Evaluation of biodistribution of a fiber-chimeric, conditionally replication-competent (oncolytic) adenovirus in CD46 receptor transgenic mice.
The limited efficacy of adenovirus type 5 (Ad5)-based oncolytic viruses seen in the clinic thus far may be attributable in part to variable expression of its receptor on tumor cells. Replacement of the Ad5 fiber knob with the Ad35 fiber knob generated the Ad5/35 chimeric virus, which has previously been demonstrated to have significant antitumor activity in murine tumor models, presumably by virtue of its recognition of the CD46 receptor, which is abundant on many types of tumor cells. In the current study, a CD46 receptor transgenic mouse strain (hCD46Ge) that expresses the CD46 receptor in a pattern closely mirroring that in humans was used to study the in vivo properties of Ad5/Ad35 chimeric viruses. Vector distribution was evaluated after intravenous administration to hCD46Ge mice of an Ad5-based oncolytic adenovirus or an Ad5/35 chimeric oncolytic adenovirus (designated OV-5 and OV-5T35H, respectively), a wild-type Ad5 virus (Ad5wt), or an Ad5-based, E1-deleted adenovirus (Addl312) at 1.25 x 10(12) viral particles/kg. The amount of OV-5T35H vector genomes in the liver was at least two orders of magnitude lower than that of Ad5-based viruses. Moreover, animals injected with OV-5T35H virus had significantly lower elevations of serum proinflammatory cytokines and liver enzyme levels. Mice injected with Ad5wt lost more than 20% of their body weight and died or required euthanasia because of poor clinical condition within 4 days of virus administration. Mice treated with OV-5 lost as much as 15% of their body weight over 8-9 days, but recovered within 14 days. Mice that were treated with Addl312 or OV-5T35H exhibited no body weight loss during the study period. These studies suggest that the Ad5/35-based chimeric viruses may have a better safety profile after intravenous injection compared with Ad5-based viruses.
Ganesh
Shanthi
S
Cell Genesys, South San Francisco, CA 94080, USA. ganeshshanti@yahoo.com
Gonzalez-Edick
Melissa
M
Gibbons
Douglas
D
Waugh
Jeff
J
Van Roey
Melinda
M
Jooss
Karin
K
D000256:Adenoviridae / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001772:Blood Cell Count; D001773:Blood Cells / Q000378:metabolism; D042783:Endothelial Cells / Q000821:virology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D008099:Liver / Q000201:enzymology / Q000276:immunology / Q000821:virology; D051916:Membrane Cofactor Protein / Q000235:genetics*; D051379:Mice; D050130:Oncolytic Virotherapy / Q000379:methods; D050504:Oncolytic Viruses / Q000235:genetics* / Q000502:physiology*; D014018:Tissue Distribution; D014161:Transduction, Genetic; D014779:Virus Replication / Q000502:physiology*
D015415:Biomarkers; D051916:Membrane Cofactor Protein; D049452:Green Fluorescent Proteins