Abstract
Pre-existing anti-adenovirus (Ad) neutralizing antibodies (AdNAbs) are a major barrier in clinical gene therapy using Ad vectors and oncolytic Ads; however, it has not been fully elucidated which Ad capsid protein-specific antibodies are involved in AdNAb-mediated inhibition of Ad infection in vivo. In this study, mice possessing antibodies specific for each Ad capsid protein were prepared by intramuscular electroporation of each Ad capsid protein-expressing plasmid. Ad vector-mediated hepatic transduction was efficiently inhibited by more than 100-fold in mice immunized with a fiber protein-expressing plasmid or a penton base-expressing plasmid. An Ad vector pre-coated with FX before administration mediated more than 100-fold lower transduction efficiencies in the liver of warfarinized mice immunized with a fiber protein-expressing plasmid or a penton base-expressing plasmid, compared with those in the liver of warfarinized non-immunized mice. These data suggest that anti-fiber protein and anti-penton base antibodies bind to an Ad vector even though FX has already bound to the hexon, and inhibit Ad vector-mediated transduction. This study provides important clues for the development of a novel Ad vector that can circumvent inhibition with AdNAbs.
Highlights
Replication-incompetent adenovirus (Ad) vectors are widely used in gene therapy studies and basic research due to their many advantages as a gene delivery vehicle
In order to examine whether anti-Ad serotype 5 (Ad5) fiber antibodies inhibited the transduction with an Ad5 vector, we examined the transduction efficiencies of a luciferase-expressing fiber-substituted Ad vector containing the fiber proteins of Ad serotype 35 (Ad35) (AdF35-L2)[26] in the liver of mice immunized with each Ad5 capsid protein-expressing plasmid
Significant reduction in the transduction efficiencies of Ad-L2 was induced by anti-hexon serum under this experimental condition, the average of transduction efficiencies in the liver of warfarinized mice possessing anti-hexon antibodies were higher than those in the liver of warfarinized mice possessing anti-fiber antibodies. These results indicated that anti-fiber protein and anti-penton base antibodies bound to an factor X (FX)-coated Ad vector, leading to the inhibition of hepatic transduction with an Ad vector
Summary
Replication-incompetent adenovirus (Ad) vectors are widely used in gene therapy studies and basic research due to their many advantages as a gene delivery vehicle. Inhibitory effects of anti-hexon antibodies on Ad infection have been demonstrated using chimeric Ads containing genetic mutation in the hexon gene[18,19,20], while several studies have reported that neutralizing antibodies in human sera and ascetic fluids were primarily directed against the fiber protein and penton base protein[12,21,22] To resolve this question, it will be necessary to prepare experimental animals possessing antibodies specific for each Ad capsid protein in order to individually and correctly evaluate the effects of antibodies against each capsid protein on Ad vector-mediated in vivo transduction. Our data suggests that anti-fiber and anti-penton base antibodies play a crucial role in the inhibition of Ad vector-mediated transduction in the liver
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