Use of a liver-specific promoter reduces immune response to the transgene in adenoviral vectors

Previous studies using adenoviral (Ad) vectors expressing human alpha(1)-an titrypsin (hAAT) under the control of ubiquitous promoters (RSV, mPGK) elic ited the production of antibodies to hAAT in some mouse strains (C3WHeJ) an d BALB/c) but not in others (C57BL/6J), In contrast, when a helper-dependen t Ad vector (AdSTK109) with all viral coding sequences deleted and expressi ng hAAT from human genomic DNA with the endogenous promoter was used, C3H/H eJ mice failed to develop antibodies and demonstrated long-term expression. These results suggested that promoter choice and/or properties of the vect or itself might influence the host immune response to the transgene product . Direct comparison of first-generation vectors expressing the hAAT cDNA fr om a ubiquitous mouse PGK promoter rather than from a liver-specific mouse albumin promoter demonstrated that an antibody response to hAAT occurred wi th the mPGK promoter but not with the albumin promoter in C3WHeJ mice. As e xpected, neither vector elicits an antibody response in C57BL/6J mice. Coin jection of the two first-generation vectors containing the mPGK and albumin promoter in C3WHeJ mice induced an antibody response with resulting loss o f detectable hAAT from the sera of the injected mice in 3-4 weeks. From the se data, we conclude that under certain conditions, the choice of promoter with its associated liver-specific expression can modulate the host immune response to the transgene independent of viral backbone.