Claims for Patent: 10,088,479

Summary for Patent: 10,088,479

Title:	Biomarker and uses thereof
Abstract:	The invention relates to a method of determining the inflammatory disorder status of a subject comprising detecting the presence or absence, or the level, of (i) citrullinated tenascin-C and/or one or more fragments of citrullinated tenascin-C; and/or (ii) autoantibodies with specificity for citrullinated tenascin-C and/or one or more fragments of citrullinated tenascin-C, in a sample from said subject.
Inventor(s):	Midwood; Kim Suzanne (Headington, GB), Venables; Patrick John (Headington, GB)
Assignee:	OXFORD UNIVERSITY INNOVATION LIMITED (Oxford, GB)
Application Number:	15/109,775
Patent Claims:	1. A method of detecting a citrullinated fibrinogen-like globe (FBG) domain of tenascin-C or a citrullinated fragment of the FBG domain of tenascin-C associated with the presence of rheumatoid arthritis (RA) in a subject, the method comprising: detecting in a biological sample obtained from the subject a citrullinated FBG domain of tenascin-C or a citrullinated fragment of the FBG domain of tenascin-C by (i) contacting the sample with an antibody that specifically binds to citrullinated arginine residues in the FBG domain of tenascin-C or to a citrullinated fragment of the FBG domain of, tenascin-C and detecting binding of the antibody to the citrullinated FBG domain of tenascin-C or to a citrullinated fragment of the FBG domain of tenascin-C; or by (ii) detecting a citrullinated FBG domain of tenascin-C or a citrullinated fragment of the FBG domain of tenascin-C using mass spectrometry. 2. The method of claim 1, further comprising measuring the level of (i) citrullinated fibrinogen-like globe (FBG) domain of tenascin-C or a citrullinated fragment of the FBG domain of tenascin-C in the sample by antibody binding or mass spectrometry relative to normal and/or reference values. 3. The method of claim 1, wherein the antibody that binds to said citrullinated arginine residues in the FBG domain of tenascin-C or to a citrullinated fragment of the FBG domain of tenascin-C is an immobilized antibody. 4. A method of monitoring the progression of rheumatoid arthritis (RA) in a subject or monitoring the efficacy of treatment for RA administered to a subject, the method comprising: (a) detecting in a biological sample obtained from a subject at a first time point the levels of (i) citrullinated fibrinogen-like globe (FBG) domain of tenascin-C or a citrullinated fragment of the FBG domain of tenascin-C by measuring binding of said citrullinated FBG domain of tenascin-C or a citrullinated fragment of the FBG domain of tenascin-C in the subject's sample to an immobilized antibody directed against the citrullinated FBG domain of tenascin-C or a citrullinated fragment of the FBG domain of tenascin-C, relative to normal and/or reference values; and/or (ii) autoantibodies with specificity for binding to the citrullinated FBG domain of tenascin-C or to a citrullinated fragment of the FBG domain of tenascin-C by measuring binding of autoantibodies in the subject's sample to an immobilized citrullinated FBG domain of tenascin-C or to immobilized citrullinated FBG domain fragments of tenascin-C, relative to normal and/or reference values; and (b) detecting in a biological sample obtained from the subject at a second and, optionally, a subsequent, time point the levels of (i) citrullinated FBG domain of tenascin-C or citrullinated fragments of the FBG domain of tenascin-C as in step (a) (i) relative to reference values; and/or (ii) autoantibodies with specificity for the citrullinated FBG domain of tenascin-C or the citrullinated fragments of the FBG domain of tenascin-C as in step (a) (ii) relative to reference values. 5. The method of claim 4 wherein the reference values are the initial levels of (i) the citrullinated FBG domain of tenascin-C or the citrullinated fragments of the FBG domain of tenascin-C; and/or (ii) autoantibodies with specificity for the citrullinated FBG domain of tenascin-C or citrullinated fragments of the FBG domain of tenascin-C in the subject, or the levels of (i) the citrullinated FBG domain of tenascin-C or citrullinated fragments of the FBG domain of tenascin-C; and/or (ii) autoantibodies with specificity for the citrullinated FBG domain of tenascin-C or citrullinated fragments of the FBG domain of tenascin-C in the subject when they were previously tested, or both. 6. The method of claim 1, wherein the sample is selected from blood, serum, plasma, synovial fluid or joint tissue obtained from the subject. 