Claims for Patent: 7,919,264

Summary for Patent: 7,919,264

Title:	Methods and compositions for determining the efficacy of a treatment for ankylosing spondylitis using biomarkers
Abstract:	The invention provides a method for determining the efficacy of a TNF.alpha. inhibitor, such as a TNF.alpha. antibody, or an antigen-binding portion thereof, for treating ankylosing spondylitis (AS), using a collagen degradation biomarker and/or a synovitis biomarker.
Inventor(s):	Maksymowych; Walter P. (Edmonton, CA), Wong; Robert L. (Basking Ridge, NJ)
Assignee:	Abbott Biotechnology Ltd. (Hamilton, BM)
Application Number:	11/591,241
Patent Claims:	1. A method for determining the efficacy of a human anti-TNF.alpha. antibody, or an antigen-binding portion thereof, for treating a subject having ankylosing spondylitis (AS), said method comprising determining a level of a collagen degradation biomarker and a synovitis biomarker in a sample(s) obtained from the subject following administration of the human anti-TNF.alpha. antibody, or an antigen-binding portion thereof; and comparing the level of the collagen degradation biomarker and the synovitis biomarker in the sample(s) obtained from the subject with a known standard level of the collagen degradation biomarker and the synovitis biomarker associated with AS, wherein a lower level of the collagen degradation biomarker and the synovitis biomarker in the sample(s) from the subject relative to the known standard level of the collagen degradation biomarker and the synovitis biomarker indicates that the human anti-TNF.alpha. antibody, or an antigen-binding portion thereof, is efficacious for the treatment of AS in the subject. 2. The method of claim 1, wherein the collagen degradation biomarker is type II collagen C-telopeptide (CTX-II). 3. The method of claim 2, wherein the collagen degradation biomarker is urinary type II collagen C-telopeptide (CTX-II). 4. The method of claim 1, wherein the synovitis biomarker is matrix metalloprotease 3 (MMP3). 5. The method of claim 4, wherein the synovitis biomarker is serum metalloprotease 3 (MMP3). 6. The method of claim 1, further comprising determining a level of C-reactive protein (CRP) in a sample obtained from the subject following administration of the human anti-TNF.alpha. antibody, or an antigen-binding portion thereof; and comparing the level of CRP in the sample with a known standard CRP level associated with AS, wherein a lower level of CRP in the sample relative to the known standard level of CRP indicates that the human anti-TNF.alpha. antibody, or an antigen-binding portion thereof, is efficacious for the treatment of AS in the subject. 7. A method for determining the efficacy of a human anti-TNF.alpha. antibody, or an antigen-binding portion thereof, for treating a subject having ankylosing spondylitis (AS), said method comprising determining a level of a collagen degradation biomarker and a synovitis biomarker in a sample(s) obtained from the subject following administration of the human anti-TNF.alpha. antibody, or antigen-binding portion thereof; and comparing the level of the collagen degradation biomarker and the synovitis biomarker in the sample(s) to a baseline level of the collagen degradation biomarker and the synovitis biomarker, wherein a lower level of the collagen degradation biomarker and the synovitis biomarker in the sample(s) relative to the baseline level of the collagen degradation biomarker and the synovitis biomarker indicates that the human anti-TNF.alpha. antibody, or an antigen-binding portion thereof, is efficacious for the treatment of AS in the subject. 8. The method of claim 7, wherein the collagen degradation biomarker is type II collagen C-telopeptide (CTX-II). 9. The method of claim 8, wherein the collagen degradation biomarker is urinary type II collagen C-telopeptide (CTX-II). 10. The method of claim 7, wherein the synovitis biomarker is matrix metalloprotease 3 (MMP3). 11. The method of claim 10, wherein the synovitis biomarker is serum metalloprotease 3 (MMP3). 12. The method of claim 1 or 7, wherein the level of the biomarker is determined by performing an ELISA. 13. A method for determining the efficacy of a human anti-TNF.alpha. antibody, or an antigen-binding portion thereof, for the treatment of ankylosing spondylitis (AS) in a subject having AS, said method comprising determining level of type II collagen C-telopeptide (CTX-II) in a sample from the subject following treatment with the human anti-TNF.alpha. antibody, or an antigen-binding portion thereof, and comparing the level of CTX-II in the sample with a baseline level of CTX-II from the subject having AS, wherein a decrease in the level of the CTX-II in the sample of at least 9% relative to the baseline level of CTX-II indicates that the human anti-TNF.alpha. antibody, or an antigen-binding portion thereof, is effective for the treatment of AS in the subject. 