TARGETED GENE DELIVERY BY TROPISM-MODIFIED ADENOVIRAL VECTORS

The utility of adenoviral vectors for gene therapy is currently limite d due, in part, to the widespread distribution of the cellular recepto r for the adenovirus fiber that precludes the targeting of specific ce ll types. In order to develop a targeted adenovirus, it is therefore n ecessary both to ablate endogenous viral tropism and to introduce nave l tropism. We hypothesized that these two goals could be achieved by e mploying a neutralizing anti-fiber antibody, or antibody fragment, che mically conjugated to a cell-specific ligand. To test this concept, we chose to target the folate receptor, which is overexpressed on the su rface of a variety of malignant cells, Therefore, we conjugated folate to the neutralizing Fab fragment of an anti-fiber monoclonal antibody . This Fab-folate conjugate was complexed with an adenoviral vector ca rrying the luciferase reporter gene and was shown to redirect adenovir al infection ob target cells via the folate receptor at a high efficie ncy Furthermore, when complexed with an adenoviral vector carrying the gene for herpes simplex virus thymidine kinase, the Fab-folate conjug ate mediated the specific killing of cells that overexpress the folate receptor. This work thus represents the first demonstration of the re targeting of a recombinant adenoviral vector vie a non-adenoviral cell ular receptor.