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

PLoS One. 2017 Aug 17;12(8):e0183326. doi: 10.1371/journal.pone.0183326. eCollection 2017.

Abstract

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.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology*
  • Enzyme-Linked Immunosorbent Assay
  • Half-Life
  • Humans
  • Macaca fascicularis
  • Primates
  • Proprotein Convertase 9 / immunology*
  • Surface Plasmon Resonance

Substances

  • Antibodies, Monoclonal
  • Proprotein Convertase 9

Grant support

This project was supported by internal funds of Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co, Ltd. (China). The funder provided support in the form of salaries for authors, YShen, HL, GL, LZ, BC, QG, BG, JW, TY and YSu, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.