14. The method of claim 13, wherein the CTX-II is urinary CTX-II. 15. The method of claim 13, wherein the level of CTX-II is determined by performing an ELISA. 16. A method of determining the efficacy of a human anti-TNF.alpha. antibody, or antigen-binding portion thereof, for the treatment of ankylosing spondylitis (AS) in a subject having AS, said method comprising determining a level of type II collagen C-telopeptide (CTX-II) in a sample obtained from the subject following administration of the anti-human TNF.alpha. antibody, or antigen-binding portion thereof, and comparing the level of CTX-II in the sample with a known standard level of CTX-II associated with AS, wherein a decrease in the level of CTX-II in the sample of at least 9% relative to the known standard level of CTX-II indicates that the human anti-TNF.alpha. antibody, or antigen-binding portion thereof, is effective for the treatment of AS in the subject. 17. A method for determining the efficacy of a human anti-TNF.alpha. antibody, or an antigen-binding portion thereof, for treating ankylosing spondylitis (AS) in a subject having AS, said method comprising determining levels of type II collagen C-telopeptide (CTX-II) and matrix metalloprotease 3 (MMP3) in a sample(s) obtained from the subject having AS following administration of the human anti-TNF.alpha. antibody, or an antigen-binding portion thereof, and comparing the levels of CTX-II and MMP3 in the sample(s) with known standard levels of CTX-II and MMP3 associated with AS, wherein lower CTX-II and MMP3 levels in the sample(s) from the subject relative to the known standard levels of CTX-II and MMP3 indicates that the human anti-TNF.alpha. antibody, or an antigen-binding portion thereof, is effective at decreasing structural damage associated with AS in the patient. 18. The method of claim 16 or 17, wherein the CTX-II is urinary CTX-II. 19. The method of claim 16 or 17, wherein the CTX-II level is determined by performing an ELISA. 20. The method of any one of claims 1, 7, 13, 16, or 17, wherein the human anti-TNF.alpha. antibody, or antigen-binding portion thereof, dissociates from human TNF.alpha. with a K.sub.d of 1.times.10.sup.-8 M or less and a K.sub.off rate constant of 1.times.10.sup.-3 s.sup.-1 or less, both determined by surface plasmon resonance, and neutralizes human TNF.alpha. cytotoxicity in a standard in vitro L929 assay with an IC.sub.50 of 1.times.10.sup.-7 M or less. 21. The method of any one of claims 1, 7, 13, 16, or 17, wherein the human anti-TNF.alpha. antibody, or antigen-binding portion thereof, has the following characteristics: a) dissociates from human TNF.alpha. with a K.sub.off rate constant of 1.times.10.sup.-3 s.sup.-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. 22. The method of any one of claims 1, 7, 13, 16, or 17, wherein the human anti-TNF.alpha. 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. 23. The method of any one of claims 1, 7, 13, 16, or 17, wherein the human anti-TNF.alpha. 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. 24. The method of any one of claims 1, 7, 13, 16, or 17, wherein the human anti-TNF.alpha. antibody, or antigen-binding portion thereof, is adalimumab. 25. The method of any one of claims 1, 7, 13, 16, or 17, wherein the human TNF.alpha. antibody, or antigen-binding portion thereof, is golimumab. 26. A method for determining the efficacy of a TNF.alpha. antibody, or an antigen-binding portion thereof, for treating a subject having ankylosing spondylitis (AS), said method comprising determining a level of a collagen degradation biomarker and a synovitis biomarker in a sample(s) obtained from the subject following administration of the TNF.alpha. antibody, or an antigen-binding portion thereof; and comparing the level of the collagen degradation biomarker and the synovitis biomarker in the sample(s) obtained from the subject with a known standard level of the collagen degradation biomarker and the synovitis biomarker associated with AS, wherein a lower level of the collagen degradation biomarker and the synovitis biomarker in the sample(s) from the subject relative to the known standard level of the collagen degradation biomarker and the synovitis biomarker indicates that the TNF.alpha. antibody, or an antigen-binding portion thereof, is efficacious for the treatment of AS in the subject. 27. The method of claim 26, wherein the collagen degradation biomarker is type II collagen C-telopeptide (CTX-II). 28. The method of claim 26, wherein the synovitis biomarker is matrix metalloprotease 3 (MMP3). 29. The method of claim 26, further comprising determining a level of C-reactive protein (CRP) in a sample obtained from the subject following administration of the TNF.alpha. antibody, or an antigen-binding portion thereof; and comparing the level of CRP in the sample with a known standard CRP level associated with AS, wherein a lower level of CRP in the sample relative to the known standard level of CRP indicates that the TNF.alpha. antibody, or an antigen-binding portion thereof, is efficacious for the treatment of AS in the subject. 