Increased half-life and enhanced potency of Fc-modified human PCSK9 monoclonal antibodies in primates

作者：Yijun Shen, Hua Li, Li Zhao, Gang Li, Ben Chen, Qingsong Guo, Bei Gao, Jinsong Wu, Tong Yang, Jin Li, Yong Su · 发表于：PLoS ONE · 年份：2017 · DOI：10.1371/journal.pone.0183326 · 被引用次数：17 · 研究领域：Lipoproteins and Cardiovascular Health、Monoclonal and Polyclonal Antibodies Research、Biosimilars and Bioanalytical Methods

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.