title: Site-specific in situ growth of an interferon-polymer conjugate that outperforms PEGASYS in cancer therapy.
abstract: Conjugating poly(ethylene glycol) (PEG), PEGylation, to therapeutic proteins is widely used as a means to improve their pharmacokinetics and therapeutic potential. One prime example is PEGylated interferon-alpha (PEGASYS). However, PEGylation usually leads to a heterogeneous mixture of positional isomers with reduced bioactivity and low yield. Herein, we report site-specific in situ growth (SIG) of a PEG-like polymer, poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA), from the C-terminus of interferon-alpha to form a site-specific (C-terminal) and stoichiometric (1:1) POEGMA conjugate of interferon-alpha in high yield. The POEGMA conjugate showed significantly improved pharmacokinetics, tumor accumulation and anticancer efficacy as compared to interferon-alpha. Notably, the POEGMA conjugate possessed a 7.2-fold higher in vitro antiproliferative bioactivity than PEGASYS. More importantly, in a murine cancer model, the POEGMA conjugate completely inhibited tumor growth and eradicated tumors of 75% mice without appreciable systemic toxicity, whereas at the same dose, no mice treated with PEGASYS survived for over 58 days. The outperformance of a site-specific POEGMA conjugate prepared by SIG over PEGASYS that is the current gold standard for interferon-alpha delivery suggests that SIG is of interest for the development of next-generation protein therapeutics.
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, 100084, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, 100084, China.
authors.forename: Guilin
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, 100084, China.
authors.forename: Wenguo
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, 100084, China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, 100084, China.
authors.forename: Libin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, 100084, China. Electronic address: gaoweiping@tsinghua.edu.cn.
authors.forename: Weiping
authors.initials: W
authors.lastname: Gao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D016898:Interferon-alpha / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D008689:Methacrylates / Q000737:chemistry; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy*; D011092:Polyethylene Glycols / Q000737:chemistry*; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D016898:Interferon-alpha; D008689:Methacrylates; D011092:Polyethylene Glycols
keywords: Cancer therapy; Interferon alpha; Protein delivery; Protein-polymer conjugate