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

被引：344

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

共 41 条

[1] Mutations in PCSK9 cause autosomal dominant hypercholesterolemia [J].

Abifadel, M ;

Varret, M ;

Rabès, JP ;

Allard, D ;

Ouguerram, K ;

Devillers, M ;

Cruaud, C ;

Benjannet, S ;

Wickham, L ;

Erlich, D ;

Derré, A ;

Villéger, L ;

Farnier, M ;

Beucler, I ;

Bruckert, E ;

Chambaz, J ;

Chanu, B ;

Lecerf, JM ;

Luc, G ;

Moulin, P ;

Weissenbach, J ;

Prat, A ;

Krempf, M ;

Junien, C ;

Seidah, NG ;

Boileau, C .

NATURE GENETICS, 2003, 34 (02) :154-156

[2] THE CCP4 SUITE - PROGRAMS FOR PROTEIN CRYSTALLOGRAPHY [J].

BAILEY, S .

ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1994, 50 :760-763

[3] Crystallography & NMR system:: A new software suite for macromolecular structure determination [J].

Brunger, AT ;

Adams, PD ;

Clore, GM ;

DeLano, WL ;

Gros, P ;

Grosse-Kunstleve, RW ;

Jiang, JS ;

Kuszewski, J ;

Nilges, M ;

Pannu, NS ;

Read, RJ ;

Rice, LM ;

Simonson, T ;

Warren, GL .

ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1998, 54 :905-921

[4] Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9 [J].

Careskey, Holly E. ;

Davis, R. Aleks ;

Alborn, William E. ;

Troutt, Jason S. ;

Cao, Guoqing ;

Konrad, Robert J. .

JOURNAL OF LIPID RESEARCH, 2008, 49 (02) :394-398

[5] Low LDL cholesterol in African Americans resulting from frequent nonsense mutations in PCSK9 [J].

Cohen, J ;

Pertsemlidis, A ;

Kotowski, IK ;

Graham, R ;

Garcia, CK ;

Hobbs, HH .

NATURE GENETICS, 2005, 37 (03) :328-328

[6] Sequence variations in PCSK9, low LDL, and protection against coronary heart disease [J].

Cohen, JC ;

Boerwinkle, E ;

Mosley, TH ;

Hobbs, HH .

NEW ENGLAND JOURNAL OF MEDICINE, 2006, 354 (12) :1264-1272

[7] Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia [J].

Cunningham, David ;

Danley, Dennis E. ;

Geoghegan, Kieran F. ;

Griffor, Matthew C. ;

Hawkins, Julie L. ;

Subashi, Timothy A. ;

Varghese, Alison H. ;

Ammirati, Mark J. ;

Culp, Jeffrey S. ;

Hoth, Lise R. ;

Mansour, Mahmoud N. ;

McGrath, Katherine M. ;

Seddon, Andrew P. ;

Shenolikar, Shirish ;

Stutzman-Engwall, Kim J. ;

Warren, Laurie C. ;

Xia, Donghui ;

Qiu, Xiayang .

NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2007, 14 (05) :413-419

[8] ACID-DEPENDENT LIGAND DISSOCIATION AND RECYCLING OF LDL RECEPTOR MEDIATED BY GROWTH-FACTOR HOMOLOGY REGION [J].

DAVIS, CG ;

GOLDSTEIN, JL ;

SUDHOF, TC ;

ANDERSON, RGW ;

RUSSELL, DW ;

BROWN, MS .

NATURE, 1987, 326 (6115) :760-765

[9]

DIETSCHY JM, 1993, J LIPID RES, V34, P1637

[10] Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia [J].

Dubuc, G ;

Chamberland, A ;

Wassef, H ;

Davignon, J ;

Seidah, NG ;

Bernier, L ;

Prat, A .

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2004, 24 (08) :1454-1459

← 1 2 3 4 5 →