부산대학교 도서관

Introduction:Increasing the quantity and function of HDL may provide cardiovascular protection by enhancing cholesterol efflux capacity (CEC), modulating vascular tone, and promoting anti-inflammatory and anti-oxidant effects. Endothelial lipase (EL), a member of the triglyceride lipase family that preferentially hydrolyses HDL phospholipids (PL) resulting in HDL particle destabilisation and clearance via glomerular filtration. A first-in-class EL-neutralising mAb, MEDI5884, was assessed in nonhuman primates (NHPs) and healthy volunteers (HVs).Hypothesis:Neutralising EL would improve the quantity and functionality of HDL by prevention of phospholipid hydrolysis, which may translate into reduced cardiovascular risk.Methods:Nonclinical studies of MEDI5884 were completed before conduct of a randomized, blinded single-ascending-dose phase 1 clinical study in HVs; 4 dosage levels (30,100, 300 and 600 mg; n= 12/4, mAb/placebo each) were evaluated. Standard lipoprotein profiles, particle size and distribution (2D gel and/or nuclear magnetic resonance analysis), CEC (macrophage efflux assay) were assessed; inhibition of inflammation was assessed in NHPs (macrophage cell culture model).Results:MEDI5884 potently neutralised EL in vitro without cross-reactivity to hepatic lipase or lipoprotein lipase. In NHPs, HDL-C increased in a dose-dependent manner with a corresponding increase in CEC and evidence of HDL anti-inflammatory effects. There were no findings from toxicology studies that precluded development. In 64 HVs, MEDI5884 was associated with a dose-dependent increase in HDL-C (statistically significant in the 100, 300 and 600 mg groups at Day 28 compared with placebo; mean of 25.1 mg/dL increase in 600 mg group), ApoA1, HDL-PL and HDL particle size and number. Safety and tolerability, including immunogenicity, and the PK profile support further development.Conclusions:Neutralisation of EL raised HDL-C and HDL particle number with parallel increases in ex vivo CEC and anti-inflammatory properties. These data are the first to demonstrate the effects of EL neutralisation in NHPs and humans. The data support further clinical development of MEDI5884 for the prevention of secondary cardiovascular events.