7. The method of claim 4, further comprising: (c) detecting: (i) decreased levels of a citrullinated fibrinogen-like globe (FBG) domain of tenascin-C or a citrullinated fragment of the FBG domain of tenascin-C, and/or decreased levels of autoantibodies with specificity for a citrullinated FBG domain of tenascin-C or for a citrullinated fragment of the FBG domain of tenascin-C in the sample obtained at the second or subsequent time point relative to the levels in the sample obtained at the first time point as indicative of reduced progression of RA in the subject or of effective treatment of RA in the subject; or (ii) increased levels of a citrullinated fibrinogen-like globe (FBG) domain of tenascin-C or a citrullinated fragment of the FBG domain of tenascin-C, and/or increased levels of autoantibodies with specificity for a citrullinated fibrinogen-like globe (FBG) domain of tenascin-C or a citrullinated fragment of the FBG domain of tenascin-C in the sample obtained at the second or subsequent time point relative to the levels in the sample obtained at the first time point as indicative of progression of RA in the subject or of ineffective treatment of RA in the subject. 8. The method of claim 4, wherein the antibody is immobilized on a support and/or the citrullinated FBG domain of tenascin-C and/or a citrullinated fragment of the FBG domain of tenascin-C is immobilized on a support. 9. The method of claim 4, wherein the sample is selected from blood, serum, plasma, synovial fluid or joint tissue obtained from the subject. 10. A method of detecting autoantibodies against a citrullinated fibrinogen-like globe (FBG) domain of tenascin-C and/or a citrullinated fragment of the FBG domain of tenascin-C associated with rheumatoid arthritis (RA) in a subject, the method comprising: (a) contacting a biological sample obtained from the subject with citrullinated FBG domain of tenascin-C and/or a citrullinated fragment of the FBG domain of tenascin-C attached to or immobilized on a support; and (b) detecting autoantibodies against the citrullinated FBG domain of tenascin-C and/or against a citrullinated fragment of the FBG domain of tenascin-C by detecting specific binding of the attached or immobilized citrullinated FBG domain of tenascin-C and/or the immobilized citrullinated fragment of the FBG domain of tenascin-C to the autoantibodies in the sample. 11. The method of claim 10, wherein the binding is detected by one or more of immunoassay, spectrometry, immunosorbent assay, enzyme linked immunosorbent assay (ELISA), sandwich ELISA, immunoprecipitation, immunoblotting, Western blot, slot blot assay, dot blot assay, isoelectric focusing, SDS-polyacrylamide gel electrophoresis and antibody microarray, immunohistological staining, radioimmunoassay (RIA), fluoroimmunoassay, or avidin-biotin or streptavidin-biotin immunoassay. 12. The method of claim 10, wherein the sample is selected from blood, serum, plasma, synovial fluid or joint tissue obtained from the subject. 13. The method of claim 1, wherein the antibody binding is detected by one or more of immunoassay, immunosorbent assay, enzyme linked immunosorbent assay (ELISA), sandwich ELISA, immunoprecipitation, immunoblotting, Western blot, slot blot assay, dot blot assay, antibody microarray, immunohistological staining, radioimmunoassay (RIA), fluoroimmunoassay, or avidin-biotin or streptavidin-biotin immunoassay. 14. The method of claim 4, wherein the binding is detected by one or more of immunoassay, spectrometry, immunosorbent assay, enzyme linked immunosorbent assay (ELISA), sandwich ELISA, immunoprecipitation, immunoblotting, Western blot, slot blot assay, dot blot assay, isoelectric focusing, SDS-polyacrylamide gel electrophoresis and antibody microarray, immunohistological staining, radioimmunoassay (RIA), fluoroimmunoassay, or avidin-biotin or streptavidin-biotin immunoassay. 