CD46 Represents a Target for Adenoviral Gene Therapy of Malignant Glioma

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Abstract
Malignant gliomas remain refractory to adenovirus serotype 5 (Ad5) gene therapy because of the lack of the primary adenoviral receptor, the coxsackie–adenovirus receptor (CAR), on tumor cells. To bypass the dependence on CAR, we investigated the expression of adenovirus serotype 3 (Ad3) receptor, or CD46, on glioma cells. First, we analyzed the expression of CD46 by RT-PCR on primary and passaged glioma cells. We then performed immunofluorescence studies to examine protein expression of CAR and CD46 on the same tumor lines. Finally, we constructed a replication-defective Ad vector that binds to CD46 and contains a luciferase transgenic cassette in place of the deleted E1 region: Ad5/3 (containing tail/shaft domain of Ad5 and knob domain of Ad3). These vectors were analyzed in vitro and in vivo against malignant glioma and compared with wild-type Ad5 or control vector Ad3/5 (containing tail of Ad5, shaft of Ad3, and knob of Ad5). The chimeric vector Ad5/3 showed a significant increase in the transduction efficiency of glioma tumor cells. At the same time, blocking the CD46 receptor caused a 65% inhibition of adenoviral infection when using Ad5/3. Taken together, these results indicate that CD46 is overexpressed by malignant glioma. Retargeting to the Ad3 receptor enhances gene transfer and offers a novel target for gene therapy of malignant brain tumors.