Expanded anticancer therapeutic window of hexon-modified oncolytic adenovirus

Elena V. Shashkova, Shannon M. May, Konstantin Doronin, Michael A. Barry

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

One of the significant hurdles toward safe and efficacious systemic treatment of cancer with oncolytic adenoviruses (Ads) is dose-limiting hepatotoxicity that prevents the increase of a therapeutic dose. In this study, we expanded the therapeutic window of oncolytic serotype 5 Ad (Ad5) by a genetic modification of hypervariable loop 5 (HVR5) in the capsid protein hexon that prevented infection of hepatocytes due to ablation of binding to blood factors. This oncolytic virus, Ad-GL-HB, had significantly reduced levels of hepatocyte transduction in immunocompetent and immunodeficient mice as compared to parental virus Ad-GL. The hepatocyte detargeting decreased liver damage and increased the maximum tolerated dose of Ad-GL-HB tenfold relative to that of Ad-GL. Intravenous (i.v.) injection of Ad-GL or Ad-GL-HB into tumor-bearing mice produced equally increased survival rates demonstrating that while Ad-GL-HB detargeted hepatocytes, it sustained tumor cell infection after systemic administration. The significantly improved safety of the virus allowed it to be used at increased doses for improved systemic antitumor efficacy. Our results suggest that hexon modifications provide valuable strategies forsystemic oncolytic Ad therapy.

Original languageEnglish (US)
Pages (from-to)2121-2130
Number of pages10
JournalMolecular Therapy
Volume17
Issue number12
DOIs
StatePublished - Dec 1 2009

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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