—CRP≤3.8.

In an embodiment of the method, the subject is between the ages of about 2 and about 17.

In various embodiments, the subject has had JIA for at least 6 months. In an embodiment, the subject has had arthritis that affected up to 4 joints during at least the first 6 months of the disease and then evolved to 5 or more joints affected after the at least first 6 months. In some embodiments, the subject has had arthritis that affected up to 4 joints during the first 6 months of the disease and then evolved to 5 or more joints affected after the first 6 months.

In an embodiment of the method, the subject has at least 5 joints with active arthritis. In an embodiment of the method, the subject has arthritis affecting 5 or more joints during the first 6 months of the disease. In an embodiment of the method, the arthritis is rheumatoid factor-negative. Alternatively, in an embodiment, the arthritis is rheumatoid factor-positive.

In an embodiment of the method, the antibody is administered subcutaneously. In various embodiments of the method, the antibody is administered every week, or every two weeks.

In an embodiment of the method, the antibody is administered at a dose from about 2 mg/kg to about 4 mg/kg. In an embodiment, the dose is administered once every week or once every 2 weeks. In various embodiments of the method, the antibody is used at a dose of about 2 mg/kg every week, about 2.5 mg/kg every week, about 2 mg/kg every two weeks, about 2.5 mg/kg every two weeks, about 3 mg/kg every two weeks, and about 4 mg/kg every two weeks. In various embodiments of the method, the antibody is used at a dose listed in Tables 1-5.

In some embodiments of the method, the subject has a body weight less than 30 kg.

In some embodiments of the method, the subject has a body weight of at least about 30 kg. In some embodiments of the method, the subject has a body weight less than 60 kg.

In some embodiments of the method, the subject is 1 to 17 years old.

In some embodiments of the method, the subject is a human and the antibody is a human antibody.

This disclosure further provides a method for treating pcJIA in a subject in need thereof comprising administering an effective amount of an antibody that specifically binds IL-6R, wherein the antibody that specifically binds to the IL-6R comprises a heavy chain variable region of sequence SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2, wherein the antibody is administered at a dose of from about 2 mg/kg to about 4 mg/kg per week or per two weeks, wherein the body weight of the subject is greater than or equal to 10 kg and less than or equal to 60 kg.

In some embodiments of the method, the body weight of the subject is greater than or equal to 30 kg and less than or equal to 60 kg and wherein the antibody is administered at a dose from about 2 mg/kg to about 3 mg/kg every other week or a dose of about 2 mg/kg every week.

In some embodiments of the method, the body weight of the subject is greater than or equal to 30 kg and less than or equal to 60 kg and wherein the antibody is administered at a dose from about 2 mg/kg to about 3 mg/kg once every other week or a dose of about 2 mg/kg once every week.

In some embodiments of the method, the body weight of the subject is greater than or equal to 30 kg and less than or equal to 60 kg and wherein the antibody is administered at a dose of about 2 mg/kg or about 3 mg/kg every other week.

In some embodiments of the method, the body weight of the subject is greater than or equal to 30 kg and less than or equal to 60 kg and wherein the antibody is administered at a dose of about 2 mg/kg or about 3 mg/kg once every other week.

In some embodiments of the method, the body weight of the subject is greater than or equal to 30 kg and less than or equal to 60 kg and wherein the antibody is administered at a dose of 2 mg/kg or 3 mg/kg every other week or 2 mg/kg every week.

In some embodiments of the method, the body weight of the subject is greater than or equal to 30 kg and less than or equal to 60 kg and wherein the antibody is administered at a dose of 2 mg/kg or 3 mg/kg once every other week or 2 mg/kg once every week.

In some embodiments of the method, the body weight of the subject is greater than or equal to 10 kg and less than 30 kg and wherein the antibody is administered at a dose from about 2.5 mg/kg to about 4 mg/kg every other week or a dose of about 2.5 mg/kg every week.

In some embodiments of the method, the body weight of the subject is greater than or equal to 10 kg and less than 30 kg and wherein the antibody is administered at a dose from about 2.5 mg/kg to about 4 mg/kg once every other week or a dose of about 2.5 mg/kg once every week.

In some embodiments of the method, the body weight of the subject is greater than or equal to 10 kg and less than 30 kg and wherein the antibody is administered at a dose of about 2.5 mg/kg or about 4 mg/kg every other week.

In some embodiments of the method, the body weight of the subject is greater than or equal to 10 kg and less than 30 kg and wherein the antibody is administered at a dose of about 2.5 mg/kg or about 4 mg/kg once every other week.

In some embodiments of the method, the body weight of the subject is greater than or equal to 10 kg and less than 30 kg and wherein the antibody is administered at a dose of 2.5 mg/kg or 4 mg/kg every other week or 2.5 mg/kg every week.

