Next-generation of targeted AAVP vectors for systemic transgene delivery against cancer.

Bacteriophage (phage) have attractive advantages as delivery systems compared with mammalian viruses, but have been considered poor vectors because they lack evolved strategies to confront and overcome mammalian cell barriers to infective agents. We reasoned that improved efficacy of delivery might be achieved through structural modification of the viral capsid to avoid pre- and postinternalization barriers to mammalian cell transduction. We generated multifunctional hybrid adeno-associated virus/phage (AAVP) particles to enable simultaneous display of targeting ligands on the phage's minor pIII proteins and also degradation-resistance motifs on the very numerous pVIII coat proteins. This genetic strategy of directed evolution bestows a next-generation of AAVP particles that feature resistance to fibrinogen adsorption or neutralizing antibodies and ability to escape endolysosomal degradation. This results in superior gene transfer efficacy in vitro and also in preclinical mouse models of rodent and human solid tumors. Thus, the unique functions of our next-generation AAVP particles enable improved targeted gene delivery to tumor cells.
Competing Interests: Conflicts of interest: J.G.G., R.P., and W.A. are founders of PhageNova Bio, which has licensed intellectual property related to the AAVP technology. R.P. is the Chief Scientific Officer and a paid consultant for PhageNova Bio. J.G.G., R.P., W.A., and A.H. are inventors on issued patents and pending patent applications related to AAVP technologies and are entitled to royalties if licensing or commercialization occurs. T.Y. and A.H. are inventors on a patent application describing the vector constructs reported here and will be entitled to royalties if licensing or commercialization occurs. These arrangements are managed in accordance with established institutional conflict of interest policies of each corresponding institution.
(Copyright © 2019 the Author(s). Published by PNAS.)