title: A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates.
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.
authors.affiliation: Department of Metabolic Disorders, Amgen Inc., South San Francisco, CA 94080, USA.
authors.forename: Joyce C Y
authors.initials: JC
authors.lastname: Chan
authors.forename: Derek E
authors.initials: DE
authors.lastname: Piper
authors.forename: Qiong
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authors.lastname: Cao
authors.forename: Dongming
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authors.lastname: Liu
authors.forename: Chadwick
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authors.lastname: King
authors.forename: Wei
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authors.forename: Yongmei
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authors.forename: Susan
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authors.lastname: Shetterly
authors.forename: Ziva
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authors.lastname: Arimura
authors.forename: Heather
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authors.lastname: Salomonis
authors.forename: William G
authors.initials: WG
authors.lastname: Romanow
authors.forename: Stephen T
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authors.lastname: Thibault
authors.forename: Richard
authors.initials: R
authors.lastname: Zhang
authors.forename: Ping
authors.initials: P
authors.lastname: Cao
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Yang
authors.forename: Timothy
authors.initials: T
authors.lastname: Yu
authors.forename: Mei
authors.initials: M
authors.lastname: Lu
authors.forename: Marc W
authors.initials: MW
authors.lastname: Retter
authors.forename: Gayle
authors.initials: G
authors.lastname: Kwon
authors.forename: Kirk
authors.initials: K
authors.lastname: Henne
authors.forename: Oscar
authors.initials: O
authors.lastname: Pan
authors.forename: Mei-Mei
authors.initials: MM
authors.lastname: Tsai
authors.forename: Bryna
authors.initials: B
authors.lastname: Fuchslocher
authors.forename: Evelyn
authors.initials: E
authors.lastname: Yang
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.forename: Ki Jeong
authors.initials: KJ
authors.lastname: Lee
authors.forename: Mark
authors.initials: M
authors.lastname: Daris
authors.forename: Jackie
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authors.lastname: Sheng
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Wenyan D
authors.initials: WD
authors.lastname: Shen
authors.forename: Wen-Chen
authors.initials: WC
authors.lastname: Yeh
authors.forename: Maurice
authors.initials: M
authors.lastname: Emery
authors.forename: Nigel P C
authors.initials: NP
authors.lastname: Walker
authors.forename: Bei
authors.initials: B
authors.lastname: Shan
authors.forename: Margrit
authors.initials: M
authors.lastname: Schwarz
authors.forename: Simon M
authors.initials: SM
authors.lastname: Jackson
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D002784:Cholesterol / Q000097:blood* / Q000276:immunology; D018360:Crystallography, X-Ray; D008252:Macaca fascicularis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009500:Neutralization Tests; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011973:Receptors, LDL / Q000235:genetics / Q000502:physiology; D012697:Serine Endopeptidases / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D011973:Receptors, LDL; D002784:Cholesterol; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases