Atypical hemolytic uremic syndrome (aHUS) biomarker proteins
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.
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-γ, 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, β2 microglobulin (β2M), 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′) 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-γ, ICAM-1, IL-1 beta, IL-12 p70, complement component C5a, β2 microglobulin (β2M), 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-γ, ICAM-1, IL-1 beta, IL-12 p70, complement component C5a, β2 microglobulin (β2M), 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.