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AssigneeAventis Pharma S.A.
InventorsEmmanuelle Vigne, Jean-Francois Dedieu, Martine Latta, Patrice Yeh, Michel Perricaudet
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Modification of internal sites of the adenovirus fiber protein and hexon protein permit effective targeting of adenovirus vectors. Accessible sites to redirect adenovirus targeting were identified. The HVR5 loop of the hexon protein and the HI loop of the fiber protein (knob) were highly permissive for the insertion of foreign protein sequences, which apparently did not impact on the viability and productivity of corresponding viruses. Accessibility and functionality of the epitope strongly depend on the size of the neighboring spacers. Other results suggest that short targeting peptides can be effectively fused to the C-terminus of the fiber protein. In a specific embodiment, a series of adenovirus vectors modified at the HVR5 site, the fiber protein HI loop, or the fiber protein C-terminus to target urokinase-type plasminogen activator receptor bearing cells were prepared. Such vectors are particularly useful for targeting the vasculature, e.g., for gene therapy of cancers or cardiovascular conditions.
An adenovirus wherein about 13 amino acids from the hexon HVR5 loop, corresponding to about amino acid residue 269 to about amino acid residue 281 of adenovirus serotype 5 (Ad5), is replaced with a targeting sequence flanked by connecting amino acid spacers so as to functionally display the targeting sequence's binding specificity at the capsid surface.
An adenovirus wherein at least a part of the hexon HI loop is replaced with a targeting sequence flanked by connecting amino acid spacers so as to functionally display the targeting sequence's binding specificity at the capsid surface.
An adenovirus hexon comprising a deletion of about 13 amino acids from the HVR5 loop corresponding to about amino acid residue 269 to about amino acid residue 281 of adenovirus serotype 5 (Ad5) and an insertion at the site of the deletion of a targeting peptide sequence connected by a first spacer at the N-terminus and a second spacer at the C-terminus of the targeting peptide sequence.
An adenovirus hexon protein comprising a deletion of about 11 amino acids from the HI loop corresponding to about amino acid residue 538 to about amino acid residue 548 of adenovirus serotype 5 (Ad5) and an insertion at the site of the deletion of a targeting peptide sequence connected by a first spacer at the N-terminus and a second spacer at the C-terminus of the targeting peptide sequence.
Dependencies are inferred from the claim text.