A proprotein convertase subtilisin / kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates

  • Chan J
  • Piper D
  • Cao Q
 et al. 
  • 12

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Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates serum LDL cholesterol (LDL-C) by interacting with the LDL receptor (LDLR) and is an attractive therapeutic target for LDL-C lowering. We have generated a neutralizing anti-PCSK9 antibody, mAb1, that binds to an epitope on PCSK9 adjacent to the region required for LDLR interaction. In vitro, mAb1 inhibits PCSK9 binding to the LDLR and attenuates PCSK9-mediated reduction in LDLR protein levels, thereby increasing LDL uptake. A combination of mAb1 with a statin increases LDLR levels in HepG2 cells more than either treatment alone. In wild-type mice, mAb1 increases hepatic LDLR protein levels approximately 2-fold and lowers total serum cholesterol by up to 36%: this effect is not observed in LDLR(-/-) mice. In cynomolgus monkeys, a single injection of mAb1 reduces serum LDL-C by 80%, and a significant decrease is maintained for 10 days. We conclude that anti-PCSK9 antibodies may be effective therapeutics for treating hypercholesterolemia.

Author-supplied keywords

  • Animals
  • Antibodies
  • Cholesterol
  • Cholesterol: blood
  • Cholesterol: immunology
  • Crystallography
  • Inbred C57BL
  • Knockout
  • LDL
  • LDL: genetics
  • LDL: physiology
  • Macaca fascicularis
  • Mice
  • Monoclonal
  • Monoclonal: immunology
  • Neutralization Tests
  • Receptors
  • Serine Endopeptidases
  • Serine Endopeptidases: immunology
  • X-Ray

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Authors

  • Joyce C Y Chan

  • Derek E Piper

  • Qiong Cao

  • Dongming Liu

  • Chadwick King

  • Wei Wang

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