In some embodiments of the method, the body weight of the subject is greater than or equal to 10 kg and less than 30 kg and wherein the antibody is administered at a dose of 2.5 mg/kg or 4 mg/kg once every other week or 2.5 mg/kg once every week.

This disclosure further provides a method for treating pcJIA in a subject in need thereof comprising administering an effective amount of an antibody that specifically binds IL-6R, wherein the antibody that specifically binds to the IL-6R comprises a heavy chain variable region of sequence SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2, wherein the body weight of the subject is greater than or equal to 30 kg and less than 33 kg and the antibody is administered at a dose of 61.25 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 33 kg and less than 37.5 kg and the antibody is administered at a dose of 70 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 37.5 kg and less than 42 kg and the antibody is administered at a dose of 78.75 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 42 kg and less than 46.5 kg and the antibody is administered at a dose of 87.5 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 46.5 kg and less than 50.5 kg and the antibody is administered at a dose of 96.25 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 50.5 kg and less than 55 kg and the antibody is administered at a dose of 105 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 55 kg and less than 59.5 kg and the antibody is administered at a dose of 113.75 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 59.5 kg and less than 64 kg and the antibody is administered at a dose of 122.5 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 64 kg and less than 68 kg and the antibody is administered at a dose of 131.25 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 68 kg and less than 72.5 kg and the antibody is administered at a dose of 140 mg once every other week or once every week; or wherein the body weight of the subject is greater than or equal to 72.5 kg and the antibody is administered at a dose of 148.75 mg once every other week or once every week.

This disclosure further provides a method for treating pcJIA in a subject in need thereof comprising administering an effective amount of an antibody that specifically binds IL-6R, wherein the antibody that specifically binds to the IL-6R comprises a heavy chain variable region of sequence SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2, wherein the body weight of the subject is greater than or equal to 30 kg and less than 31 kg and the antibody is administered at a dose of 87.5 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 31 kg and less than 34 kg and the antibody is administered at a dose of 96.25 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 34 kg and less than 37 kg and the antibody is administered at a dose of 105 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 37 kg and less than 39.5 kg and the antibody is administered at a dose of 113.75 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 39.5 kg and less than 42.5 kg and the antibody is administered at a dose of 122.5 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 42.5 kg and less than 45 kg and the antibody is administered at a dose of 131.25 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 45 kg and less than 48.5 kg and the antibody is administered at a dose of 140 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 48.5 kg and less than 51.5 kg and the antibody is administered at a dose of 148.75 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 51.5 kg and less than 54.5 kg and the antibody is administered at a dose of 157.5 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 54.5 kg and less than 57 kg and the antibody is administered at a dose of 166.25 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 57 kg and less than 63 kg and the antibody is administered at a dose of 175 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 63 kg and the antibody is administered at a dose of 192.5 mg once every other week or once every week.

This disclosure further provides a method for treating pcJIA in a subject in need thereof comprising administering an effective amount of an antibody that specifically binds IL-6R, wherein the antibody that specifically binds to the IL-6R comprises a heavy chain variable region of sequence SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2, wherein the body weight of the subject is greater than or equal to 10 kg and less than 12.5 kg and the antibody is administered at a dose of 26.25 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 12.5 kg and less than 16 kg and the antibody is administered at a dose of 35 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 16 kg and less than 19.5 kg and the antibody is administered at a dose of 43.75 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 19.5 kg and less than 23 kg and the antibody is administered at a dose of 52.5 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 23 kg and less than 26.5 kg and the antibody is administered at a dose of 61.25 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 26.5 kg and less than 30 kg and the antibody is administered at a dose of 70 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 30 kg and less than 37.5 kg and the antibody is administered at a dose of 70 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 37.5 kg and less than 42 kg and the antibody is administered at a dose of 78.75 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 42 kg and less than 46.5 kg and the antibody is administered at a dose of 87.5 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 46.5 kg and less than 50.5 kg and the antibody is administered at a dose of 96.25 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 50.5 kg and less than 55 kg and the antibody is administered at a dose of 105 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 55 kg and less than 59.5 kg and the antibody is administered at a dose of 113.75 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 59.5 kg and less than 64 kg and the antibody is administered at a dose of 122.5 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 64 kg and less than 68 kg and the antibody is administered at a dose of 131.25 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 68 kg and less than 72.5 kg and the antibody is administered at a dose of 140 mg once every other week or once every week; or wherein the body weight of the subject is greater than or equal to 72.5 kg and the antibody is administered at a dose of 148.75 mg once every other week or once every week.

