Antibodies against adenovirus fiber and penton base proteins inhibit adenovirus vector-mediated transduction in the liver following systemic administration

Sci Rep. 2018 Aug 17;8(1):12315. doi: 10.1038/s41598-018-30947-z.

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.

MeSH terms

  • Adenoviridae / genetics
  • Adenoviridae / immunology*
  • Animals
  • Antibodies, Viral / immunology*
  • Capsid Proteins / immunology*
  • Female
  • Gene Dosage / genetics
  • Genetic Vectors / genetics
  • Liver / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Plasmids / genetics
  • Transduction, Genetic / methods

Substances

  • Antibodies, Viral
  • Capsid Proteins
  • penton protein, adenovirus