Assessment of genetic shielding for adenovirus vectors

Abstract

Development of adenovirus (Ad) vectors in the clinical context has highlighted that vector efficacy may be limited by the host humoral response due to pre-existing titers of neutralizing antibodies against the vector itself in humans. Further, multiple dosing of Ad vectors based on serotype 5 would be limited. Current immune evasion strategies being investigated by other laboratories are only applicable to non-replicating vectors. Therefore we have proposed genetic shielding as an alternate that would be applicable to both non-replicating and conditionally replicating Ad vectors. Genetic shielding would encapsulate fusion of a self-protein to Ad minor capsid protein, pIX, as a means to cloak immunogenic capsid epitopes and prevent neutralization of Ad vectors through Ad specific antibodies. In the development of a suitably shielded Ad vector we choose several self-proteins that we attempted to fuse to pIX. We have also used an indirect method to conjugate albumin to the capsid through an albumin binding domain fused to pIX. Despite attaining novel pIX modified Ad vectors we found that none of the pIX attached molecules in this study prevented neutralizing antibodies from halting gene transfer. © Hedley et al.