The University of Southampton
University of Southampton Institutional Repository

In vivo retargeting of adenovirus type 5 to ?v?6 integrin results in reduced hepatotoxicity and improved tumor uptake following systemic delivery

In vivo retargeting of adenovirus type 5 to ?v?6 integrin results in reduced hepatotoxicity and improved tumor uptake following systemic delivery
In vivo retargeting of adenovirus type 5 to ?v?6 integrin results in reduced hepatotoxicity and improved tumor uptake following systemic delivery
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 ?v?6 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, ?v?6-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 ?v?6. The corresponding ?v?6-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 ?v?6-positive human carcinoma lines compared with Ad5-EGFPWT. Using an ?v?6-positive (DX3-?6) 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 ?v?6, combined with its reduced hepatic tropism and toxicity, highlights its potential as a prototype virus for future clinical investigation.
0022-538X
6416-6428
Coughlan, Lynda
82661ec1-9633-48cd-9112-ed272ad6f845
Vallath, Sabari
150b0213-08da-4fc6-96e1-1ba503bf6a08
Saha, Antonio
5c8fa745-a9fd-4548-a246-113c4addd4f3
Flak, Magdalena
8473c32c-315a-48fa-bb27-0d4ffcd9b4b5
MacNeish, Ian A.
5562b671-9736-42f0-90c0-26f936114046
Vassaux, Georges
b62b4cf5-7f60-4c75-bf94-706aa67d8fdf
Marshall, John F.
1134b21f-7f23-4ee6-aaf5-c7580b73c10b
Hart, Ian R.
6a3728fc-5385-4dd4-a5e3-edd5168a0e8d
Thomas, Gareth J.
2ff54aa9-a766-416b-91ee-cf1c5be74106
Coughlan, Lynda
82661ec1-9633-48cd-9112-ed272ad6f845
Vallath, Sabari
150b0213-08da-4fc6-96e1-1ba503bf6a08
Saha, Antonio
5c8fa745-a9fd-4548-a246-113c4addd4f3
Flak, Magdalena
8473c32c-315a-48fa-bb27-0d4ffcd9b4b5
MacNeish, Ian A.
5562b671-9736-42f0-90c0-26f936114046
Vassaux, Georges
b62b4cf5-7f60-4c75-bf94-706aa67d8fdf
Marshall, John F.
1134b21f-7f23-4ee6-aaf5-c7580b73c10b
Hart, Ian R.
6a3728fc-5385-4dd4-a5e3-edd5168a0e8d
Thomas, Gareth J.
2ff54aa9-a766-416b-91ee-cf1c5be74106

Coughlan, Lynda, Vallath, Sabari, Saha, Antonio, Flak, Magdalena, MacNeish, Ian A., Vassaux, Georges, Marshall, John F., Hart, Ian R. and Thomas, Gareth J. (2009) In vivo retargeting of adenovirus type 5 to ?v?6 integrin results in reduced hepatotoxicity and improved tumor uptake following systemic delivery. Journal of Virology, 83 (13), 6416-6428. (doi:10.1128/JVI.00445-09).

Record type: Article

Abstract

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 ?v?6 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, ?v?6-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 ?v?6. The corresponding ?v?6-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 ?v?6-positive human carcinoma lines compared with Ad5-EGFPWT. Using an ?v?6-positive (DX3-?6) 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 ?v?6, combined with its reduced hepatic tropism and toxicity, highlights its potential as a prototype virus for future clinical investigation.

Text
Coughlan_et_al.,_2009.pdf - Version of Record
Restricted to Repository staff only
Request a copy

More information

Published date: July 2009

Identifiers

Local EPrints ID: 66680
URI: http://eprints.soton.ac.uk/id/eprint/66680
ISSN: 0022-538X
PURE UUID: 536cba17-62fe-4023-a249-0d8eafae62a8

Catalogue record

Date deposited: 10 Jul 2009
Last modified: 13 Mar 2024 18:28

Export record

Altmetrics

Contributors

Author: Lynda Coughlan
Author: Sabari Vallath
Author: Antonio Saha
Author: Magdalena Flak
Author: Ian A. MacNeish
Author: Georges Vassaux
Author: John F. Marshall
Author: Ian R. Hart

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×