This disclosure further provides a method for treating pcJIA in a subject in need thereof comprising administering an effective amount of an antibody that specifically binds IL-6R, wherein the antibody that specifically binds to the IL-6R comprises a heavy chain variable region of sequence SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2, wherein the body weight of the subject is greater than or equal to 10 kg and less than 12.5 kg and the antibody is administered at a dose of 43.75 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 12.5 kg and less than 14.5 kg and the antibody is administered at a dose of 52.5 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 14.5 kg and less than 16.5 kg and the antibody is administered at a dose of 61.25 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 16.5 kg and less than 19 kg and the antibody is administered at a dose of 70 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 19 kg and less than 21 kg and the antibody is administered at a dose of 78.75 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 21 kg and less than 23.5 kg and the antibody is administered at a dose of 87.5 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 23.5 kg and less than 25.5 kg and the antibody is administered at a dose of 96.25 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 25.5 kg and less than 27.5 kg and the antibody is administered at a dose of 105 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 27.5 kg and less than 30 kg and the antibody is administered at a dose of 113.75 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 30 kg and less than 39.5 kg and the antibody is administered at a dose of 113.75 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 39.5 kg and less than 42.5 kg and the antibody is administered at a dose of 122.5 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 42.5 kg and less than 45 kg and the antibody is administered at a dose of 131.25 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 45 kg and less than 48.5 kg and the antibody is administered at a dose of 140 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 48.5 kg and less than 51.5 kg and the antibody is administered at a dose of 148.75 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 51.5 kg and less than 54.5 kg and the antibody is administered at a dose of 157.5 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 54.5 kg and less than 57 kg and the antibody is administered at a dose of 166.25 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 57 kg and less than 60.5 kg and the antibody is administered at a dose of 175 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 60.5 kg and less than 63 kg and the antibody is administered at a dose of 175 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 63 kg and the antibody is administered at a dose of 192.5 mg once every other week or once every week.

This disclosure further provides a method for treating sJIA in a subject in need thereof comprising administering an effective amount of an antibody that specifically binds IL-6R, wherein the antibody that specifically binds to the IL-6R comprises a heavy chain variable region of sequence SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2, wherein the antibody is administered at a dose of from about 2 mg/kg to about 2.5 mg/kg per week or from about 3 mg/kg to about 4 mg/kg per two weeks, wherein the body weight of the subject is greater than or equal to 30 kg and less than or equal to 210 kg.

In some embodiments of the method, the body weight of the subject is greater than or equal to 30 kg and less than or equal to 60 kg and wherein the antibody is administered at a dose of about 2 mg/kg every week or a dose of about 3 mg/kg every other week.

In some embodiments of the method, the body weight of the subject is greater than or equal to 30 kg and less than or equal to 60 kg and wherein the antibody is administered at a dose of about 2 mg/kg once every week or a dose of about 3 mg/kg once every other week.

In some embodiments of the method, the body weight of the subject is greater than or equal to 30 kg and less than or equal to 60 kg and wherein the antibody is administered at a dose of 2 mg/kg every week or a dose of 3 mg/kg every other week.

In some embodiments of the method, the body weight of the subject is greater than or equal to 30 kg and less than or equal to 60 kg and wherein the antibody is administered at a dose of 2 mg/kg once every week or a dose of 3 mg/kg once every other week.

In some embodiments of the method, the body weight of the subject is greater than or equal to 30 kg and less than or equal to 210 kg and wherein the antibody is administered at a dose of about 2.5 mg/kg every week or a dose of about 4 mg/kg every other week.

In some embodiments of the method, the body weight of the subject is greater than or equal to 30 kg and less than or equal to 210 kg and wherein the antibody is administered at a dose of about 2.5 mg/kg once every week or a dose of about 4 mg/kg once every other week.

In some embodiments of the method, the body weight of the subject is greater than or equal to 30 kg and less than or equal to 210 kg and wherein the antibody is administered at a dose of 2.5 mg/kg every week or a dose of 4 mg/kg every other week.

In some embodiments of the method, the body weight of the subject is greater than or equal to 30 kg and less than or equal to 210 kg and wherein the antibody is administered at a dose of 2.5 mg/kg once every week or a dose of 4 mg/kg once every other week.

This disclosure shows an antibody for use in treating JIA in a subject in need thereof, wherein the antibody specifically binds IL-6R.

In an embodiment, the JIA is sJIA.

In an embodiment, the antibody that specifically binds to the IL-6R comprises a heavy chain variable region of sequence SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO: 2.

