| Literature DB >> 19443683 |
Joyce C Y Chan1, Derek E Piper, Qiong Cao, Dongming Liu, Chadwick King, Wei Wang, Jie Tang, Qiang Liu, Jared Higbee, Zhen Xia, Yongmei Di, Susan Shetterly, Ziva Arimura, Heather Salomonis, William G Romanow, Stephen T Thibault, Richard Zhang, Ping Cao, Xiao-Ping Yang, Timothy Yu, Mei Lu, Marc W Retter, Gayle Kwon, Kirk Henne, Oscar Pan, Mei-Mei Tsai, Bryna Fuchslocher, Evelyn Yang, Lei Zhou, Ki Jeong Lee, Mark Daris, Jackie Sheng, Yan Wang, Wenyan D Shen, Wen-Chen Yeh, Maurice Emery, Nigel P C Walker, Bei Shan, Margrit Schwarz, Simon M Jackson.
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.Entities:
Mesh：
Substances：
Year: 2009 PMID： 19443683 PMCID： PMC2682542 DOI： 10.1073/pnas.0903849106
Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 11.205