Abstract 11838: CSL112, a Novel Formulation of Apolipoprotein A-I Exhibits Potent Anti-Inflammatory Activity in Whole Blood

Abstract

Inflammatory responses caused by cholesterol accumulation in the artery wall contribute to the pathogenesis of coronary artery disease. Emerging evidence suggests that the atheroprotective property of HDL to ameliorate inflammation is closely related to its capacity to efflux cholesterol via transport proteins such as ATP-binding cassette transporter A1 (ABCA1). We have recently described a formulation of full length human apoA-I purified from human plasma and reconstituted to form HDL particles suitable for IV infusion (CSL112). We have shown that CSL112 is more effective than HDL3 in enhancing the ability of plasma to support ABCA1-dependent cholesterol efflux from lipid-laden macrophages in vitro. In this study we assessed the anti-inflammatory properties of CSL112 using human whole blood stimulated with phytohemagglutinin (PHA-M) in vitro as a model of inflammation. To gauge potency, parallel studies used HDL3 isolated from pooled human plasma. We demonstrate that at clinically relevant concentrations of 0.25-1 mg/ml, CSL112 causes a strong inhibition of the expression of ICAM1 (CD54) on both monocytes and neutrophils. Further we find that CSL112 inhibits the secretion of pro-inflammatory cytokines (TNFα, IL-1β and IL-6) and chemokines (IL-8, RANTES and Mip-1β) in PHA-stimulated human blood. Approximately two-fold higher concentrations of HDL3 were required to achieve a similar extent of inhibition of pro-inflammatory mediator secretion compared to CSL112. An explanation for the greater potency of CSL112 might come from our recent observation that CSL112 is rapidly remodeled in plasma producing strong acceptors of cellular cholesterol from ABCA1. The potent anti-inflammatory effects of CSL112 observed in vitro were supported by in vivo experiments in rabbits demonstrating that CSL112 causes a strong reduction in the expression of tumor necrosis factor alpha (TNFα) and interleukin 1 beta (IL-1β) in post-infused rabbit blood stimulated ex vivo. Taken together our data demonstrate that CSL112 exhibits anti-inflammatory properties that may prove to be beneficial for rapidly reducing active inflammation and the early excess risk of cardiovascular events in patients with acute coronary syndrome.