In various embodiments, the antibody comprises a VH and a VL, wherein the VH comprises the three CDRs found within the sequence of SEQ ID NO:1 and wherein the VL comprises the three CDRs found within the sequence of SEQ ID NO:2. In various embodiments, the anti-IL-6R antibody or antigen-binding fragment thereof comprises three HCDRs (i.e., HCDR1, HCDR2 and HCDR3) and three LCDRs (i.e., LCDR1, LCDR2 and LCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; the HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; the LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 8.

In an embodiment, the antibody is sarilumab.

In various embodiments, no other DMARD is administered with the antibody. In some embodiments, at least one other DMARD is administered to the subject. In an embodiment, at least one other DMARD is administered to the subject concurrently with or at the same time as the antibody.

In some embodiments, the subject is suffering from at least one symptom of sJIA such as arthritis in at least 1 joint for at least 6 weeks duration with or preceded by fever lasting at least 2 weeks; evanescent erythematous rash predominantly on the trunk and the extremities; generalized lymphadenopathy; hepatomegaly and/or splenomegaly; polyserositis; weight loss; fatigue; malaise; fever; elevated peripheral WBC count (25 000 to 50 000/mL3); increased platelet count (e.g., >1×106), markedly elevated ESR of >100 mm/h; anemia; and/or a high ferritin level relative to a healthy subject. In an embodiment, treating the subject comprises reducing, slowing or halting the progression of, or otherwise ameliorating any one of (or any combination of) these symptoms.

In various embodiments, the subject is suffering from at least one symptom of sJIA, such as limping; stiffness when awakening; reluctance of the subject to use an arm or leg; reduced activity level; quotidian, high spiking (e.g., reaching about 40° C. or at least 40° C.) fever; joint swelling; and/or difficulty with fine motor activities. In an embodiment of the antibody, the at least one symptom of sJIA in the subject is improved after administering the antibody.

In various embodiments, the antibody improves at least one score or metric such as JIA ACR (e.g., JIA ACR30, JIA ACR50, JIA ACR70, JIA ACR90, and JIA ACR100), a JIA ACR component (e.g., count of joints with active arthritis, count of joints with limited range of motion, physician global assessment of disease activity, acute phase reactant such as erythrocyte sedimentation rate or C-reactive protein, childhood health assessment questionnaire, patient (or parent) global assessment of overall well-being), and/or reduced fever (e.g., in subjects with a fever when the antibody is first administered), reduction from baseline of amount of corticosteroid use (e.g., glucocorticoids), and/or Juvenile Arthritis Disease Activity Score (such as Juvenile Arthritis Disease Activity Score-27). In various embodiments of the antibody, the improvement is characterized by at least one score or metric, such as JIA ACR30, JIA ACR50, JIA ACR70, JIA ACR90, and/or JIA ACR100. In various embodiments of the antibody, the improvement is characterized by at least one score or metric, such as physician global assessment of disease activity score, patient or parent assessment of overall well-being, childhood health assessment questionnaire, number of joints with active arthritis, number of joints with limited motion, high sensitivity C-reactive protein, and/or reduced fever (e.g., in subjects with a fever when the antibody is first administered). In various embodiments, the improvement is characterized by at least one biomarker.

In various embodiments of the method, the antibody causes clinically inactive disease, as defined by Wallace criteria. Wallace criteria are defined as physician global VAS< 1/10, no active arthritis, no active uveitis, and CRP<10 mg/L. In various embodiments of the method, the antibody causes clinically inactive disease, as defined by Juvenile Arthritis Disease Activity Score-27—CRP≤1. In various embodiments of the method, the antibody causes clinically inactive disease or low disease activity, as defined by Juvenile Arthritis Disease Activity Score-27—CRP≤3.8.

In an embodiment of the use, the subject has an inadequate response to current treatment and is considered as a candidate for a biologic disease modifying antirheumatic drug.

In an embodiment of the use, the subject is between the ages of about 1 and about 17. In other embodiments, the subject is between the ages of about 4 and about 6 or between the ages of about 12 and about 18.

In an embodiment of the use, the subject has either 5 or more active joints, or 2 active joints and systemic symptoms (e.g., a fever). In an embodiment of the antibody, the subject has either 5 or more active joints or 2 or more active joints and sJIA fever of greater than about 37.5° C. for at least 3 out of any 7 consecutive days despite glucocorticoids at a dose stable for at least 3 days.

In an embodiment of the use, the JIA is pcJIA. In certain embodiments, the pcJIA is extended oligoarticular JIA. In various embodiments, the pcJIA is RF-positive polyarticular JIA. In some embodiments, the pcJIA is RF-negative polyarticular JIA.

In an embodiment, the antibody that specifically binds to the IL-6R comprises a heavy chain variable region of sequence SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO: 2.

