Development of a therapeutic for fibrotic diseases; diabetic nephropathy, idopath

DESCRIPTION (provided by applicant): Chronic kidney disease affects twenty million Americans and current treatments, at the cost of 32 billion in 2004, only slow the progression to renal failure. In chronic kidney diseases (CKD) such as diabetic nephropath y, fibrosis, the accumulation of extracellular matrix proteins, disrupts tissue architecture and function and ultimately results in organ failure. The end point of this proposal is to demonstrate the therapeutic activity of a humanized antibody CT100 which targets a major regulator of extracellular matrix protein degradation, plasminogen activator inhibitor -1, PAI-1. First, a final drug candidate will be selected from CT100 and a couple of variants of CT100. Selection will be based on their overall drug-li ke properties including; 1) affinity, which will be determined by surface plasmon resonance, 2) neutralization of the target protein, 3) binding to proteins related to the target protein, and 4) stability in plasma. The last three properties are determined in enzymatic based assays. The selected CT100 will then be tested for its ability to protect animals from kidney disease. Initially, the pharmacokinetic profile will be determined in the chosen animal, rat or mouse. CT100 will then be administered to anim als at a dose calculated to protect animals in a model of fibrotic kidney disease. The efficacy of CT100 will be determined through measuring changes in biomarkers and histology. Having demonstrated proof of concept in an animal model CT100 will progress t oward becoming a novel therapeutic to treat chronic kidney diseases. PUBLIC HEALTH RELEVANCE The overall goal of this proposal is the initial demonstration that the humanized antibody, CT100, has therapeutic activity in an animal model of kidney fibrosis o r chronic kidney disease. If this is demonstrated the antibody will progress toward becoming a novel treatment for an unmet medical need effecting 20 million individuals in the US. Treatment costs for end stage renal disease in the US in 2004 was 32.4 bill ion (NIH, kidney.niddk.nih.gov).