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

Gene Therapy volume 17, pages 1000–1010 (2010)Cite this article

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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.

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Abbreviations

EGFR:

epidermal growth factor receptor

GCV:

ganciclovir

hCAR:

human coxsackie B and adenovirus receptor

HSVtk:

herpes simplex virus thymidine kinase

2-ME:

2-mercaptoethanol

RGD:

Arginine-Glycine-Aspartate

sCAR:

extracellular domain of hCAR

uPAR:

urokinase-type plasminogen activator receptor.

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Acknowledgements

This work was supported by Cancer Research UK. Thanks to Katie Hasler and Karen King for secretarial support.

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Author notes

  1. T J Harvey and D Burdon: These authors contributed equally to this work.

Authors and Affiliations

  1. Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds, UK

    T J Harvey, D Burdon, L Steele, N Ingram, G D Hall, P J Selby & J D Chester

  2. Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA

    R G Vile

  3. Institute of Cancer Therapeutics, University of Bradford, Bradford, UK

    P A Cooper & S D Shnyder

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  1. T J Harvey
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Correspondence to J D Chester.

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Harvey, T., Burdon, D., Steele, L. et al. Retargeted adenoviral cancer gene therapy for tumour cells overexpressing epidermal growth factor receptor or urokinase-type plasminogen activator receptor. Gene Ther 17, 1000–1010 (2010). https://doi.org/10.1038/gt.2010.45

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