Blocking endothelial lipase with monoclonal antibody MEDI5884 durably increases high density lipoprotein in nonhuman primates and in a phase 1 trial PMID: 33883272

Target-related Cytokines

2026-09-23

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

Sci Transl Med. 2021 Apr 21;13(590):eabb0602. doi: 10.1126/scitranslmed.abb0602.

John E Le Lay ¹ , Qun Du ² , Minal B Mehta ¹ , Nicholas Bhagroo ¹ , B Timothy Hummer ³ , Judith Falloon ⁴ , Glenn Carlson ⁵ , Anton I Rosenbaum ⁶ , ChaoYu Jin ⁷ , Holly Kimko ⁸ , Lan-Feng Tsai ⁹ , Steven Novick ¹⁰ , Bill Cook ⁴ , David Han ¹¹ , Chang Yeop Han ¹² , Tomas Vaisar ¹² , Alan Chait ¹² , Sotirios K Karathanasis ¹³ , Christopher J Rhodes ¹³ , Boaz Hirshberg ⁴ , Melissa M Damschroder ² , Judith Hsia ⁴ , Joseph S Grimsby ¹⁴

Affiliations

1. Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA.
2. Biologic Therapeutics, Antibody Discovery and Protein Engineering, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA.
3. CVRM Safety, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA.
4. Clinical Development, Research and Early Development, CVRM, BioPharmaceuticals Medical, AstraZeneca, Gaithersburg, MD 20878, USA.
5. Clinical CV, Late Stage Development, CVRM, BioPharmaceuticals Medical, AstraZeneca, Gaithersburg, MD 20878, USA.
6. Integrated Bioanalysis, Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, South San Francisco, CA 94080, USA.
7. Clinical Immunology and Bioanalysis, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, South San Francisco, CA 94080, USA.
8. Clinical Pharmacology and DMPK, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA.
9. CVRM Biometrics, Data Sciences and AI, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA.
10. Data Sciences and Quantitative Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA.
11. Parexel International, Glendale, CA 91206, USA.
12. Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA 98915, USA.
13. Research and Early Development, Cardiovascular, Renal, and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA.
14. Research and Early Development, Cardiovascular, Renal, and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA. [email protected].

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.