Claims for Patent: 9,494,601

Summary for Patent: 9,494,601

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:	15/013,833
Patent Claims:	1. A method for treating a patient having atypical hemolytic uremic syndrome (aHUS) whose blood or urine has been determined to contain elevated levels at least two aHUS-associated biomarker proteins selected from the group consisting of TNFR1, MCP-1, 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), the method comprising administering to the patient an inhibitor of complement C5 in an amount and with a frequency sufficient to reduce the concentration of the at least two aHUS-associated biomarker proteins compared to the concentration measured in the patient's blood or urine prior to treatment with the complement C5 inhibitor. 2. The method of claim 1, wherein the subject: (a) has received dialysis at least once within the three months immediately prior to treatment with the complement C5 inhibitor; or (b) is experiencing a first acute aHUS manifestation. 3. The method of claim 1, wherein the reduced concentration of the at least two aHUS-associated biomarker proteins occurs within two weeks or two months after the first administration of the complement C5 inhibitor. 4. The method of claim 1, wherein the subject is chronically treated with a complement C5 inhibitor. 5. 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. 6. 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. 7. The method of claim 1, wherein the complement C5 inhibitor is an antibody, or an antigen-binding fragment thereof. 8. The method of claim 7, 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. 9. The method of claim 7, wherein the antibody, or antigen-binding fragment thereof, binds to complement component C5 and inhibits cleavage of C5 into fragments C5a and C5b. 10. The method of claim 9, wherein the antibody is eculizumab or a variant of eculizumab. 11. The method of claim 10, wherein the antigen-binding fragment is pexelizumab. 12. The method of claim 1, wherein at least one of the aHUS-associated biomarkers is selected from the group consisting of: proteolytic fragment Ba of factor B, TNFR1, VCAM-1, D-dimer, thrombomodulin, and cystatin C. 13. The method of claim 1, wherein the at least two aHUS-associated biomarker proteins are measured using an immunoassay, such as an enzyme-linked immunosorbent assay (ELISA) or a radioimmunoas say (RIA). 14. The method of claim 1, wherein the biological fluid is blood, a blood fraction, or urine. 15. The method of claim 14, wherein the blood fraction is serum or plasma. 16. The method of claim 1, wherein: (i) the concentration of at least one aHUS-associated biomarker is measured in two or more types of biological fluid; or (ii) the concentration of a first of the at least two aHUS-associated biomarker proteins is measured in one type of biological fluid and the concentration of a second of the at least two aHUS biomarker proteins is measured in a second type of fluid. 17. The method of claim 1, wherein: (i) the concentration of CXCL9, IFN-.gamma., MCP-1, CCL5, sCD40L, or sTNFR1 in the serum of the subject is determined; (ii) the concentration of at least one of (32 microglobulin (.beta.2M), clusterin, cystatin C, NAG, TIMP-1, NGAL, fatty acid binding protein 1 (FABP-1), CXCL9, albumin, and KIM-1 in the urine of the subject is determined; (iii) the concentration of NGAL, a proteolytic fragment of complement component factor B, soluble C5b9 (sC5b9), prothrombin fragment F1+2, D-dimer, thrombomodulin, or von Willebrand Factor (vWF) in the plasma of the subject is determined; and/or (iv) the concentration of Ba in plasma obtained from the subject is determined. 18. The method of claim 1, wherein the normal concentration of sTNFR1 is less than 2000 pg/mL. 19. The method of claim 1, wherein the concentration of sTNFR1 in the biological sample is deemed elevated when it is: (i) at least two fold greater than the normal concentration of sTNFR1; or (ii) at least 10,000 .mu.g/mL.

Details for Patent 9,494,601

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