In various embodiments, the antibody comprises a VH and a VL, wherein the VH comprises the three CDRs found within the sequence of SEQ ID NO:1 and wherein the VL comprises the three CDRs found within the sequence of SEQ ID NO:2. In various embodiments, the anti-IL-6R antibody or antigen-binding fragment thereof comprises three HCDRs (i.e., HCDR1, HCDR2 and HCDR3) and three LCDRs (i.e., LCDR1, LCDR2 and LCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; the HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; the LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 8.

In an embodiment, the antibody is sarilumab.

In various embodiments, no other DMARD is administered with the antibody. In some embodiments, at least one other DMARD is administered to the subject. In an embodiment, at least one other DMARD is administered to the subject concurrently with or at the same time as the antibody.

In some embodiments, the subject is suffering from at least one symptom of RF-positive polyarticular JIA. In some embodiments, the subject is suffering from at least one symptom of RF-positive polyarticular JIA such as deforming symmetrical polyarthritis that can evolve to joint subluxation (e.g., in a wrist and/or thumb); a joint contracture (e.g., proximal and distal interphalangeals, bone overgrowth of proximal interphalangeals, and finger deformities such as swan-neck or boutonniere deformities); chronic synovial inflammation; articular cartilage loss and erosion of juxta-articular bone; normocytic chronic anemia; elevated ESR and C-reactive protein; white blood cell count; asymptomatic arthritis of the cervical spine; and/or micrognathia. In various embodiments, a subject has joint subluxation (e.g., in a wrist and/or thumb) and/or a joint contracture (e.g., proximal and distal interphalangeals, bone overgrowth of proximal interphalangeals, and finger deformities such as swan-neck or boutonniere deformities). In an embodiment, treating the subject comprises reducing, slowing or halting the progression of, or otherwise ameliorating any one of (or any combination of) these symptoms.

In various embodiments, the subject is suffering from at least one symptom of RF-negative polyarticular JIA. In various embodiments, the subject is suffering from at least one symptom of RF-negative polyarticular JIA such as symmetrical polyarthritis with reduced motion, muscle weakness, and/or decreased physical function. In an embodiment, treating the subject comprises reducing, slowing or halting the progression of, or otherwise ameliorating any one of (or any combination of) these symptoms.

In an embodiment, the subject is suffering from at least one symptom of extended oligoarticular JIA, In an embodiment, the subject is suffering from at least one symptom of extended oligoarticular JIA such as an aseptic inflammatory synovitis that affects more than 4 joints (e.g., in larger joints, such as knees, ankles, wrists) after the first 6 months of disease; ambulating with a limp; chronic anterior uveitis; chronic arthritis in a knee or ankle leading to overgrowth of that limb with subsequent leg length discrepancy; muscle atrophy (e.g., in extensor muscles such as vastus lateralis, quadriceps when knee affected); and/or flexion contractures in the knees or wrists. In an embodiment, treating the subject comprises reducing, slowing or halting the progression of, or otherwise ameliorating any one of (or any combination of) these symptoms.

In various embodiments, the subject is suffering from at least one symptom of pcJIA, such as limping; stiffness when awakening; reluctance of the subject to use an arm or leg; reduced activity level; joint swelling; and/or difficulty with fine motor activities.

In an embodiment of the antibody, the at least one symptom of pcJIA in the subject is improved after administering the antibody. In various embodiments of the antibody, the improvement is characterized by at least one score or metric, such as JIA ACR30, JIA ACR50, JIA ACR70, JIA ACR90, and JIA ACR100 defined as improvement in ≥ 3/6 of the following core set variables with no more than ⅙ worsened: (i) a physician global assessment of disease activity (e.g., by Visual Analogue Scale (VAS)), (ii) patient or parent assessment of overall well-being, (iii) childhood health assessment questionnaire (e.g., by a CHAQ-DI), (iv) number of joints with active arthritis, (v) number of joints with limited motion, and (vi) an index of inflammation (e.g., high sensitivity C-reactive protein). In an embodiment, a JIA ACR30 response is when the ≥ 3/6 core set variables improve ≥30% from baseline with no more than ⅙ worsened by ≥30%.

In various embodiments of the antibody, the improvement in disease activity is characterized by at least one Juvenile Arthritis Disease Activity Score (such as the Juvenile Arthritis Disease Activity Score-27 that includes 4 measures: Physician global assessment of disease activity, Parent/patient global assessment of well-being, Count of joints with active disease, and Index of inflammation (hs-CRP or ESR level)).

In various embodiments of the antibody, the improvement is characterized by at least one score or metric, such as physician global assessment of disease activity, patient or parent assessment of overall well-being, childhood health assessment questionnaire, number of joints with active arthritis, number of joints with limited motion, high sensitivity C-reactive protein, and/or Juvenile Arthritis Disease Activity Score (such as Juvenile Arthritis Disease Activity Score-27).

