ANGPTL3 blockade with a human monoclonal antibody reduces plasma lipids in dyslipidemic mice and monkeys

Gusarova, Viktoria; Alexa, Corey A.; Wang, Yan; Rafique, Ashique; Kim, Jee Hae; Buckler, David G; Mintah, Ivory J.; Shihanian, Lisa M.; Cohen, Jonathan C.; Hobbs, Helen H.; Xin, Yurong; Valenzuela, David M.; Murphy, Andrew J.; Yancopouloš, George D.; Gromada, Jesper

doi:10.1194/jlr.m054890

Cited by 181 publications

(185 citation statements)

References 39 publications

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“…(10,12), as well as with our observation that homozygous, but not heterozygous, FHBL2 individuals have significantly increased postheparin LPL activity (17). In addition, our findings also agree with the recent observation that mice injected with a blocking monoclonal anti-ANGPTL3 antibody showed a minimal increase of TG levels in response to a fat challenge (43). Taken together, the present observations are in line with the view that ANGPTL3 modulates postprandial metabolism of TRLs in humans via its action on LPL function.…”

Section: 1supporting

confidence: 82%

Effects of angiopoietin-like protein 3 deficiency on postprandial lipid and lipoprotein metabolism

Minicocci

Tikka

Poggiogalle

et al. 2016

Journal of Lipid Research

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Section: 1supporting

confidence: 82%

Effects of angiopoietin-like protein 3 deficiency on postprandial lipid and lipoprotein metabolism

Minicocci

Tikka

Poggiogalle

et al. 2016

Journal of Lipid Research

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“…REGN1500 is a monoclonal antibody developed against human ANGPTL3 that binds mouse, rat, and monkey ANGPTL3 with a similar affi nity. A full description of REGN1500 is provided in the companion article ( 24 ).…”

Section: Resultsmentioning

confidence: 99%

“…REGN1500, a fully human monoclonal antibody, was derived using Regeneron's Velocimmune® technology platform ( 24 ) . An isotype-matched antibody with irrelevant specifi city was used as control.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion

Wang¹,

Gusarova²,

Banfi³

et al. 2015

Journal of Lipid Research

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165

127

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This article is available online at http://www.jlr.org an enzyme that catalyzes an early step in cholesterol biosynthesis, effectively lower plasma LDL-C levels and prevent CHD ( 2 ). Human genetic studies have provided several new targets for LDL-C lowering. Individuals who lack ApoB ( 3 ), or microsomal transfer protein (MTP), the enzyme that transfers TG to TG-rich lipoproteins in the liver and intestine ( 4 ), have very low LDL levels. Agents that suppress ApoB expression ( 5 ) or inhibit MTP activity ( 6 ) are now available for treatment of severe hypercholesterolemia in individuals with homozygous familial hypercholesterolemia. Loss-of-function mutations in PCSK9, a secreted proprotein convertase that promotes degradation of the LDL receptor (LDLR), cause a 30% reduction in LDL-C and substantial protection from CHD ( 7 ). Anti-PCSK9 antibodies lower circulating LDL-C levels ( 8 ) and clinical trials are now underway to determine whether there is an associated reduction in CHD ( 9 ).More recently, several families with inactivating mutations in angiopoietin-like protein 3 ( ANGPTL3 ) were identifi ed ( 10-12 ). Family members with two loss-of-function mutations in ANGPTL3 have striking pan-hypolipidemia; plasma levels of TGs, NEFAs, VLDL-cholesterol (VLDL-C), LDL-C, and HDL-cholesterol (HDL-C) are all markedly reduced. The mechanisms by which ANGPTL3 modulates TG metabolism have been extensively investigated ( 13 ). ANGPTL3 inhibits the activity of two intravascular lipases: LPL, which catalyzes hydrolysis of TGs in TG-rich lipoproteins, and endothelial lipase (EL), which hydrolyzes lipoprotein phospholipids ( 14-16 ). Thus, increased activity of LPL and EL may account for the low plasma levels of TG Abstract Humans and mice lacking angiopoietin-like protein 3 (ANGPTL3) have pan-hypolipidemia. ANGPTL3 inhibits two intravascular lipases, LPL and endothelial lipase, and the low plasma TG and HDL-cholesterol levels in ANG-PTL3 defi ciency refl ect increased activity of these enzymes. The mechanism responsible for the low LDL-cholesterol levels associated with ANGPTL3 defi ciency is not known. Here we used an anti-ANGPTL3 monoclonal antibody (REGN1500) to inactivate ANGPTL3 in mice with genetic defi ciencies in key proteins involved in clearance of ApoBcontaining lipoproteins. REGN1500 treatment consistently reduced plasma cholesterol levels in mice in which Apoe , Ldlr , Lrp1 , and Sdc1 were inactivated singly or in combination, but did not alter clearance of rabbit 125 I-␤ VLDL or mouse 125 I-LDL. Despite a 61% reduction in VLDL-TG production, VLDL-ApoB-100 production was unchanged in REGN1500-treated animals. Hepatic TG content, fatty acid synthesis, and fatty acid oxidation were similar in REGN1500 and control antibody-treated animals. Taken together, our fi ndings indicate that inactivation of ANGPTL3 does not affect the number of ApoB-containing lipoproteins secreted by the liver but alters the particles that are made such that they are cleared more rapidly from the circulation via a noncanonical pathway(...

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“…Use of an anti-ANGPTL3 monoclonal antibody, REGN1500 has been reported in various animal models, with increased LPL activity, and significant reduction in plasma triglyceride levels in normolipidemic and dyslipidemic mice, and dyslipidemic monkeys [39,40]. Phase 1 and 2 human trials are ongoing (NCT02107872, NCT01749878, NCT02265952, www.clinicaltrials.…”

Section: Anti-angiopoietin-like Protein Therapymentioning

confidence: 97%

Novel therapeutics in hypertriglyceridemia

Gryn

Hegele

2015

Current Opinion in Lipidology

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Several promising triglyceride-lowering therapies are at various stages of development; a few are even available in some markets. Although existing data suggest good biochemical efficacy, data on long-term clinical outcomes are still limited. For some therapies, cost will be an important consideration, and use will likely be restricted to orphan indications, for example very severe cases of hypertriglyceridemia as seen in familial chylomicronemia syndrome, although some therapies could theoretically be more broadly used one day for cardiovascular disease prevention.

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ANGPTL3 blockade with a human monoclonal antibody reduces plasma lipids in dyslipidemic mice and monkeys

Cited by 181 publications

References 39 publications

Effects of angiopoietin-like protein 3 deficiency on postprandial lipid and lipoprotein metabolism

Effects of angiopoietin-like protein 3 deficiency on postprandial lipid and lipoprotein metabolism

Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion

Novel therapeutics in hypertriglyceridemia

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