title: In vitro and in vivo properties of adenovirus vectors with increased affinity to CD46.
abstract: 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 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.
authors.affiliation: Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Wang
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Zongyi
authors.initials: Z
authors.lastname: Li
authors.forename: Sebastian
authors.initials: S
authors.lastname: Tuve
authors.forename: Daniel
authors.initials: D
authors.lastname: Stone
authors.forename: Oleksandr
authors.initials: O
authors.lastname: Kalyushniy
authors.forename: Dmitry
authors.initials: D
authors.lastname: Shayakhmetov
authors.forename: Christophe L M
authors.initials: CL
authors.lastname: Verlinde
authors.forename: Thilo
authors.initials: T
authors.lastname: Stehle
authors.forename: John
authors.initials: J
authors.lastname: McVey
authors.forename: Andrew
authors.initials: A
authors.lastname: Baker
authors.forename: Kah-Whye
authors.initials: KW
authors.lastname: Peng
authors.forename: Steve
authors.initials: S
authors.lastname: Roffler
authors.forename: André
authors.initials: A
authors.lastname: Lieber