Molecular adaptors for vascular-targeted adenoviral gene delivery.
Gene therapy would be considerably more effective if vectors could be targeted to specific organs or tissues after systemic administration. We previously developed an in vivo selection system to isolate organ- and tumor-homing peptides from phage display peptide libraries. The peptides isolated by this approach bind to receptors expressed in vascular endothelia. We describe here the development of molecular adaptors to target adenoviral gene therapy vectors to selective vascular "addresses." The adaptor design consists of an organhoming peptide conjugated to an adenovirus-binding moiety. We isolated and characterized several monoclonal antibodies that bind to adenovirus type 5 (Ad5). Two of the antibodies neutralized Ad5 infection. We linked the Fab fragments of one of these antibodies to a synthetic lung-homing peptide (CGFECVRQCPERC or GFE-1 peptide) and tested the ability of the resulting bispecific conjugate to retarget Ad5. Cells that express the receptor for the GFE-1 peptide and are resistant to Ad5 infection were sensitized to recombinant Ad5 vectors in the presence of the Fab-GFE adaptor. Our findings indicate that selective gene therapy delivery may be developed on the basis of our vascular targeting technology.
Trepel
M
M
Department of GU Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Grifman
M
M
Weitzman
M D
MD
Pasqualini
R
R
D000256:Adenoviridae / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006367:HeLa Cells; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D019151:Peptide Library; D011233:Precipitin Tests; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D019151:Peptide Library