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

被引：343

作者：

Chan, Joyce C. Y. ^{[1
]}

Piper, Derek E. ^{[2
]}

Cao, Qiong ^{[1
]}

Liu, Dongming ^{[1
]}

King, Chadwick ^{[5
]}

Wang, Wei ^{[6
]}

Tang, Jie ^{[3
]}

Liu, Qiang ^{[3
]}

Higbee, Jared ^{[3
]}

Xia, Zhen ^{[3
]}

Di, Yongmei ^{[1
]}

Shetterly, Susan ^{[1
]}

Arimura, Ziva ^{[1
]}

Salomonis, Heather ^{[1
]}

Romanow, William G. ^{[2
]}

Thibault, Stephen T. ^{[2
]}

Zhang, Richard ^{[3
]}

Cao, Ping ^{[3
]}

Yang, Xiao-Ping ^{[3
]}

Yu, Timothy ^{[3
]}

Lu, Mei ^{[3
]}

Retter, Marc W. ^{[7
,8
]}

Kwon, Gayle ^{[7
,8
]}

Henne, Kirk ^{[4
]}

Pan, Oscar ^{[5
]}

Tsai, Mei-Mei ^{[6
]}

Fuchslocher, Bryna ^{[6
]}

Yang, Evelyn ^{[6
]}

Zhou, Lei ^{[9
]}

Lee, Ki Jeong ^{[6
]}

Daris, Mark ^{[6
]}

Sheng, Jackie ^{[6
]}

Wang, Yan ^{[3
]}

Shen, Wenyan D. ^{[3
]}

Yeh, Wen-Chen ^{[1
]}

Emery, Maurice ^{[7
,8
]}

Walker, Nigel P. C. ^{[2
]}

Shan, Bei ^{[1
]}

Schwarz, Margrit ^{[1
]}

Jackson, Simon M. ^{[1
]}

机构：

[1] Amgen Inc, Dept Metab Disorders, 1120 Vet Blvd, San Francisco, CA 94080 USA

[2] Amgen Inc, Dept Mol Struct, San Francisco, CA 94080 USA

[3] Amgen Inc, Dept Prot Sci, San Francisco, CA 94080 USA

[4] Amgen Inc, Dept Pharmacokinet & Drug Metab, San Francisco, CA 94080 USA

[5] Amgen Inc, Dept Prot Sci, Burnaby, BC V5A 1V7, Canada

[6] Amgen Inc, Dept Prot Sci, Thousand Oaks, CA 91320 USA

[7] Amgen Inc, Dept Pharmacokinet, Seattle, WA 98119 USA

[8] Amgen Inc, Dept Drug Metab, Seattle, WA 98119 USA

[9] Amgen Inc, Biostat & Epidemiol, Thousand Oaks, CA 91320 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2009年 / 106卷 / 24期

关键词：

antibody; LDL-C; LDLR; PCSK9; hypercholesterolemia; DENSITY-LIPOPROTEIN-RECEPTOR; SECRETED PCSK9; PLASMA-CHOLESTEROL; LDL RECEPTORS; LIVER; DEGRADATION; EXPRESSION; DECREASES; MUTATIONS; STATINS;

D O I：

10.1073/pnas.0903849106

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 approximate to 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.

引用

页码：9820 / 9825

页数：6

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