Targeting of adenovirus vectors carrying a tumor cell-specific peptide: in vitro and in vivo studies.
Previously, we have identified a tumor cell-specific peptide, HEW, by panning of phage display libraries on the human colorectal cancer cell line WiDr. In this report we demonstrate that this peptide can modify the infection properties of adenovirus vectors. Increased infectivity of replication-deficient adenovirus 5 vectors in WiDr cells was observed upon genetic insertion of the HEW peptide in the HI loop of the fiber knob. Moreover, whereas the coxsackie and adenovirus receptor (CAR)-ablating fiber mutation S408E abolished apparent infection in CAR-positive WiDr cells, the insertion of HEW completely restored infectivity toward these cells in vitro. To assess whether the de- and re-targeted infection profile was maintained in vivo, the fiber-modified adenovirus vectors were injected intratumorally or intravenously in WiDr tumor-bearing Swiss nu/nu mice. No significant differences in efficiency of infection could be observed suggesting alternative viral uptake mechanisms in vivo. Next, we have included the fiber shaft mutation S(*) in our studies, which was described to confer a de-targeted phenotype in vivo. Reduced gene transfer due to the S(*) mutation both in vitro and in vivo could be confirmed. Insertion of HEW in the HI knob loop of shaft-mutated fiber, however, did not rescue infectivity in target cells neither in vitro nor in vivo. We demonstrate the efficient ligand-mediated re-targeting of adenoviral vector infection to the human cancer cell line WiDr. The lack of apparent re-targeting in the in vivo situation is described.
Rittner
K
K
Transgene SA, 11 rue de Molsheim, Strasbourg, Bas-Rhin, France. rittner@transgene.fr
Schreiber
V
V
Erbs
P
P
Lusky
M
M
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015179:Colorectal Neoplasms / Q000628:therapy*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D009842:Oligopeptides / Q000235:genetics*; D014779:Virus Replication / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D009842:Oligopeptides; C521496:histidyl-glutamyl-tryptophyl-seryl-tyrosyl-leucyl-alanyl-prolyl-tyrosyl-prolyl-tryptophyl-phenylalanine