In an embodiment of the antibody, the subject is between the ages of about 2 and about 17.

In various embodiments, the subject has had JIA for at least 6 months. In an embodiment, the subject has had arthritis that affected up to 4 joints during at least the first 6 months of the disease and then evolved to 5 or more joints affected after the at least first 6 months. In some embodiments, the subject has had arthritis that affected up to 4 joints during the first 6 months of the disease and then evolved to 5 or more joints affected after the first 6 months.

In an embodiment of the antibody, the subject has at least 5 joints with active arthritis. In an embodiment of the antibody, the subject has arthritis affecting 5 or more joints during the first 6 months of the disease. In an embodiment of the antibody, the arthritis is rheumatoid factor-negative. Alternatively, in an embodiment, the arthritis is rheumatoid factor-positive.

In an embodiment, the antibody is administered subcutaneously. In various embodiments, the antibody is administered every week, or every two weeks.

In an embodiment, the antibody is administered at a dose from about 2 mg/kg to about 4 mg/kg. In an embodiment, the dose is administered once every week or once every 2 weeks. In various embodiments, the antibody is used at a dose of about 2 mg/kg every week, about 2.5 mg/kg every week, about 2 mg/kg every two weeks, about 2.5 mg/kg every two weeks, about 3 mg/kg every two weeks, and about 4 mg/kg every two weeks. In various embodiments, the antibody is used at a dose listed in Tables 1-5.

In some embodiments, the subject has a body weight of at least about 10 kg. In some embodiments, the subject has a body weight less than 30 kg.

In some embodiments, the subject has a body weight of at least about 30 kg.

In some embodiments, the subject has a body weight less than 60 kg.

In various embodiments, the subject is 1 to 17 years old.

In certain embodiments, the subject is a human and the antibody is a human antibody.

This disclosure further provides an antibody for use in treating pcJIA in a subject in need thereof, wherein the antibody specifically binds IL-6R, wherein the antibody that specifically binds to the IL-6R comprises a heavy chain variable region of sequence SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2, wherein the antibody is administered at a dose of from about 2 mg/kg to about 4 mg/kg per week or per two weeks, wherein the body weight of the subject is greater than or equal to 10 kg and less than or equal to 60 kg.

In some embodiments, the body weight of the subject is greater than or equal to 30 kg and less than or equal to 60 kg and wherein the antibody is administered at a dose from about 2 mg/kg to about 3 mg/kg every other week or a dose of about 2 mg/kg every week.

In certain embodiments, the body weight of the subject is greater than or equal to 30 kg and less than or equal to 60 kg and wherein the antibody is administered at a dose from about 2 mg/kg to about 3 mg/kg once every other week or a dose of about 2 mg/kg once every week.

In various embodiments, the body weight of the subject is greater than or equal to 30 kg and less than or equal to 60 kg and wherein the antibody is administered at a dose of about 2 mg/kg or about 3 mg/kg every other week.

In some embodiments, the body weight of the subject is greater than or equal to 30 kg and less than or equal to 60 kg and wherein the antibody is administered at a dose of about 2 mg/kg or about 3 mg/kg once every other week.

In various embodiments, the body weight of the subject is greater than or equal to 30 kg and less than or equal to 60 kg and wherein the antibody is administered at a dose of 2 mg/kg or 3 mg/kg every other week or 2 mg/kg every week.

In certain embodiments, the body weight of the subject is greater than or equal to 30 kg and less than or equal to 60 kg and wherein the antibody is administered at a dose of 2 mg/kg or 3 mg/kg once every other week or 2 mg/kg once every week.

In some embodiments, the body weight of the subject is greater than or equal to 10 kg and less than 30 kg and wherein the antibody is administered at a dose from about 2.5 mg/kg to about 4 mg/kg every other week or a dose of about 2.5 mg/kg every week.

In various embodiments, the body weight of the subject is greater than or equal to 10 kg and less than 30 kg and wherein the antibody is administered at a dose from about 2.5 mg/kg to about 4 mg/kg once every other week or a dose of about 2.5 mg/kg once every week.

In certain embodiments, the body weight of the subject is greater than or equal to 10 kg and less than 30 kg and wherein the antibody is administered at a dose of about 2.5 mg/kg or about 4 mg/kg every other week.

In some embodiments, the body weight of the subject is greater than or equal to 10 kg and less than 30 kg and wherein the antibody is administered at a dose of about 2.5 mg/kg or about 4 mg/kg once every other week.

In various embodiments, the body weight of the subject is greater than or equal to 10 kg and less than 30 kg and wherein the antibody is administered at a dose of 2.5 mg/kg or 4 mg/kg every other week or 2.5 mg/kg every week.

