Specific depletion of human anti-adenovirus antibodies facilitates transduction in an in vivo model for systemic gene therapy

Recombinant adenoviral (rAd) vectors are capable of mediating high-efficien cy gene transfer in vivo. Under conditions requiring systemic administratio n, however, the use of rAd vectors can be problematic due to the presence o f circulating anti-adenovirus antibodies developed either through natural i nfection or during the course of treatment. We developed a passive immuniza tion model in SCID/Beige mice to assess the effect of human and mouse anti- adenovirus antibodies on systemic administration of a rAd vector expressing beta -galactosidase (rAd-beta gal). In this model, the in vitro neutralizi ng activity of human or mouse antibodies used for passive immunization corr elated well with inhibition of transduction of the liver following i.v. adm inistration of rAd-beta gal. Depletion of antibodies to individual adenovir us structural proteins (hexon, penton, fiber) by affinity chromatography de monstrated that antibodies to each of the three virion components contribut ed to neutralization of infectivity in vitro and to inhibition of transduct ion in vivo. Depletion of antibodies against all three structural proteins from human or mouse immune serum prior to passive immunization restored in vivo transduction activity to levels comparable to those obtained with noni mmune serum. Our data suggest that depletion of both murine and human anti- adenoviral antibodies can restore transduction in vivo during systemic rAd gene therapy in hosts previously exposed to adenovirus.