Blocking endothelial lipase with monoclonal antibody MEDI5884 durably increases high density lipoprotein in nonhuman primates and in a phase 1 trial
| Autor: | Judith Hsia, Chang Yeop Han, Bill Cook, Minal B. Mehta, Tomas Vaisar, Melissa Damschroder, ChaoYu Jin, Alan Chait, Holly Kimko, Lan-Feng Tsai, Glenn Carlson, Qun Du, David Han, Boaz Hirshberg, B. Timothy Hummer, Nicholas Bhagroo, Judith Falloon, Anton I. Rosenbaum, Joseph Grimsby, Steven Novick, Sotirios K. Karathanasis, John E. Le Lay, Christopher J. Rhodes |
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| Rok vydání: | 2021 |
| Předmět: |
Primates
0301 basic medicine Endothelial lipase medicine.medical_specialty 030204 cardiovascular system & hematology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine High-density lipoprotein Internal medicine medicine Animals Risk factor biology business.industry Cholesterol PCSK9 Cholesterol HDL Antibodies Monoclonal nutritional and metabolic diseases Lipase General Medicine 030104 developmental biology Endocrinology chemistry Monoclonal biology.protein lipids (amino acids peptides and proteins) Proprotein Convertase 9 Antibody Lipoproteins HDL business Lipoprotein |
| Zdroj: | Science Translational Medicine. 13 |
| ISSN: | 1946-6242 1946-6234 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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