Abstract 622: Development of an Antioxidized Phospholipid Neutralizing Antibody as an Atheroprotective Therapeutic Agent

Abstract

Atherosclerosis is a chronic disease of the arterial wall, which contributes to >40% of all deaths in developed societies. Widespread use of statins and life style modifications within developed nations have resulted in modest reductions in the incidences and severity of atherosclerotic disease, but as yet there is no clear evidence that statins can prevent late stage clinical consequences of atherosclerosis including plaque rupture with possible myocardial infarction or stroke.

Atherosclerosis is a complex disease characterized by two key processes, lipid deposition and inflammation within the arterial wall, and oxidative stress providing the link between the two. Oxidized phospholipids (OxPL), such as oxidized PAPC (1-palmitoil-2-arachodonoyl-sn-glycero-3-phosphorylcholine) and its derivatives are the biologically active components of minimally oxidized LDL, whose role in cardiovascular diseases is well recognized. Atherosclerotic ApoE knockout (KO) mice fed a high fat Western diet develop antibodies (Abs) to OxPL, and hybridoma B cell lines producing natural auto-Abs against OxPL have been successfully generated and characterized. However, as yet, no studies have been reported demonstrating that treatment with OxPL neutralizing Abs can be used to prevent or reverse atherosclerosis.

Of major importance, we recently generated an anti-OxPL auto-Ab (10C12) that demonstrates potent OxPL neutralizing activity in vitro. Sequence analysis showed that 10C12 Ab is structurally different from previously described anti-OxPL EO6 type neutralizing Abs. Moreover, we found that 10C12 Ab injections (IP, twice a week) in ApoE KO mice fed a Western diet for four weeks resulted in: 1) high circulating titers of Abs to OxPL as measured by ELISA; 2) significantly decreased accumulation of macrophages within the brachiocephalic artery, a site of advanced plaque formation in mice; and 3) a decreased OxPL-induced inflammatory response following IP injection of OxPL as determined by analysis of inflammatory gene expression in abdominal lavage cells.

Results of our work give insight into the role of OxPL in atherosclerosis and lead to potential novel therapeutic approaches to treat it or prevent clinical complications of atherosclerosis.