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Journal of Virology, July 2009, p. 6416-6428, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.00445-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

In Vivo Retargeting of Adenovirus Type 5 to {alpha}vβ6 Integrin Results in Reduced Hepatotoxicity and Improved Tumor Uptake following Systemic Delivery{triangledown}

Lynda Coughlan,1* Sabari Vallath,1 Antonio Saha,1 Magdalena Flak,2 Iain A. McNeish,2 Georges Vassaux,3 John F. Marshall,1 Ian R. Hart,1 and Gareth J. Thomas1,{dagger}

Centre for Tumour Biology, Institute of Cancer, Barts and the London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, United Kingdom,1 Centre for Molecular Oncology, Institute of Cancer, Barts and the London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, United Kingdom,2 INSERM U948 Biothérapies Hépatiques and Institut des Maladies de l'Appareil Digestif, CHU Hôtel Dieu, Nantes, France3

Received 3 March 2009/ Accepted 9 April 2009

A key impediment to successful cancer therapy with adenoviral vectors is the inefficient transduction of malignant tissue in vivo. Compounding this problem is the lack of cancer-specific targets, coupled with a shortage of corresponding high-efficiency ligands, permitting selective retargeting. The epithelial cell-specific integrin {alpha}vβ6 represents an attractive target for directed therapy since it is generally not expressed on normal epithelium but is upregulated in numerous carcinomas, where it plays a role in tumor progression. We previously have characterized a high-affinity, {alpha}vβ6-selective peptide (A20FMDV2) derived from VP1 of foot-and-mouth disease virus. We generated recombinant adenovirus type 5 (Ad5) fiber knob, incorporating A20FMDV2 in the HI loop, for which we validated the selectivity of binding and functional inhibition of {alpha}vβ6. The corresponding {alpha}vβ6-retargeted virus Ad5-EGFPA20 exhibited up to 50-fold increases in coxsackievirus- and-adenovirus-receptor-independent transduction and up to 480-fold-increased cytotoxicity on a panel of {alpha}vβ6-positive human carcinoma lines compared with Ad5-EGFPWT. Using an {alpha}vβ6-positive (DX3-β6) xenograft model, we observed a ~2-fold enhancement in tumor uptake over Ad5-EGFPWT following systemic delivery. Furthermore, ~5-fold-fewer Ad5-EGFPA20 genomes were detected in the liver (P = 0.0002), correlating with reduced serum transaminase levels and E1A expression. Warfarin pretreatment, to deplete coagulation factors, did not improve tumor uptake significantly with either virus but did significantly reduce liver sequestration and hepatic toxicity. The ability of Ad5-EGFPA20 to improve delivery to {alpha}vβ6, combined with its reduced hepatic tropism and toxicity, highlights its potential as a prototype virus for future clinical investigation.

* Corresponding author. Mailing address: Centre for Tumour Biology, Institute of Cancer, Barts and the London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, United Kingdom. Phone: 44 020 70140400. Fax: 44 020 70140401. E-mail: l.t.coughlan{at}qmul.ac.uk

{triangledown} Published ahead of print on 15 April 2009.

{dagger} Present address: Cancer Sciences Division, University of Southampton School of Medicine, Southampton SO16 6YD, United Kingdom.

Journal of Virology, July 2009, p. 6416-6428, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.00445-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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