ANGPTL3 blockade with a human monoclonal antibody reduces plasma lipids in dyslipidemic mice and monkeys
Open accessAbstract
Angiopoietin-like protein 3 (ANGPTL3) is a circulating protein synthesized exclusively in the liver that inhibits LPL and endothelial lipase (EL), enzymes that hydrolyze TGs and phospholipids in plasma lipoproteins. Here we describe the development and testing of a fully human monoclonal antibody (REGN1500) that binds ANGPTL3 with high affinity. REGN1500 reversed ANGPTL3-induced inhibition of LPL activity in vitro. Intravenous administration of REGN1500 to normolipidemic C57Bl/6 mice increased LPL activity and decreased plasma TG levels by ≥50%. Chronic administration of REGN1500 to dyslipidemic C57Bl/6 mice for 8 weeks reduced circulating plasma levels of TG, LDL-cholesterol (LDL-C), and HDL-cholesterol (HDL-C) without any changes in liver, adipose, or heart TG contents. Studies in EL knockout mice revealed that REGN1500 reduced serum HDL-C through an EL-dependent mechanism. Finally, administration of a single dose of REGN1500 to dyslipidemic cynomolgus monkeys caused a rapid and pronounced decrease in plasma TG, nonHDL-C, and HDL-C. REGN1500 normalized plasma TG levels even in monkeys with a baseline plasma TG greater than 400 mg/dl. Collectively, these data demonstrate that neutralization of ANGPTL3 using REGN1500 reduces plasma lipids in dyslipidemic mice and monkeys, and thus provides a potential therapeutic agent for treatment of patients with hyperlipidemia.
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In murine models, IONIS-ANGPTL3-LRx reduced hepatic TG content, which differentiates it from anti-ANGPTL3 antibodies.
“In murine models, it reduced hepatic TG content, which differentiates it from anti-ANGPTL3 antibodies.83”
From Clinical review on triglycerides (2020) · cites this paper as [83]
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- Authors
- Gusarova, V., Alexa, C. A., Wang, Y., Rafique, A., Kim, J. H., Buckler, D., Mintah, I. J., Shihanian, L. M., Cohen, J. C., Hobbs, H. H., Xin, Y., Valenzuela, D. M., Murphy, A. J., Yancopoulos, G. D., & Gromada, J.
- Affiliations
- Regeneron (United States) (US)
- Howard Hughes Medical Institute (US)
- The University of Texas Southwestern Medical Center (US)
- ORCID
- Venue
- Journal of Lipid Research
- Publisher
- Elsevier BV
- Published
- 2015-07
- Volume
- 56
- Issue
- 7
- Pages
- 1308-1317
- ISSN
- 0022-2275 (ISSN-L)
- PMC
- PMC4479335
- OpenAlex
- W1944135887
- Cited by
- 210
- References
- 37
- Citations by year
- 2026: 15 · 2025: 14 · 2024: 18 · 2023: 17 · 2022: 22 · 2021: 32 · 2020: 26 · 2019: 15 · 2018: 12 · 2017: 17 · 2016: 18 · 2015: 4
- FWCI
- 12.25
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Lipid Research (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Howard Hughes Medical Institute
- National Heart, Lung, and Blood Institute (P01HL020948)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- ANGPTL3, monoclonal antibodies, hypertriglyceridemia, dyslipidemia, lipoprotein lipase, endothelial lipase, plasma triglycerides, HDL cholesterol, LDL cholesterol, Macaca fascicularis, mouse model
- MeSH terms
- Angiopoietin-like Proteins, Angiopoietin-Like Protein 3, Animals, Antibodies, Monoclonal, Humans, Lipase, Lipids, Lipoprotein Lipase, Cholesterol, HDL, Cholesterol, LDL, Macaca fascicularis, Male, Triglycerides, Angiopoietins, Dyslipidemias, Mice, Rats
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