Endothelial Lipase: a novel therapeutic target for HDL and atherosclerosis

DESCRIPTION (provided by applicant): There is mounting evidence indicating that endothelial lipase (EL) plays a key role in the regulation of circulating cholesterol levels by modulating high-density lipoprotein-cholesterol (HDL-C) levels and hence reverse cholesterol transport. Therefore, EL provides a promising target for therapeutic intervention to combat atherosclerosis. However, identification of small molecule inhibitors has proved difficult both in providing agents with adequate inhibitory activity as well as adequate specificity for the EL enzymatic site compared to lipoprotein (LPL) and hepatic (HL) lipases. Antibodies, in contrast, can provide the necessary specificity and blocking activity. The goals of this project are to utilize our novel yeast display platform to screen for monoclonal human antibody clones that display antibodies that bind human EL, screen the isolated clones for antibodies that block El activity, and test the selected antibody for efficacy at modulating HDL-C in mice to identify an antibody therapeutic candidate for development. A successful outcome of these Phase I studies will have identified an antibody therapeutic candidate suitable for toxicology and clinical development in the Phase II stage of this project. PUBLIC HEALTH RELEVANCE: Elevated cholesterol levels leading to atherosclerosis, heart attacks and strokes remain a major health issue. Currently billions of dollars are spent on chemical agents known as statins but these agents cannot reverse disease and are associated with side effects. The goals of this study are to develop an alternative approach to reducing bad cholesterol by generating a biologic antibody against endothelial lipase (EL) that plays a key role in the regulation of circulating cholesterol levels. This antibody will be isolated using our novel technology platform that provides a rapid and efficient means of identifying useful antibodies that can be used directly in patients.