Claims for Patent: 9,658,236

Summary for Patent: 9,658,236

Title:	Atypical hemolytic uremic syndrome (aHUS) biomarker proteins
Abstract:	The disclosure provides biomarker proteins, a change in the concentration or activity level of which are associated with atypical hemolytic uremic syndrome (aHUS) or clinically meaningful treatment of aHUS with a complement inhibitor. Also provided are compositions and methods for interrogating the concentration and/or activity of one or more of the biomarker proteins in a biological fluid. The compositions and methods are useful for, among other things, evaluating risk for developing aHUS, diagnosing aHUS, determining whether a subject is experiencing the first acute presentation of aHUS, monitoring progression or abatement of aHUS, and/or monitoring response to treatment with a complement inhibitor or optimizing such treatment.
Inventor(s):	McKnight; Susan Faas (Old Lyme, CT), Cofiell; Roxanne (Glastonbury, CT), Kukreja; Anjli (Fairfield, CT), Bedard; Krystin A. (N/A), Yan; Yan (Cheshire, CT)
Assignee:	Alexion Pharmaceuticals, Inc. (New Haven, CT)
Application Number:	15/287,162
Patent Claims:	1. A method for monitoring responsiveness of a subject to treatment with an inhibitor of complement C5, the method comprising: determining the concentration of at least two aHUS-associated biomarker proteins in a biological fluid obtained from the subject, wherein: (a) the aHUS-associated biomarker proteins are selected from the group consisting of TNFR1, MCP-1, TNFR1, IFN-.gamma., IL-6, a proteolytic fragment of complement component factor B, soluble C5b9 (sC5b9), prothrombin fragment F1+2, D-dimer, thrombomodulin, VCAM-1, von Willebrand Factor (vWF), complement component C5a, .beta.2 microglobulin (.beta.2M), clusterin, cystatin C, NAG, TIMP-1, NGAL, fatty acid binding protein 1 (FABP-1), albumin, CXCL9, KIM-1, and CCL5, soluble CD40 ligand (sCD40L), ICAM-1, IL-1 beta, IL-12 p70, IL-8, and vascular endothelial cell growth factor (VEGF); (b) the subject has, is suspected of having, or is at risk for developing aHUS; (c) the subject has been or is being treated with an inhibitor of complement C5; and (d) the subject has a reduced concentration of the at least two aHUS biomarker proteins compared to the concentration measured in a sample of biological fluid of the same type obtained from the subject prior to treatment with the complement C5 inhibitor. 2. The method of 1, wherein the complement C5 inhibitor is selected from the group consisting of a small molecule, a polypeptide, a polypeptide analog, a peptidomimetic, and an aptamer. 3. The method of 1, wherein the complement C5 inhibitor is selected from the group consisting of MB12/22, MB12/22-RGD, ARC187, ARC1905, SSL7, and OmCI. 4. The method of claim 1, wherein the complement C5 inhibitor is an antibody, or an antigen-binding fragment thereof. 5. The method of claim 4, wherein the antibody, or antigen-binding fragment thereof, is selected from the group consisting of a humanized antibody, a recombinant antibody, a diabody, a chimerized or chimeric antibody, a monoclonal antibody, a deimmunized antibody, a fully human antibody, a single chain antibody, an Fv fragment, an Fd fragment, an Fab fragment, an Fab' fragment, and an F(ab').sub.2 fragment. 6. The method of claim 4, wherein the antibody, or antigen-binding fragment thereof, binds to complement component C5 and inhibits cleavage of C5 into fragments C5a and C5b. 7. The method of claim 6, wherein the antibody is eculizumab or a variant of eculizumab. 8. The method of claim 6, wherein the antigen-binding fragment is pexelizumab. 9. The method of claim 1, wherein at least one of the aHUS-associated biomarkers is selected from the group consisting of: a proteolytic fragment Ba of factor B, TNFR1, VCAM-1, D-dimer, thrombomodulin, and cystatin C. 10. A method for diagnosing a subject as having or being at risk for developing atypical hemolytic uremic syndrome (aHUS), the method comprising: determining the concentration of at least two aHUS-associated biomarker proteins in a biological fluid obtained from a subject, wherein the aHUS-associated biomarker proteins are selected from the group consisting of TNFR1, a proteolytic fragment of complement component factor B, soluble C5b9 (sC5b9), thrombomodulin, VCAM-1, von Willebrand Factor (vWF), soluble CD40 ligand (sCD40L), prothrombin fragment F1+2, D-dimer, MCP-1, TNFR1, IFN-.gamma., ICAM-1, IL-1 beta, IL-12 p70, complement component C5a, .beta.2 microglobulin (.beta.2M), clusterin, cystatin C, NAG, TIMP-1, NGAL, fatty acid binding protein 1 (FABP-1), CXCL9, KIM-1, IL-18, vascular endothelial cell growth factor (VEGF), IL-6, albumin, IL-8, and CCL5, wherein an elevated concentration of the at least two aHUS-associated biomarker proteins compared to the concentration of the aHUS-associated biomarker proteins measured in a sample of biological fluid of the same type indicates that the subject has, or is at risk for developing, aHUS. 11. A kit for diagnosing aHUS, wherein the kit comprises (a) an assay plate and (b) at least three binding agents, wherein the binding agent is an antibody, or an antigen-binding fragment thereof, capable of binding to a different biological analyte, wherein the analytes are proteins, wherein the proteins are selected from the group consisting of TNFR-1, a proteolytic fragment of complement component factor B, soluble C5b9 (sC5b9), thrombomodulin, VCAM-1, von Willebrand Factor (vWF), soluble CD40 ligand (sCD40L), prothrombin fragment F1+2, D-dimer, MCP-1, TNFR1, IFN-.gamma., ICAM-1, IL-1 beta, IL-12 p70, complement component C5a, .beta.2 microglobulin (.beta.2M), clusterin, cystatin C, NAG, TIMP-1, NGAL, fatty acid binding protein 1 (FABP-1), CXCL9, KIM-1, IL-18, vascular endothelial cell growth factor (VEGF), IL-6, albumin, IL-8 and CCL5.

Details for Patent 9,658,236

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Alexion Pharmaceuticals, Inc.	SOLIRIS	eculizumab	Injection	125166	03/16/2007		2033-08-07