15. A method of detecting (i) citrullinated tenascin-C and/or one or more citrullinated fragments of tenascin-C; and/or (ii) autoantibodies that specifically bind citrullinated tenascin-C and/or one or more citrullinated fragments of tenascin-C in a sample from a subject, said method comprising: a) obtaining a sample from the subject; b) contacting the sample with an antibody or an antigen binding fragment thereof directed against citrullinated tenascin-C comprising one or more citrullinated amino acid residues selected from cit50, cit51, cit55, cit72, cit120, cit169, cit173, cit209, cit214, cit219m, cit220, or cit222 of SEQ ID NO: 70 and/or one or more citrullinated fragments of citrullinated tenascin-C comprising one or more citrullinated amino acid residues selected from cit50, cit51, cit55, cit72,cit120, cit169, cit173, cit209, cit214, cit219m, cit220, or cit222 of SEQ ID NO: 70, wherein said antibody or an antigen binding fragment thereof is immobilized on a support, and detecting specific binding between the antibody or an antigen binding fragment thereof and the citrullinated tenascin-C and/or the one or more citrullinated fragments of citrullinated tenascin-C, wherein said binding is indicative of the presence of citrullinated tenascin-C and/or one or more citrullinated fragments of citrullinated tenascin-C in the subject; and/or c) contacting the sample with citrullinated tenascin-C comprising one or more citrullinated amino acid residues selected from cit50, cit51, cit55, cit72, cit120, cit169, cit173, cit209, cit214, cit219m, cit220, or cit222 of SEQ ID NO: 70 and/or the one or more citrullinated fragments of citrullinated tenascin-C comprising one or more citrullinated amino acid residues selected from cit50, cit51, cit55, cit72, cit120, cit169, cit173, cit209, cit214, cit219m, cit220, or cit222 of SEQ ID NO: 70, immobilized on a support, and detecting specific binding between autoantibodies in the sample and the immobilized citrullinated tenascin-C and/or the one or more citrullinated fragments of the citrullinated tenascin-C, wherein said binding is indicative of the presence of autoantibodies that bind the citrullinated tenascin-C and/or one or more citrullinated fragments of the citrullinated tenascin-C in the sample. 16. The method of claim 15, wherein the sample is selected from blood, serum, plasma, synovial fluid or joint tissue obtained from the subject. 17. The method of claim 15, wherein the binding is detected by one or more of immunoassay, spectrometry, immunosorbent assay, enzyme linked immunosorbent assay (ELISA), sandwich ELISA, immunoprecipitation, immunoblotting, Western blot, slot blot assay, dot blot assay, isoelectric focusing, SDS-polyacrylamide gel electrophoresis and antibody microarray, immunohistological staining, radioimmunoassay (RIA), fluoroimmunoassay, or avidin-biotin or streptavidin-biotin immunoassay. 18. The method of claim 15, further comprising measuring the levels of the citrullinated tenascin-C and/or the one or more of the citrullinated fragments of citrullinated tenascin-C in step (b) relative to a control or reference; and/or measuring the levels of the autoantibodies that bind to the citrullinated tenascin-C and/or to the one or more citrullinated fragments of the citrullinated tenascin-C in step (c) relative to a control or reference. 19. A method of diagnosing and treating rheumatoid arthritis (RA) in a subject, the method comprising: (a) detecting in a sample obtained from the subject specific binding of citrullinated tenascin-C comprising one or more citrullinated amino acid residues selected from cit50, cit51, cit55, cit72, cit120, cit169, cit173, cit209, cit214, cit219m, cit220, or cit222 of SEQ ID NO: 70, and/or one or more citrullinated fragments of citrullinated tenascin-C comprising one or more citrullinated amino acid residues selected from cit50, cit51, cit55, cit72, cit120, cit169, cit173, cit209, cit214, cit219m, cit220, or cit222 of SEQ ID NO:70 in the subject's sample to an immobilized antibody directed to citrullinated tenascin-C and/or one or more citrullinated fragments of citrullinated tenascin-C; and/or (b) detecting specific binding of autoantibodies in the subject's sample to immobilized citrullinated tenascin-C comprising one or more citrullinated amino acid residues selected from cit50, cit51, cit55, cit72, cit120, cit169, cit173, cit209, cit214, cit219m, cit220, or cit222 of SEQ ID NO: 70 and/or to one or more immobilized citrullinated fragments of citrullinated tenascin-C comprising one or more