Chan Joyce C Y, Piper Derek E, Cao Qiong, Liu Dongming, King Chadwick, Wang Wei, Tang Jie, Liu Qiang, Higbee Jared, Xia Zhen, Di Yongmei, Shetterly Susan, Arimura Ziva, Salomonis Heather, Romanow William G, Thibault Stephen T, Zhang Richard, Cao Ping, Yang Xiao-Ping, Yu Timothy, Lu Mei, Retter Marc W, Kwon Gayle, Henne Kirk, Pan Oscar, Tsai Mei-Mei, Fuchslocher Bryna, Yang Evelyn, Zhou Lei, Lee Ki Jeong, Daris Mark, Sheng Jackie, Wang Yan, Shen Wenyan D, Yeh Wen-Chen, Emery Maurice, Walker Nigel P C, Shan Bei, Schwarz Margrit, Jackson Simon M
Department of Metabolic Disorders, Amgen Inc., South San Francisco, CA 94080, USA.
Proc Natl Acad Sci U S A. 2009 Jun 16;106(24):9820-5. doi: 10.1073/pnas.0903849106. Epub 2009 May 14.
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.
前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）通过与低密度脂蛋白受体（LDLR）相互作用来调节血清低密度脂蛋白胆固醇（LDL-C），是降低LDL-C的一个有吸引力的治疗靶点。我们制备了一种中和性抗PCSK9抗体mAb1，它与PCSK9上与LDLR相互作用所需区域相邻的一个表位结合。在体外，mAb1抑制PCSK9与LDLR的结合，并减弱PCSK9介导的LDLR蛋白水平降低，从而增加LDL摄取。mAb1与他汀类药物联合使用比单独使用任何一种治疗方法都能更有效地增加HepG2细胞中的LDLR水平。在野生型小鼠中，mAb1使肝脏LDLR蛋白水平增加约2倍，并使总血清胆固醇降低多达36%：在LDLR基因敲除小鼠中未观察到这种效应。在食蟹猴中，单次注射mAb1可使血清LDL-C降低80%，且显著降低持续10天。我们得出结论，抗PCSK9抗体可能是治疗高胆固醇血症的有效疗法。
