Claims for Patent: 8,092,998

Summary for Patent: 8,092,998

Title:	Biomarkers predictive of the responsiveness to TNF.alpha. inhibitors in autoimmune disorders
Abstract:	The invention provides methods for predicting responsiveness to TNF.alpha. inhibitors in a subject suffering from an autoimmune disorder, such as rheumatoid arthritis. The methods involve assaying for expression of one or more biomarkers in the subject that are predictive of responsiveness to TNF.alpha. inhibitors. A preferred biomarker of the invention is CD11c. The methods can further comprise selecting a treatment regimen with a TNF.alpha. inhibitor in an autoimmune disorder subject based upon expression of the biomarker(s) in the subject. The methods can further comprise administering a TNF.alpha. inhibitor to the subject according to the selected treatment regimen. Kits that include means for measuring expression of one or more biomarkers that are predictive of responsiveness to TNF.alpha. inhibitors for an autoimmune disorder are also provided. Methods of preparing and using databases, and computer program products therefore, for selecting an autoimmune disorder subject for treatment with a TNF.alpha. inhibitor are also provided.
Inventor(s):	Stuhlmuller; Bruno (Berlin, DE), Burmester; Gerd-Reudiger (Berlin, DE)
Assignee:	Abbott Laboratories (Abbott Park, IL)
Application Number:	12/130,373
Patent Claims:	1. A method for predicting responsiveness to a TNF.alpha. inhibitor in a subject having an autoimmune disorder, the method comprising: (i) assaying the subject for expression of one or more biomarkers predictive of responsiveness to a TNF.alpha. inhibitor in an autoimmune disorder, and (ii) predicting responsiveness of the subject to the TNF.alpha. inhibitor based on expression of the one or more biomarkers in the subject, wherein the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs:11, 29, 44, 62, 65, and 74, wherein decreased expression of the one or more biomarkers encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs:11, 29, 65, and 74 is predictive of responsiveness of the subject to a TNF.alpha. inhibitor and/or wherein increased expression of the one or more biomarkers encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs:44 and 62 is predictive of responsiveness of the subject to a TNF.alpha. inhibitor. 2. The method of claim 1, wherein a sample from the subject is assayed for expression of an mRNA encoding the one or more biomarkers. 3. The method of claim 1, which further comprises selecting a treatment regimen with the TNF.alpha. inhibitor based upon expression of the one or more biomarkers in the subject or administering the TNF.alpha. inhibitor to the subject according to the treatment regimen such that the autoimmune disorder is inhibited in the subject. 4. The method of claim 1, wherein the TNF.alpha. inhibitor is an anti-tumor necrosis factor-alpha (TNF.alpha.) antibody, or antigen-binding portion thereof. 5. The method of claim 4, wherein the anti-TNF.alpha. antibody, or antigen-binding portion thereof, is selected from the group consisting of a human antibody, a humanized antibody, a chimeric antibody, or a multivalent antibody. 6. The method of claim 4, wherein the anti-TNF.alpha. antibody, or antigen-binding portion thereof, is adalimumab. 7. The method of claim 4, wherein the anti-TNF.alpha. antibody, or antigen-binding portion thereof, is infliximab. 8. The method of claim 4, wherein the anti-TNF.alpha. antibody, or antigen-binding portion thereof, is golimumab. 9. The method of claim 5, wherein the human anti-TNF.alpha. antibody, or antigen-binding portion thereof, is selected from the group consisting of i) an isolated human antibody that 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; ii) an isolated human antibody with 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: 305, or modified from SEQ ID NO: 305 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: 306, or modified from SEQ ID NO: 306 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; and iii) an isolated human antibody with a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 303 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 304. 10. The method of claim 1, wherein the TNF.alpha. inhibitor is etanercept. 11. The method of claim 1, wherein the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence of SEQ ID NO:44. 12. The method of claim 1, wherein the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs:11 and 74. 13. The method of claim 1, wherein a sample from the subject is assayed for protein expression of the one or more biomarkers. 14. The method of claim 1, wherein the subject is a human. 15. The method of claim 1, wherein the autoimmune disorder is rheumatoid arthritis. 16. A method for predicting responsiveness to a TNF.alpha. inhibitor in a subject having an autoimmune disorder, the method comprising: (i) assaying the subject for expression of one or more biomarkers predictive of responsiveness to a TNF.alpha. inhibitor in an autoimmune disorder, and (ii) predicting responsiveness of the subject to the TNF.alpha. inhibitor based on expression of the one or more biomarkers in the subject, wherein the one or more biomarkers is selected from the group consisting of Homo sapiens predicted osteoblast protein (GS3786) (Genbank Accession Nos. NM.sub.--014888, NM.sub.--001040020); Charcot-Leyden crystal protein (Genbank Accession No. NM.sub.--001828); Integrin alpha-X (antigen CD11c) (Genbank Accession No. NM.sub.--000887); Amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) (Genbank Accession Nos. NM.sub.--201413, NM.sub.--000484, NM.sub.--201414); Neugrin, neurite outgrowth associated (Genbank Accession Nos. NM_016645, NM_001033088); and Homo sapiens hypothetical protein FLJ10134 (Genbank Accession No. NM.sub.