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Journal of Virology, November 2008, p. 10567-10579, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.01308-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

In Vitro and In Vivo Properties of Adenovirus Vectors with Increased Affinity to CD46{triangledown}

Hongjie Wang,1 Ying Liu,1 ZongYi Li,1 Sebastian Tuve,1 Daniel Stone,1,{dagger} Oleksandr Kalyushniy,2 Dmitry Shayakhmetov,1 Christophe L. M. Verlinde,2 Thilo Stehle,4 John McVey,5 Andrew Baker,6 Kah-Whye Peng,7 Steve Roffler,8 and André Lieber1,3*

Division of Medical Genetics,1 Department of Biochemistry,2 Department of Pathology, University of Washington, 1705 NE Pacific St., Seattle, Washington 98195,3 Interfaculty Institute for Biochemistry, University of Tübingen, D-72076 Tübingen, Germany, and Vanderbilt University School of Medicine, Nashville, Tennessee 37232,4 Thrombosis Research Institute, Manresa Road, London SW3 6LR, United Kingdom,5 British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, United Kingdom,6 Molecular Medicine Program, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 559057,7 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan8

Received 23 June 2008/ Accepted 21 August 2008

Gene transfer vectors containing adenovirus (Ad) serotype 35 (Ad35) fibers have shown promise for cancer and stem cell gene therapy. In this study, we attempted to improve the in vitro and in vivo infection properties of these vectors by increasing their affinity to the Ad35 fiber receptor CD46. We constructed Ad vectors containing either the wild-type Ad35 fiber knob (Ad5/35) or Ad35 knob mutants with 4-fold- and 60-fold-higher affinity to CD46 (Ad5/35+ and Ad5/35++, respectively). In in vitro studies with cell lines, the higher affinities of Ad5/35+ and Ad5/35++ to CD46 did not translate into correspondingly higher transduction efficiencies, regardless of the CD46 receptor density present on cells. However, in vivo, in a mouse model with preestablished CD46high liver metastases, intravenous injection of Ad5/35++ resulted in more-efficient tumor cell transduction. We conclude that Ad5/35 vectors with increased affinity to CD46 have an advantage in competing with non-CD46-mediated sequestration of vector particles after intravenous injection.

* Corresponding author. Mailing address: Division of Medical Genetics, University of Washington, 1705 NE Pacific St., Seattle, WA 98195. Phone: (206) 221-3973. Fax: (206) 685-8675. E-mail: lieber00{at}u.washington.edu

{triangledown} Published ahead of print on 27 August 2008.

{dagger} Present address: Department of Chemical Engineering, University of California, Berkeley, CA 94720.

Journal of Virology, November 2008, p. 10567-10579, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.01308-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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