In certain embodiments, the body weight of the subject is greater than or equal to 10 kg and less than 30 kg and wherein the antibody is administered at a dose of 2.5 mg/kg or 4 mg/kg once every other week or 2.5 mg/kg once every week.

This disclosure further provides an antibody for use in treating pcJIA in a subject in need thereof, wherein the antibody specifically binds IL-6R, wherein the antibody that specifically binds to the IL-6R comprises a heavy chain variable region of sequence SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2, wherein the body weight of the subject is greater than or equal to 30 kg and less than 33 kg and the antibody is administered at a dose of 61.25 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 33 kg and less than 37.5 kg and the antibody is administered at a dose of 70 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 37.5 kg and less than 42 kg and the antibody is administered at a dose of 78.75 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 42 kg and less than 46.5 kg and the antibody is administered at a dose of 87.5 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 46.5 kg and less than 50.5 kg and the antibody is administered at a dose of 96.25 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 50.5 kg and less than 55 kg and the antibody is administered at a dose of 105 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 55 kg and less than 59.5 kg and the antibody is administered at a dose of 113.75 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 59.5 kg and less than 64 kg and the antibody is administered at a dose of 122.5 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 64 kg and less than 68 kg and the antibody is administered at a dose of 131.25 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 68 kg and less than 72.5 kg and the antibody is administered at a dose of 140 mg once every other week or once every week; or wherein the body weight of the subject is greater than or equal to 72.5 kg and the antibody is administered at a dose of 148.75 mg once every other week or once every week.

This disclosure further provides an antibody for use in treating pcJIA in a subject in need thereof, wherein the antibody specifically binds IL-6R, wherein the antibody that specifically binds to the IL-6R comprises a heavy chain variable region of sequence SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2, wherein the body weight of the subject is greater than or equal to 30 kg and less than 31 kg and the antibody is administered at a dose of 87.5 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 31 kg and less than 34 kg and the antibody is administered at a dose of 96.25 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 34 kg and less than 37 kg and the antibody is administered at a dose of 105 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 37 kg and less than 39.5 kg and the antibody is administered at a dose of 113.75 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 39.5 kg and less than 42.5 kg and the antibody is administered at a dose of 122.5 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 42.5 kg and less than 45 kg and the antibody is administered at a dose of 131.25 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 45 kg and less than 48.5 kg and the antibody is administered at a dose of 140 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 48.5 kg and less than 51.5 kg and the antibody is administered at a dose of 148.75 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 51.5 kg and less than 54.5 kg and the antibody is administered at a dose of 157.5 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 54.5 kg and less than 57 kg and the antibody is administered at a dose of 166.25 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 57 kg and less than 63 kg and the antibody is administered at a dose of 175 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 63 kg and the antibody is administered at a dose of 192.5 mg once every other week or once every week.

This disclosure further provides an antibody for use in treating pcJIA in a subject in need thereof, wherein the antibody specifically binds IL-6R, wherein the antibody that specifically binds to the IL-6R comprises a heavy chain variable region of sequence SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2, wherein the body weight of the subject is greater than or equal to 10 kg and less than 12.5 kg and the antibody is administered at a dose of 26.25 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 12.5 kg and less than 16 kg and the antibody is administered at a dose of 35 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 16 kg and less than 19.5 kg and the antibody is administered at a dose of 43.75 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 19.5 kg and less than 23 kg and the antibody is administered at a dose of 52.5 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 23 kg and less than 26.5 kg and the antibody is administered at a dose of 61.25 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 26.5 kg and less than 30 kg and the antibody is administered at a dose of 70 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 30 kg and less than 37.5 kg and the antibody is administered at a dose of 70 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 37.5 kg and less than 42 kg and the antibody is administered at a dose of 78.75 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 42 kg and less than 46.5 kg and the antibody is administered at a dose of 87.5 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 46.5 kg and less than 50.5 kg and the antibody is administered at a dose of 96.25 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 50.5 kg and less than 55 kg and the antibody is administered at a dose of 105 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 55 kg and less than 59.5 kg and the antibody is administered at a dose of 113.75 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 59.5 kg and less than 64 kg and the antibody is administered at a dose of 122.5 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 64 kg and less than 68 kg and the antibody is administered at a dose of 131.25 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 68 kg and less than 72.5 kg and the antibody is administered at a dose of 140 mg once every other week or once every week; or wherein the body weight of the subject is greater than or equal to 72.5 kg and the antibody is administered at a dose of 148.75 mg once every other week or once every week.

