Liver Toxicities Typically Induced by First-Generation Adenoviral Vectors Can Be Reduced by Use of E1,E2b-Deleted Adenoviral Vectors

Abstract

Adenoviral vectors from which the E1 region has been deleted ([E1^-] Ad) are known to induce strong immune responses after systemic delivery. In this study we have evaluated liver toxicities in mice after intravenous injection with high doses of [E1^-] or modified [E1^-, E2b^-] Ad vectors (both expressing the bacterial β-galactosidase [lacZ] marker gene) in C57BL/6, BALB/c, and SCID mice. Our data demonstrate a marked reduction in maximal liver toxicities and pathologies (typically noted at 21 days postinjection) with the use of the [E1^-, E2b^-] modified vector in all strains of mice tested. Our data also demonstrated that despite the use of the [E1^-, E2b^-] Ad vector, significant liver toxicities were still observed. To address this issue and the fact that the lacZ gene was perceived as a foreign antigen in the immune-competent C57BL/6 and BALB/c mice, we similarly injected mice tolerant of LacZ (lacZ-TG). In contrast to our studies in C57BL/6 and BALB/c mice, LacZ-TG mice exhibited virtually no evidence of hepatotoxicity after intravenous injection with the [E1^-, E2b^-] vector, in contrast to use of the [E1^-] Ad vector. Our results demonstrate that the [E1^-, E2b^-] Ad vector class can reduce liver toxicities typically ascribed to Ad vector-mediated gene transfer after transfer of a highly immunogenic or foreign gene, whereas transfer of a transgene that is perceived as nonforeign by the host can be delivered with virtually no evidence of toxicity. On the basis of a careful review of the literature, these improvements in vector safety rival those noted with other, more significantly modified Ad vectors described to date.