Abstract 403: Generation of PreBeta1 High Density Lipoprotein by CSL112 in Human Plasma

The ability of apoA-I to remove cholesterol from atherosclerotic plaque is thought to underlie its inverse correlation with cardiovascular risk. CSL112 was designed as an infusible formulation of human apoA-I to rapidly remove plaque cholesterol and reduce risk after an ACS. We have recently shown that infusion of CSL112 into rabbits caused a strong and immediate increase in the ABCA1-dependent efflux capacity of plasma, an increase in plasma unesterified cholesterol and rapid subsequent esterification of the cholesterol. In the presence of human plasma, CSL112 was significantly more potent than human HDL 3 at enhancing cholesterol efflux, and the efflux elevation was predominantly via the ABCA1 transporter. Consistent with this observation, addition of CSL112 to plasma led to generation of high levels of PreBeta1-HDL, a favorable substrate for ABCA1. Phase 1 studies of CSL112 have confirmed the elevation of efflux capacity in humans and the rapid generation of PreBeta1. Here we examine the steps leading to formation of PreBeta1-HDL. Plasma spiked with 0.8 mg/mL CSL112 and held at 0[[Unable to Display Character: ⁰]]C did not increase PreBeta1-HDL levels. However, incubation at 37[[Unable to Display Character: ⁰]]C caused the generation of PreBeta1 that reached half-maximal levels at 15-20 min and maximal levels at 2 h (7-fold over baseline). By contrast, addition of HDL 3 to plasma caused minimal generation of PreBeta1-HDL at any time point. Native gradient gel electrophoresis showed that formation of PreBeta1 was accompanied by elevation in the size and protein content of HDL 3 and HDL 2 . These data suggest that the remarkable ability of CSL112 to elevate efflux and PreBeta1 derives from engaging plasma proteins in a process of lipoprotein remodeling.