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J. Virol. doi:10.1128/JVI.01308-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

In vitro and in vivo properties of adenovirus vectors with increased affinity to CD46

University of Washington, Division of Medical Genetics, Department of Biochemistry, Department of Pathology, 1705 NE Pacific St., Seattle, WA 98195; Interfaculty Institute for Biochemistry, University of Tübingen, D-72076 Tübingen, Germany, and Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Thrombosis Research Institute, Manresa Road, London SW3 6LR, UK; British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK; Molecular Medicine Program, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

^* To whom correspondence should be addressed. Email: lieber00{at}u.washington.edu.

	Abstract

Gene transfer vectors containing adenovirus (Ad) serotype 35 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 in 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 in correspondingly higher transduction efficiencies, regardless of the CD46 receptor density present on cells. However, in vivo, in a mouse model with pre-established CD46^high 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.