Research ArticleDrug Development

Blocking endothelial lipase with monoclonal antibody MEDI5884 durably increases high density lipoprotein in nonhuman primates and in a phase 1 trial

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Science Translational Medicine  21 Apr 2021:
Vol. 13, Issue 590, eabb0602
DOI: 10.1126/scitranslmed.abb0602

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Limiting lipase to control cholesterol

Strategies to reduce low-density lipoprotein cholesterol (LDL-C) while promoting high-density lipoprotein cholesterol (HDL-C) are of interest for combating atherosclerosis. Le Lay et al. developed a monoclonal antibody that neutralizes endothelial lipase, an enzyme that hydrolyzes HDL. Antibody treatment in nonhuman primates increased plasma HDL-C, and pretreatment with a PCSK9-neutralizing antibody reduced LDL-C. Results from a phase 1 study showed that the endothelial lipase-neutralizing antibody was safe and elevated HDL-C. This approach may help reduce cardiovascular risk.

Abstract

Cardiovascular disease (CVD) is the leading global cause of death, and treatments that further reduce CV risk remain an unmet medical need. Epidemiological studies have consistently identified low high-density lipoprotein cholesterol (HDL-C) as an independent risk factor for CVD, making HDL elevation a potential clinical target for improved CVD resolution. Endothelial lipase (EL) is a circulating enzyme that regulates HDL turnover by hydrolyzing HDL phospholipids and driving HDL particle clearance. Using MEDI5884, a first-in-class, EL-neutralizing, monoclonal antibody, we tested the hypothesis that pharmacological inhibition of EL would increase HDL-C by enhancing HDL stability. In nonhuman primates, MEDI5884 treatment resulted in lasting, dose-dependent elevations in HDL-C and circulating phospholipids, confirming the mechanism of EL action. We then showed that a favorable lipoprotein profile of elevated HDL-C and reduced low-density lipoprotein cholesterol (LDL-C) could be achieved by combining MEDI5884 with a PCSK9 inhibitor. Last, when tested in healthy human volunteers, MEDI5884 not only raised HDL-C but also increased HDL particle numbers and average HDL size while enhancing HDL functionality, reinforcing EL neutralization as a viable clinical approach aimed at reducing CV risk.

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