Uses and compositions for treatment of ankylosing spondylitis

Abstract

The invention provides methods, uses and compositions for the treatment of ankylosing spondylitis (AS). The invention describes methods and uses for treating ankylosing spondylitis, wherein a TNFα inhibitor, such as a human TNFα antibody, or antigen-binding portion thereof, is used to reduce signs and symptoms of ankylosing spondylitis in a subject. Also described are methods for determining the efficacy of a TNFα inhibitor for treatment of ankylosing spondylitis in a subject.

1 . A method of decreasing pain and fatigue in a subject having AS comprising administering a human TNFα antibody, or antigen-binding portion thereof, to the subject such that pain and fatigue are decreased. 
     
     
         2 . The method of  claim 1 , wherein the decrease in fatigue in the subject is determined by a score selected from the group consisting of FACIT-F, BASDAI, and SF-36. 
     
     
         3 . The method of  claim 1 , wherein the decrease in fatigue is determined by a decrease of at least about 1.9 in a BASDAI score of the subject or a decrease of at least about 2.0 in a BASDAI score of the subject. 
     
     
         4 . (canceled) 
     
     
         5 . A method of determining the efficacy of a human TNFα antibody, or antigen-binding fragment thereof, for treating ankylosing spondylitis (AS) in a subject comprising
 determining a partial remission rate of a patient population having AS and who was administered the human TNFα antibody, or antigen-binding fragment thereof,   wherein a partial remission rate of at least about 20% of the patient population indicates that the human TNFα antibody, or antigen-binding fragment thereof, is an effective human TNFα antibody, or antigen-binding fragment thereof, for the treatment of AS.   
     
     
         6 . A method of determining the efficacy of a human TNFα antibody, or antigen-binding fragment thereof, for treating ankylosing spondylitis (AS) in a subject comprising
 determining a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) response of a patient population having AS and who was administered the human TNFα antibody, or antigen-binding fragment thereof,   wherein the BASDAI response selected from the group comprising a BASDAI 20 response in at least 60% of the patient population, a BASDAI 20 response in at least about 70% of the patient population, a BASDAI 20 response in at least about 80% of the patient population, a BASDAI 20 response in at least about 85% of the patient population, a BASDAI 50 response of at least about 23% of the patient population, a BASDAI 50 response of at least about 30% of the patient population, a BASDAI 50 response of at least about 40% of the patient population, a BASDAI 50 response of at least about 50% of the patient population, a BASDAI 50 response of at least about 60% of the patient population, a BASDAI 70 response in at least about 10% of the patient population, a BASDAI 70 response in at least about 20% of the patient population, a BASDAI 70 response in at least about 30% of the patient population, a BASDAI 70 response in at least about 40% of the patient population, and a BASDAI 70 response in at least about 45% of the patient population, indicates that the human TNFα antibody, or antigen-binding fragment thereof, is an effective human TNFα antibody, or antigen-binding fragment thereof, for the treatment of AS.   
     
     
         7 - 19 . (canceled) 
     
     
         20 . A method of determining the efficacy of a human TNFα antibody, or antigen-binding fragment thereof, for treating ankylosing spondylitis (AS) in a subject comprising
 determining a Assessment in Ankylosing Spondylitis (ASAS) response of a patient population having AS and who was administered the human TNFα antibody, or antigen-binding fragment thereof,   wherein the ASAS response selected from the group consisting of an ASAS20 response in at least about 27% of the patient population, an ASAS20 response in at least about 50% of the patient population, an ASAS20 response in at least about 55% of the patient population, an ASAS20 response in at least about 70% of the patient population, an ASAS40 response in at least about 10% of the patient population, an ASAS40 response in at least about 20% of the patient population, an ASAS40 response in at least about 30% of the patient population, an ASAS40 response in at least about 45% of the patient population, an ASAS70 response in at least about 5% of the patient population, an ASAS70 response in at least about 20% of the patient population, an ASAS70 response in at least about 23% of the patient population, an ASAS70 response in at least about 30% of the patient population, and an ASAS70 response in at least about 40% of the patient population, indicates that the human TNFα antibody, or antigen-binding fragment thereof, is an effective human TNFα antibody, or antigen-binding fragment thereof, for the treatment of AS.   
     
     
         21 - 33 . (canceled) 
     
     
         34 . The method of  claim 6  or  20 , further comprising administering the effective human TNFα antibody, or antigen-binding fragment thereof, to a subject for the treatment of AS. 
     
     
         35 . A method of treating AS in a subject comprising administering an effective human TNFα antibody, or antigen-binding fragment thereof, to the subject such that AS is treated, wherein the administration of the effective human TNFα antibody, or antigen-binding fragment thereof, was previously identified as resulting in a response selected from the group consisting of a BASDAI 20 response in at least about 60% of a patient population having AS, a BASDAI 50 response in at least about 23% of a patient population having AS, a BASDAI 70 response in at least about 10% of a patient population having AS, an ASAS20 response in at least about 50% of a patient population having AS, an ASAS50 response in at least about 39% of a patient population having AS, and an ASAS70 response in at least about 5% of a patient population having AS. 
     
     
         36 - 41 . (canceled) 
     
     
         42 . The method of any one of  claims 6 ,  20  or  35 , wherein the TNFα antibody, or antigen-binding portion thereof, is a multivalent antibody. 
     
     
         43 . The method of any one of  claims 6 ,  20  or  35 , wherein the human TNFα antibody, or antigen-binding portion thereof, is golimumab. 
     
     
         44 . The method of any one of  claims 1 ,  5 ,  6 ,  20 ,  35  or  42 , wherein the human TNFα antibody, or antigen-binding portion thereof, is selected from the group consisting of:
 i) a human TNFα antibody, or antigen-binding portion thereof, that dissociates from human TNFα with a K d  of 1×10 −8  M or less and a K off  rate constant of 1×10 −3  s −1  or less, both determined by surface plasmon resonance, and neutralizes human TNFα cytotoxicity in a standard in vitro L929 assay with an IC 50  of 1×10 −7  M or less;   ii) a human TNFα antibody, or antigen-binding portion thereof, that:
 a) dissociates from human TNFα with a K off  rate constant of 1×10 −3  s −1  or less, as determined by surface plasmon resonance; 
 b) has a light chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or 8 or by one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9; 
 c) has a heavy chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or by one to five conservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9, 10, 11 and/or 12; 
   iii) a human TNFα antibody, or antigen-binding portion thereof, that comprises a light chain variable region (LCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or 8, and comprises a heavy chain variable region (HCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11;   iv) a human TNFα antibody, or antigen-binding portion thereof, a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2; and   v) adalimumab.   
     
     
         45 - 48 . (canceled) 
     
     
         49 . The method of any one of  claims 1 ,  5 ,  6 ,  20  or  35 , wherein the human TNFα antibody, or an antigen-binding portion thereof, is administered to the subject on a biweekly dosing regimen. 
     
     
         50 . The method of any one of  claims 1 ,  5 ,  6 ,  20  or  35 , wherein the human TNFα antibody, or an antigen-binding portion thereof, is administered in a dose of about 40 mg. 
     
     
         51 . The method of any one of  claims 1 ,  5 ,  6 ,  20  or  35  wherein the human TNFα antibody, or an antigen-binding portion thereof, is administered to the subject subcutaneously.