citrullinated amino acid residues selected from cit50, cit51, cit55, cit72, cit120, cit169, cit173, cit209, cit214, cit219m, cit220, or cit222 of SEQ ID NO: 70; (c) diagnosing RA in the subject when specific binding of the citrullinated tenascin-C and/or of the one or more citrullinated fragments of citrullinated tenascin-C in the subject's sample to the immobilized antibody is detected relative to control or reference levels; and/or when specific binding of autoantibodies in the subject's sample to the immobilized citrullinated tenascin-C and/or to the one or more immobilized citrullinated fragments of citrullinated tenascin-C is detected relative to control or reference levels; and (d) treating RA in the diagnosed subject. 20. The method of claim 19, wherein the treatment comprises administering to the subject one or more of an anti-TNF drug; an anti-IL17 therapy; a T-cell co-stimulation modulator; an interleukin-6 (IL-6) inhibitor; an anti-CD20 antibody; a B cell activating factor; an inhibitor of Janus kinase (JAK); an inhibitor of spleen tyrosine kinase (Syk); an anti-TNC antibody; an antibody to citrullinated domains of citrullinated tenascin-C; or an agent that modulates the biological activity of citrullinated and/or non-citrullinated tenascin-C. 21. The method of claim 20, wherein the T-cell co-stimulation modulator is abatacept, a fusion protein comprising the Fc region of IgG1 fused to the extracellular domain of CTLA-4; the interleukin-6 (IL-6) inhibitor is tocilizumab, a humanized monoclonal antibody which binds to the interleukin-6 receptor; the anti-CD20 antibody is rituximab, a chimeric monoclonal antibody which binds to the B cell surface protein CD20; the B cell activating factor is anti-B cell activating factor (BAFF); the inhibitor of Janus kinase (JAK) is compound 3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piper- idin-1-yl]-3-oxopropanenitrile; and the inhibitor of spleen tyrosine kinase (Syk) is compound [6-({5-Fluoro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)-2,2-- dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyl dihydrogen phosphate. 22. The method of claim 19, wherein the subject's sample is selected from blood, peripheral blood, serum, plasma, cerebrospinal fluid (CSF), urine, saliva, stool or synovial fluid. 23. The method of claim 19, wherein the binding is detected by one or more of immunoassay, spectrometry, immunosorbent assay, enzyme linked immunosorbent assay (ELISA), sandwich ELISA, immunoprecipitation, immunoblotting, Western blot, slot blot assay, dot blot assay, isoelectric focusing, SDS-polyacrylamide gel electrophoresis and antibody microarray, immunohistological staining, radioimmunoassay (RIA), fluoroimmunoassay, or avidin-biotin or streptavidin-biotin immunoassay. 24. The method of claim 15, wherein the citrullinated tenascin-C or the one or more citrullinated fragments of citrullinated tenascin-C comprise a peptide selected from SEQ ID NO: 55, SEQ ID NO: 57, SEQ ID NO: 59, SEQ ID NO: 61, SEQ ID NO: 63, or SEQ ID NO: 64. 25. The method of claim 15, wherein the citrullinated tenascin-C or the one or more citrullinated fragments of citrullinated tenascin-C comprise one or more citrullinated amino acid residues selected from cit55, cit209, cit214, cit219, or cit220 of SEQ ID NO: 70. 26. The method of claim 19, wherein the citrullinated tenascin-C or the one or more citrullinated fragments of citrullinated tenascin-C comprise a peptide selected from SEQ ID NO: 55, SEQ ID NO: 57, SEQ ID NO: 59, SEQ ID NO: 61, SEQ ID NO: 63, or SEQ ID NO: 64. 27. The method of claim 19, wherein the citrullinated tenascin-C or the one or more citrullinated fragments of citrullinated tenascin-C comprise one or more citrullinated amino acid residues selected from cit55, cit209, cit214, cit219, or cit220 of SEQ ID NO: 70.

Details for Patent 10,088,479

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2034-01-13
Bristol-myers Squibb Company	ORENCIA	abatacept	For Injection	125118	12/23/2005		2034-01-13
Bristol-myers Squibb Company	ORENCIA	abatacept	Injection	125118	07/29/2011		2034-01-13
Bristol-myers Squibb Company	ORENCIA	abatacept	Injection	125118	06/07/2016		2034-01-13
Bristol-myers Squibb Company	ORENCIA	abatacept	Injection	125118	03/30/2017		2034-01-13
Genentech, Inc.	ACTEMRA	tocilizumab	Injection	125276	01/08/2010		2034-01-13