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 alphavbeta6 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, alphavbeta6-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 alphavbeta6. The corresponding alphavbeta6-retargeted virus Ad5-EGFP(A20) exhibited up to 50-fold increases in coxsackievirus- and-
adenovirus-receptor-independent transduction and up to 480-fold-increased cytotoxicity on a panel of alphavbeta6-positive human
carcinoma lines compared with Ad5-EGFP(WT). Using an alphavbeta6-positive (DX3-beta6) xenograft model, we observed a approximately 2-fold enhancement in
tumor uptake over Ad5-EGFP(WT) following systemic delivery. Furthermore, approximately 5-fold-fewer Ad5-EGFP(A20) 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-EGFP(A20) to improve delivery to alphavbeta6, combined with its reduced hepatic tropism and toxicity, highlights its potential as a prototype virus for future clinical investigation.