Retroviral vectors bearing IgG-binding motifs for antibody-mediated targeting of vascular endothelial growth factor receptors.
Targeting retroviral vectors to tumor vasculature is an important goal of cancer gene therapy. In this study, we report a novel targeting approach wherein IgG-binding peptides were inserted into the Moloney murine leukemia virus (MuLV) envelope (env) protein. The modifications on the viral env included replacement of the entire receptor binding region of the viral env with protein A (or ZZ) domains. The truncated env incorporating IgG-binding motifs (known as proteins) provided the targeting function, while the co-expressed wild-type (WT) env protein enabled viral fusion and cell entry. An anti-human VEGF receptor (Flk-1/KDR) antibody served as a molecular bridge, directing the retroviral vector to the endothelial cell. Hence, the IgG-targeted vectors bound to the Flk-1/KDR antibody which in turn bound to VEGF receptors on Kaposi sarcoma, KSY1, endothelial cells. The net effect was increased viral fusion and infectivity of IgG-bound retroviral vectors when compared to non-targeted vectors bearing WT env alone. These data provide the proof of concept that IgG-binding vector/VEGF receptor antibody complexes may be used to enhance retroviral gene delivery to activated endothelial cells.
Masood
R
R
Department of Medicine, University of Southern California School of Medicine, Los Angeles, CA 90033, USA.
Gordon
E M
EM
Whitley
M D
MD
Wu
B W
BW
Cannon
P
P
Evans
L
L
Anderson
W F
WF
Gill
P
P
Hall
F L
FL
D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000276:immunology*; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D002460:Cell Line; D015686:Gene Products, env / Q000235:genetics / Q000378:metabolism; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008979:Moloney murine leukemia virus / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology*; D017978:Receptors, Growth Factor / Q000276:immunology*; D017452:Receptors, IgG / Q000235:genetics* / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor; D012190:Retroviridae / Q000235:genetics; D013205:Staphylococcal Protein A / Q000235:genetics / Q000378:metabolism; D014162:Transfection / Q000379:methods; D014407:Tumor Cells, Cultured
D000906:Antibodies; D015686:Gene Products, env; D017978:Receptors, Growth Factor; D017452:Receptors, IgG; D013205:Staphylococcal Protein A; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor