Abstract 502: CSL112, a Novel Formulation of Human ApoA-I, Enhances the Capacity of Serum to Efflux Cholesterol from Macrophages

The ability of HDL to remove cholesterol from macrophages in atherosclerotic plaque is thought to underlie its inverse correlation with cardiovascular risk. Indeed, cholesterol efflux from macrophages is a functional serum marker that has an even stronger inverse association with coronary heart disease than HDL cholesterol (Khera et al. 2011, NEJM 364;2;127). We recently described CSL112, a novel formulation of full length human apoA-I and phospholipids designed to resemble nascent HDL and to maximize cholesterol efflux from macrophages. Here we studied the effects of CSL112 vs HDL3 on ex vivo cholesterol efflux in human plasma and serum. Addition of HDL3 to pooled plasma significantly increased ABCA1-independent efflux but had little or no effect on ABCA1-dependent efflux. In contrast, the addition of CSL112 increased not only ABCA1-independent efflux but also strongly increased ABCA1-dependent efflux in a concentration dependent fashion. Through a range of concentrations, CSL112 was significantly more efficacious in global cholesterol efflux than was HDL3. For example, at 5 μg/mL, CSL112 increased global efflux by 152% ± 5.6% vs 66% ± 7.4% for HDL3. Additional studies examined serum samples from five subjects with a range of lipid phenotypes including low, normal and high levels of HDL. When spiked into these sera, CSL112 increased both ABCA1-dependent and independent efflux in all subjects, regardless of lipid profile. In all subjects, the relative increase in ABCA1-dependent efflux was larger than that observed with ABCA1-independent efflux indicating selectivity of the interaction of CSL112 with the ABCA1 transporter. We speculate that the disproportionate rise in ABCA1-dependent efflux with CSL112 may be explained by the observation that PreBeta1-HDL levels measured by ELISA increase dramatically upon incubation of CSL112 with human plasma. We conclude that CSL112 robustly enhances the capacity of human serum to promote cholesterol efflux; the enhancement appears independent of lipid phenotype, is greater than that observed with HDL3 and that the efflux derives disproportionately from the ABCA1 pathway.