Abstract 10978: MDCO-216 (Apo A-I Milano/POPC Complex) Administered to Cynomolgus Monkeys Induces Pronounced Changes in Plasma Lipids and Apolipoproteins
MDCO-216 is a complex of dimeric recombinant apolipoprotein A-I Milano (Apo A-IM, a genetic variant of naturally occurring apolipoprotein A-I with Cys for Arg at position 173) and POPC, a naturally occurring phospholipid. MDCO-216 mimics pre-beta HDL in both structure and function, and in earlier studies it was shown to reduce atherosclerotic plaque size and volume in animal models and ACS patients. The objective of this study was to investigate the effects of MDCO-216 on serum lipid profiles and apoproteins in cynomolgus monkeys. Animals were randomly divided into 4 groups (3 males and 3 females /group) and treated with vehicle or MDCO-216 at 30, 100 and 300 mg/kg dose as 60 min. IV infusion every 2 days over a period of 41 days. Lipid and apoprotein levels were determined at Day -6 (baseline) and on days 15, 41 and day 71. Samples on day 15 and 41 taken just prior to next dosing.
Results: Effects of increasing doses of MDCO-216 on lipids and apoproteins at day 15, expressed as percent of baseline, are given in the Table. Effects were similar for males and females and therefore values were pooled. Effects at day 41 were similar to day 15, while all values had returned to baseline on day 71.
Conclusions: 1. MDCO-216 increased the level of free cholesterol (by over 10-fold at the highest dose), in line with the expected action of the drug on cholesterol transporters. FreeChol/Total Chol ratio increased from 0.24 at baseline to 0.76 at the highest dose suggesting that cholesterol esterification by LCAT was not able to cope with the increased influx of cholesterol into plasma. 2. Triglycerides and ApoB levels moderately increased at the higher doses, possibly due to increased delivery of free cholesterol and phospholipids to the liver, known to result in increased VLDL production. 3. ApoA-I and ApoA-II both decreased (by 50 and 80%, respectively) probably due to enhanced rate of clearance of these proteins, as previously shown in patients with the ApoA-IM mutation.
- © 2011 by American Heart Association, Inc.