This disclosure further provides an antibody for use in treating pcJIA in a subject in need thereof, wherein the antibody specifically binds IL-6R, wherein the antibody that specifically binds to the IL-6R comprises a heavy chain variable region of sequence SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2, wherein the body weight of the subject is greater than or equal to 10 kg and less than 12.5 kg and the antibody is administered at a dose of 43.75 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 12.5 kg and less than 14.5 kg and the antibody is administered at a dose of 52.5 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 14.5 kg and less than 16.5 kg and the antibody is administered at a dose of 61.25 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 16.5 kg and less than 19 kg and the antibody is administered at a dose of 70 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 19 kg and less than 21 kg and the antibody is administered at a dose of 78.75 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 21 kg and less than 23.5 kg and the antibody is administered at a dose of 87.5 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 23.5 kg and less than 25.5 kg and the antibody is administered at a dose of 96.25 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 25.5 kg and less than 27.5 kg and the antibody is administered at a dose of 105 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 27.5 kg and less than 30 kg and the antibody is administered at a dose of 113.75 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 30 kg and less than 39.5 kg and the antibody is administered at a dose of 113.75 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 39.5 kg and less than 42.5 kg and the antibody is administered at a dose of 122.5 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 42.5 kg and less than 45 kg and the antibody is administered at a dose of 131.25 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 45 kg and less than 48.5 kg and the antibody is administered at a dose of 140 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 48.5 kg and less than 51.5 kg and the antibody is administered at a dose of 148.75 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 51.5 kg and less than 54.5 kg and the antibody is administered at a dose of 157.5 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 54.5 kg and less than 57 kg and the antibody is administered at a dose of 166.25 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 57 kg and less than 60.5 kg and the antibody is administered at a dose of 175 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 60.5 kg and less than 63 kg and the antibody is administered at a dose of 175 mg once every other week or once every week; wherein the body weight of the subject is greater than or equal to 63 kg and the antibody is administered at a dose of 192.5 mg once every other week or once every week.

This disclosure further provides an antibody for use in treating sJIA in a subject in need thereof, wherein the antibody specifically binds IL-6R, wherein the antibody that specifically binds to the IL-6R comprises a heavy chain variable region of sequence SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2, wherein the antibody is administered at a dose of from about 2 mg/kg to about 2.5 mg/kg per week or from about 3 mg/kg to about 4 mg/kg per two weeks, wherein the body weight of the subject is greater than or equal to 30 kg and less than or equal to 210 kg.

In some embodiments, the body weight of the subject is greater than or equal to 30 kg and less than or equal to 60 kg and wherein the antibody is administered at a dose of about 2 mg/kg every week or a dose of about 3 mg/kg every other week.

In various embodiments, the body weight of the subject is greater than or equal to 30 kg and less than or equal to 60 kg and wherein the antibody is administered at a dose of about 2 mg/kg once every week or a dose of about 3 mg/kg once every other week.

In certain embodiments, the body weight of the subject is greater than or equal to 30 kg and less than or equal to 60 kg and wherein the antibody is administered at a dose of 2 mg/kg every week or a dose of 3 mg/kg every other week.

In some embodiments, the body weight of the subject is greater than or equal to 30 kg and less than or equal to 60 kg and wherein the antibody is administered at a dose of 2 mg/kg once every week or a dose of 3 mg/kg once every other week.

In various embodiments, the body weight of the subject is greater than or equal to 30 kg and less than or equal to 210 kg and wherein the antibody is administered at a dose of about 2.5 mg/kg every week or a dose of about 4 mg/kg every other week.

In certain embodiments, the body weight of the subject is greater than or equal to 30 kg and less than or equal to 210 kg and wherein the antibody is administered at a dose of about 2.5 mg/kg once every week or a dose of about 4 mg/kg once every other week.

In some embodiments, the body weight of the subject is greater than or equal to 30 kg and less than or equal to 210 kg and wherein the antibody is administered at a dose of 2.5 mg/kg every week or a dose of 4 mg/kg every other week.

In various embodiments, the body weight of the subject is greater than or equal to 30 kg and less than or equal to 210 kg and wherein the antibody is administered at a dose of 2.5 mg/kg once every week or a dose of 4 mg/kg once every other week.

In certain embodiments, the antibody is in a pharmaceutical composition. In some embodiments, is an aqueous solution with a volume of less than about 1 mL. In various embodiments, is an aqueous solution with a volume of from about 0.5 to 1 mL. In certain embodiments, is an aqueous solution with a volume of from about 0.75 to 1 mL. In some embodiments, is an aqueous solution with a volume of from about 0.5 to 0.75 mL. In various embodiments, is an aqueous solution with a volume of from about 0.15 to 0.25 mL. In certain embodiments, is an aqueous solution with a volume of from about 0.25 to 0.5 mL.

