Retargeted adenoviral cancer gene therapy for tumour cells overexpressing epidermal growth factor receptor or urokinase-type plasminogen activator receptor

T. J. Harvey, D. Burdon, L. Steele, N. Ingram, G. D. Hall, P. J. Selby, R. G. Vile, P. A. Cooper, S. D. Shnyder, J. D. Chester

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

We have assessed the ability of bispecific fusion proteins to improve adenovirus-mediated transfer of therapeutic and marker transgenes. We constructed an expression vector that can be easily modified to synthesize a variety of fusion proteins for retargeting adenoviral gene therapy vectors to cell surface markers, which are differentially expressed between normal and cancer cells. Adenoviral transduction can be improved in a number of tumour cell lines which overexpress EGFR (epidermal growth factor receptor) or uPAR (urokinase-type plasminogen activator receptor), but which have only low levels of endogenous hCAR (human coxsackie B and adenovirus receptor) expression. Up to 40-fold improvement in Β-galactosidase transgene expression was seen using an EGFR retargeting protein, and up to 16-fold using a second fusion protein targeting uPAR. In vitro, our uPAR retargeting fusion protein improved the sensitivity to adenoviral herpes simplex virus thymidine kinase/ganciclovir by an order of magnitude, whereas in vivo, our EGFR retargeting protein is able to significantly delay tumour growth in rodent animal models in a dose-dependent manner. The cassette design of our fusion protein constructs offers a flexible method for the straightforward synthesis of multiple adenoviral retargeting proteins, directed against a variety of tumour-associated antigens, for use in clinical trials.

Original languageEnglish (US)
Pages (from-to)1000-1010
Number of pages11
JournalGene Therapy
Volume17
Issue number8
DOIs
StatePublished - Aug 2010

Keywords

  • EGFR
  • adenovirus
  • bladder cancer
  • hCAR
  • retargeting
  • uPAR

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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    Harvey, T. J., Burdon, D., Steele, L., Ingram, N., Hall, G. D., Selby, P. J., Vile, R. G., Cooper, P. A., Shnyder, S. D., & Chester, J. D. (2010). Retargeted adenoviral cancer gene therapy for tumour cells overexpressing epidermal growth factor receptor or urokinase-type plasminogen activator receptor. Gene Therapy, 17(8), 1000-1010. https://doi.org/10.1038/gt.2010.45