A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates.
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.
Chan
Joyce C Y
JC
Department of Metabolic Disorders, Amgen Inc., South San Francisco, CA 94080, USA.
Piper
Derek E
DE
Cao
Qiong
Q
Liu
Dongming
D
King
Chadwick
C
Wang
Wei
W
Tang
Jie
J
Liu
Qiang
Q
Higbee
Jared
J
Xia
Zhen
Z
Di
Yongmei
Y
Shetterly
Susan
S
Arimura
Ziva
Z
Salomonis
Heather
H
Romanow
William G
WG
Thibault
Stephen T
ST
Zhang
Richard
R
Cao
Ping
P
Yang
Xiao-Ping
XP
Yu
Timothy
T
Lu
Mei
M
Retter
Marc W
MW
Kwon
Gayle
G
Henne
Kirk
K
Pan
Oscar
O
Tsai
Mei-Mei
MM
Fuchslocher
Bryna
B
Yang
Evelyn
E
Zhou
Lei
L
Lee
Ki Jeong
KJ
Daris
Mark
M
Sheng
Jackie
J
Wang
Yan
Y
Shen
Wenyan D
WD
Yeh
Wen-Chen
WC
Emery
Maurice
M
Walker
Nigel P C
NP
Shan
Bei
B
Schwarz
Margrit
M
Jackson
Simon M
SM
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*
D000911:Antibodies, Monoclonal; D011973:Receptors, LDL; D002784:Cholesterol; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases