Therapeutic Protein PEPylation: The Helix of Nonfouling Synthetic Polypeptides Minimizes Antidrug Antibody Generation

作者：Yingqin Hou, Yu Zhou, Hao Wang, Jialing Sun, Ruijue Wang, Kai Sheng, Jingsong Yuan, Yali Hu, Yu Chao, Zhuang Liu, Hua Lu · 发表于：ACS Central Science · 年份：2019 · DOI：10.1021/acscentsci.8b00548 · 被引用次数：82 · 研究领域：Monoclonal and Polyclonal Antibodies Research、Protein purification and stability、Peptidase Inhibition and Analysis

High Resolution Image Download MS PowerPoint Slide Polymer conjugation is a clinically proven approach to generate long acting protein drugs with decreased immune responses. Although poly(ethylene glycol) (PEG) is one of the most commonly used conjugation partners due to its unstructured conformation, its therapeutic application is limited by its poor biodegradability, propensity to induce an anti-PEG immune response, and the resultant accelerated blood clearance (ABC) effect. Moreover, the prevailing preference of unstructured polymers for protein conjugation still lacks strong animal data support with appropriate control reagents. By using two biodegradable synthetic polypeptides with similar structural compositions ( l -P(EG 3 Glu) and dl -P(EG 3 Glu)) for site-specific protein modification, in the current study, we systematically investigate the effect of the polymer conformation on the in vivo pharmacological performances of the resulting conjugates. Our results reveal that the conjugate l 20K -IFN, interferon (IFN) modified with the helical polypeptide l -P(EG 3 Glu) shows improved binding affinity, in vitro antiproliferative activity, and in vivo efficacy compared to those modified with the unstructured polypeptide analogue dl -P(EG 3 Glu) or PEG. Moreover, l 20K -IFN triggered significantly less antidrug and antipolymer antibodies than the other two. Importantly, the unusual findings observed in the IFN series are reproduced in a human growth hormone (GH) conjugate se...