30. A method for determining the efficacy of a TNF.alpha. antibody, or an antigen-binding portion thereof, for treating a subject having ankylosing spondylitis (AS), said method comprising determining a level of a collagen degradation biomarker and a synovitis biomarker in a sample(s) obtained from the subject following administration of the TNF.alpha. antibody, or antigen-binding portion thereof; and comparing the level of the collagen degradation biomarker and the synovitis biomarker in the sample(s) to a baseline level of the collagen degradation biomarker and the synovitis biomarker, wherein a lower level of the collagen degradation biomarker and the synovitis biomarker in the sample(s) relative to the baseline level of the collagen degradation biomarker and the synovitis biomarker indicates that the TNF.alpha. antibody, or an antigen-binding portion thereof, is efficacious for the treatment of AS in the subject. 31. The method of claim 30, wherein the collagen degradation biomarker is urinary type II collagen C-telopeptide (CTX-II). 32. The method of claim 30, wherein the synovitis biomarker is serum metalloprotease 3 (MMP3). 33. A method for determining the efficacy of a TNF.alpha. antibody, or an antigen-binding portion thereof, for the treatment of ankylosing spondylitis (AS) in a subject having AS, said method comprising determining level of type II collagen C-telopeptide (CTX-II) in a sample from the subject following treatment with the TNF.alpha. antibody, or an antigen-binding portion thereof, and comparing the level of CTX-II in the sample with a baseline level of CTX-II from the subject having AS, wherein a decrease in the level of the CTX-II in the sample of at least 9% relative to the baseline level of CTX-II indicates that the TNF.alpha. antibody, or an antigen-binding portion thereof, is effective for the treatment of AS in the subject. 34. A method of determining the efficacy of a TNF.alpha. antibody, or antigen-binding portion thereof, for the treatment of ankylosing spondylitis (AS) in a subject having AS, said method comprising determining a level of type II collagen C-telopeptide (CTX-II) in a sample obtained from the subject following administration of the TNF.alpha. antibody, or antigen-binding portion thereof, and comparing the level of CTX-II in the sample with a known standard level of CTX-II associated with AS, wherein a decrease in the level of CTX-II in the sample of at least 9% relative to the known standard level of CTX-II indicates that the TNF.alpha. antibody, or antigen-binding portion thereof, is effective for the treatment of AS in the subject. 35. A method for determining the efficacy of a TNF.alpha. antibody, or an antigen-binding portion thereof, for treating ankylosing spondylitis (AS) in a subject having AS, said method comprising determining levels of type II collagen C-telopeptide (CTX-II) and matrix metalloprotease 3 (MMP3) in a sample(s) obtained from the subject having AS following administration of the TNF.alpha. antibody, or an antigen-binding portion thereof, and comparing the levels of CTX-II and MMP3 in the sample(s) with known standard levels of CTX-II and MMP3 associated with AS, wherein lower CTX-II and MMP3 levels in the sample(s) from the subject relative to the known standard levels of CTX-II and MMP3 indicates that the TNF.alpha. antibody, or an antigen-binding portion thereof, is effective at decreasing structural damage associated with AS in the patient. 36. The method of any one of claims 33, 34, or 35, wherein the level of CTX-II is determined by performing an ELISA. 37. A method for determining the efficacy of a TNF.alpha. antibody, or an antigen-binding portion thereof, for treating ankylosing spondylitis (AS) in a subject having AS, said method comprising determining levels of type II collagen C-telopeptide (CTX-II) and matrix metalloprotease 3 (MMP3) in a sample(s) obtained from the subject having AS following administration of the human anti-TNF.alpha. antibody, or an antigen-binding portion thereof, and comparing the levels of CTX-II and MMP3 in the sample(s) with baseline levels of CTX-II and MMP3 associated with AS, wherein lower CTX-II and MMP3 levels in the sample(s) from the subject relative to the baseline levels of CTX-II and MMP3 indicates that the anti-TNF.alpha. antibody, or an antigen-binding portion thereof, is effective at decreasing structural damage associated with AS in the patient. 38. The method of any one of claims 26, 30, 33-35, or 37, wherein the TNF.alpha. antibody, or an antigen-binding portion thereof, is infliximab.

Details for Patent 7,919,264

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Janssen Biotech, Inc.	REMICADE	infliximab	For Injection	103772	08/24/1998		2021-03-07
Abbvie Inc.	HUMIRA	adalimumab	Injection	125057	12/31/2002		2021-03-07
Abbvie Inc.	HUMIRA	adalimumab	Injection	125057	02/21/2008		2021-03-07