--018004), wherein increased expression of the one or more biomarkers selected from the group consisting of Integrin alpha-X (antigen CD11c); and Amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) is predictive of responsiveness of the subject to a TNF.alpha. inhibitor and/or wherein decreased expression of the one or more biomarkers selected from the group consisting of Homo sapiens predicted osteoblast protein (GS3786); Charcot-Leyden crystal protein; Neugrin, neurite outgrowth associated; and Homo sapiens hypothetical protein FLJ10134 is predictive of responsiveness of the subject to a TNF.alpha. inhibitor. 17. The method of claim 16, wherein the one or more biomarkers is Integrin alpha-X (antigen CD11c). 18. The method of claim 16, wherein the one or more biomarkers is selected from the group consisting of Homo sapiens predicted osteoblast protein (GS3786) and Homo sapiens hypothetical protein FLJ10134. 19. The method of claim 16, wherein the TNF.alpha. inhibitor is an anti-tumor necrosis factor-alpha (TNF.alpha.) antibody, or antigen-binding portion thereof. 20. The method of claim 16, wherein a sample from the subject is assayed for protein expression of the one or more biomarkers. 21. The method of claim 16, wherein the subject is a human. 22. The method of claim 16, wherein the autoimmune disorder is rheumatoid arthritis. 23. The method of claim 16, wherein a sample from the subject is assayed for expression of an mRNA encoding the one or more biomarkers. 24. The method of claim 16, which further comprises selecting a treatment regimen with the TNF.alpha. inhibitor based upon expression of the one or more biomarkers in the subject or administering the TNF.alpha. inhibitor to the subject according to the treatment regimen such that the autoimmune disorder is inhibited in the subject. 25. A method for predicting responsiveness to a TNF.alpha. inhibitor in a subject having an autoimmune disorder, the method comprising: (i) assaying the subject for increased expression of a biomarker, which biomarker is Integrin alpha-X (antigen CD11c), and (ii) predicting responsiveness of the subject to the TNF.alpha. inhibitor based on increased expression of Integrin alpha-X (antigen CD11c) in the subject. 26. The method of claim 25, wherein the TNF.alpha. inhibitor is an anti-tumor necrosis factor-alpha (TNF.alpha.) antibody, or antigen-binding portion thereof. 27. The method of claim 25, wherein a sample from the subject is assayed for protein expression of the one or more biomarkers. 28. The method of claim 25, wherein the subject is a human. 29. The method of claim 25, wherein the autoimmune disorder is rheumatoid arthritis. 30. The method of claim 25, wherein a sample from the subject is assayed for expression of an mRNA encoding the one or more biomarkers. 31. The method of claim 25, which further comprises selecting a treatment regimen with the TNF.alpha. inhibitor based upon expression of the one or more biomarkers in the subject or administering the TNF.alpha. inhibitor to the subject according to the treatment regimen such that the autoimmune disorder is inhibited in the subject. 32. A method for predicting responsiveness to a TNF.alpha. inhibitor, which TNF.alpha. inhibitor is adalimumab, in a subject having an autoimmune disorder, the method comprising: (i) assaying the subject for expression of one or more biomarkers predictive of responsiveness to adalimumab in an autoimmune disorder, wherein the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs:11, 29, 44, 62, 65, and 74, and (ii) predicting responsiveness of the subject to adalimumab based on expression of the one or more biomarkers in the subject, wherein decreased expression of the one or more biomarkers encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs:11, 29, 65, and 74 is predictive of responsiveness of the subject to a TNF.alpha. inhibitor and/or wherein increased expression of the one or more biomarkers encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs:44 and 62 is predictive of responsiveness of the subject to a TNF.alpha. inhibitor. 33. The method of claim 32, wherein a sample from the subject is assayed for protein expression of the one or more biomarkers. 34. The method of claim 32, wherein the subject is a human. 35. The method of claim 32, wherein the autoimmune disorder is rheumatoid arthritis. 36. The method of claim 32, wherein a sample from the subject is assayed for expression of an mRNA encoding the one or more biomarkers. 37. A method of monitoring an autoimmune disorder in a subject having the autoimmune disorder, the method comprising: assaying the subject for expression of one or more biomarkers following treatment with a TNF.alpha. inhibitor, wherein the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs:29, 91, and 176, thereby monitoring the autoimmune disorder in the subject. 38. The method of claim 37, further comprising monitoring the subject prior to treatment with a TNF.alpha. inhibitor. 39. The method of claim 37, wherein a sample from the subject is assayed for protein expression of the one or more biomarkers. 40. The method of claim 37, wherein the subject is a human. 41. The method of claim 37, wherein the autoimmune disorder is rheumatoid arthritis. 42. The method of claim 37, wherein a sample from the subject is assayed for expression of an mRNA encoding the one or more biomarkers.

Details for Patent 8,092,998

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Janssen Biotech, Inc.	REMICADE	infliximab	For Injection	103772	08/24/1998		2027-05-31
Immunex Corporation	ENBREL	etanercept	For Injection	103795	11/02/1998		2027-05-31
Immunex Corporation	ENBREL	etanercept	For Injection	103795	05/27/1999		2027-05-31