title: In situ growth of a C-terminal interferon-alpha conjugate of a phospholipid polymer that outperforms PEGASYS in cancer therapy.
abstract: Conjugating therapeutic proteins and peptides to poly(ethylene glycol) (PEG) can improve their pharmacokinetics and therapeutic potential. However, PEGylation suffers from non-specific conjugation, low yield and immunogenicity. Herein we report a new and general methodology to synthesize a protein-polymer conjugate with site-specificity, high yield and activity, long circulation half-life and excellent therapeutic efficacy. A phospholipid polymer, poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC), was grown solely from the C-terminus of interferon-alpha to form a site-specific (C-terminal) and stoichiometric (1:1) PMPC conjugate of interferon-alpha in high yield. Notably, the PMPC conjugate showed 194- and 158-fold increases in systemic exposure and tumor uptake as compared with interferon-alpha, respectively. The in vitro antiproliferative bioactivity of the PMPC conjugate was 8.7-fold higher than that of PEGylated interferon-alpha (PEGASYS). In a murine cancer model, the PMPC conjugate completely inhibited tumor growth and cured 75% mice, whereas at the same dose, no mice treated with interferon-alpha or PEGASYS survived. We believe that this new approach to synthesize C-terminal protein conjugates of PMPC may be applicable to a large subset of protein and peptide drugs, thereby providing a general platform 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. Electronic address: gaoweiping@tsinghua.edu.cn.
authors.forename: Weiping
authors.initials: W
authors.lastname: Gao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D016898:Interferon-alpha / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy*; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011109:Polymethacrylic Acids / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D016898:Interferon-alpha; D011109:Polymethacrylic Acids; D011994:Recombinant Proteins; C115766:poly(2-methacryloyloxyethyl-phosphorylcholine); D010767:Phosphorylcholine; D011092:Polyethylene Glycols; C100416:peginterferon alfa-2a
keywords: Atom transfer radical polymerization; Interferon-alpha; Protein delivery; Protein-polymer conjugate