Shen Yijun, Li Hua, Zhao Li, Li Gang, Chen Ben, Guo Qingsong, Gao Bei, Wu Jinsong, Yang Tong, Jin Li, Su Yong
Ministry of Education Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai, China.
R&D Department of Genetic Engineering, Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd., Shanghai, China.
PLoS One. 2017 Aug 17;12(8):e0183326. doi: 10.1371/journal.pone.0183326. eCollection 2017.
Blocking proprotein convertase subtilisin kexin type 9 (PCSK9) binding to low-density lipoprotein receptor (LDLR) can profoundly lower plasma LDL levels. Two anti-PCKS9 monoclonal antibodies (mAbs), alirocumab and evolocumab, were approved by the FDA in 2015. The recommended dose is 75 mg to 150 mg every two weeks for alirocumab and 140mg every two weeks or 420 mg once a month for evolocumab. This study attempted to improve the pharmacokinetic properties of F0016A, an IgG1 anti-PCKS9 mAb, to generate biologically superior molecules. We engineered several variants with two or three amino acid substitutions in the Fc fragment based on prior knowledge. The Fc-modified mAbs exhibited increased binding to FcRn, resulting in prolonged serum half-life and enhanced efficacy in vivo. These results demonstrate that Fc-modified anti-PCKS9 antibodies may enable less frequent or lower dosing of antibodies by improved recycling into the blood.
阻断前蛋白转化酶枯草溶菌素9型（PCSK9）与低密度脂蛋白受体（LDLR）的结合可显著降低血浆低密度脂蛋白水平。两种抗PCSK9单克隆抗体（mAb），阿利西尤单抗和依洛尤单抗，于2015年获得美国食品药品监督管理局（FDA）批准。阿利西尤单抗的推荐剂量为每两周75毫克至150毫克，依洛尤单抗为每两周140毫克或每月一次420毫克。本研究试图改善一种IgG1抗PCSK9单克隆抗体F0016A的药代动力学特性，以产生生物学上更优的分子。我们根据先验知识在Fc片段中设计了几个有两到三个氨基酸取代的变体。Fc修饰的单克隆抗体与FcRn的结合增加，导致血清半衰期延长和体内疗效增强。这些结果表明，Fc修饰的抗PCSK9抗体可能通过改善循环回血液中的过程，减少抗体给药频率或降低给药剂量。
