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

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

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1308-1317
Number of pages10
JournalJournal of Lipid Research
Volume56
Issue number7
DOIs
StatePublished - Jul 1 2015

Fingerprint

Angiopoietins
Haplorhini
Monoclonal Antibodies
Lipids
Plasmas
Lipase
Proteins
Liver
HDL Cholesterol
Macaca fascicularis
Proxy
Hyperlipidemias
Knockout Mice
Intravenous Administration
LDL Cholesterol
Lipoproteins
Phospholipids
Testing
Enzymes
Therapeutics

Keywords

  • Angiopoietin-like protein 3
  • Cholesterol
  • Dyslipidemia
  • Endothelial lipase
  • Hyperlipidemia
  • Lipoprotein lipase
  • Triglycerides

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Endocrinology

Cite this

Gusarova, V., Alexa, C. A., Wang, Y., Rafique, A., Kim, J. H., Buckler, D., ... Gromada, J. (2015). ANGPTL3 blockade with a human monoclonal antibody reduces plasma lipids in dyslipidemic mice and monkeys. Journal of Lipid Research, 56(7), 1308-1317. https://doi.org/10.1194/jlr.M054890

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; Mintah, Ivory J.; Shihanian, Lisa M.; Cohen, Jonathan C.; Hobbs, Helen H.; Xin, Yurong; Valenzuela, David M.; Murphy, Andrew J.; Yancopoulos, George D.; Gromada, Jesper.

In: Journal of Lipid Research, Vol. 56, No. 7, 01.07.2015, p. 1308-1317.

Research output: Contribution to journalArticle

Gusarova, V, Alexa, CA, Wang, Y, Rafique, A, Kim, JH, Buckler, D, Mintah, IJ, Shihanian, LM, Cohen, JC, Hobbs, HH, Xin, Y, Valenzuela, DM, Murphy, AJ, Yancopoulos, GD & Gromada, J 2015, 'ANGPTL3 blockade with a human monoclonal antibody reduces plasma lipids in dyslipidemic mice and monkeys', Journal of Lipid Research, vol. 56, no. 7, pp. 1308-1317. https://doi.org/10.1194/jlr.M054890
Gusarova, Viktoria ; Alexa, Corey A. ; Wang, Yan ; Rafique, Ashique ; Kim, Jee Hae ; Buckler, David ; Mintah, Ivory J. ; Shihanian, Lisa M. ; Cohen, Jonathan C. ; Hobbs, Helen H. ; Xin, Yurong ; Valenzuela, David M. ; Murphy, Andrew J. ; Yancopoulos, George D. ; Gromada, Jesper. / ANGPTL3 blockade with a human monoclonal antibody reduces plasma lipids in dyslipidemic mice and monkeys. In: Journal of Lipid Research. 2015 ; Vol. 56, No. 7. pp. 1308-1317.
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abstract = "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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AU - Gusarova, Viktoria

AU - Alexa, Corey A.

AU - Wang, Yan

AU - Rafique, Ashique

AU - Kim, Jee Hae

AU - Buckler, David

AU - Mintah, Ivory J.

AU - Shihanian, Lisa M.

AU - Cohen, Jonathan C.

AU - Hobbs, Helen H.

AU - Xin, Yurong

AU - Valenzuela, David M.

AU - Murphy, Andrew J.

AU - Yancopoulos, George D.

AU - Gromada, Jesper

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AB - 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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KW - Endothelial lipase

KW - Hyperlipidemia

KW - Lipoprotein lipase

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