Uses and Compositions for Treatment of Ankylosing Spondylitis
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 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 treating early axial spondylarthritis in a subject comprising administering a human TNFα antibody, or antigen-binding portion thereof, to the subject, such that early axial spondylarthritis is treated.
2 . The method of claim 1 , wherein the human TNFα antibody, or antigen-binding portion thereof, 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.
3 . The method of claim 1 , wherein the human TNFα antibody, or an antigen-binding portion thereof, has the following characteristics:
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.
4 . The method of claim 1 , wherein the human TNFα antibody, or an antigen-binding portion thereof, 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.
5 . The method of claim 1 , wherein the human TNFα antibody, or an antigen-binding portion thereof, comprises 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.
6 . The method of claim 1 , wherein the human TNFα antibody, or an antigen-binding portion thereof, is adalimumab.
7 . The method of claim 1 , wherein the human TNFα antibody, or an antigen-binding portion thereof, is administered to the subject on a biweekly dosing regimen.
8 . The method of claim 1 , wherein the human TNFα antibody, or an antigen-binding portion thereof, is administered in a dose of about 40 mg.
9 . The method of claim 1 , wherein the human TNFα antibody, or an antigen-binding portion thereof, is administered to the subject subcutaneously.
10 . A method of determining the efficacy of a TNFα inhibitor for treating ank:ylosing spondylitis (AS) in a subject comprising
determining an Assessment in Ankylosing Spondylitis (ASAS) response of a patient population having AS and who was administered the TNFα inhibitor,
wherein an ASAS20 response in at least about 61% of the patient population indicates that the TNFα inhibitor is an effective TNFα inhibitor for the treatment of AS in the subject.
11 . The method of claim 10 , wherein an ASAS20 response in at least about 70% of the patient population indicates that the TNFα inhibitor is an effective TNFα inhibitor for the treatment of AS in the subject.
12 . The method of claim 10 , wherein an ASAS20 response in at least about 73% of the patient population indicates that the TNFcr inhibitor is an effective TNFα inhibitor for the treatment of AS in the subject.
13 . The method of claim 10 , wherein an ASAS20 response in at least about 75% of the patient population indicates that the TNFcr inhibitor is an effective TNFα inhibitor for the treatment of AS in the subject.
14 . The method of claim 10 , further comprising administering the effective TNFα inhibitor to a subject for the treatment of AS.
15 . An article of manufacture comprising
a human TNFα antibody, or antigen-binding portion thereof, and
a package insert comprising instructions for administering the human
TNFα antibody, or antigen-binding portion thereof, to a human subject for the treatment of adults with moderate to severe active ankylosing spondylitis who have had an inadequate response to conventional therapy.
16 . The article of claim 15 , wherein the human TNFα antibody, or antigen-binding portion thereof, 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.
17 . The article of claim 15 , wherein the human TNFα antibody, or antigen-binding portion thereof, has the following characteristics:
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.
18 . The article of claim 15 , wherein the human TNFα antibody, or antigen-binding portion thereof, 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.
19 . The article of claim 15 , wherein the human TNFα antibody, or antigen-binding portion thereof, comprises 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.
20 . The article of claim 15 , wherein the human TNFα antibody, or antigen-binding portion thereof, is adalimumab.