Targeted In Vivo Delivery of Therapeutic Gene into Experimental Squamous Cell Carcinomas Using Anti-Epidermal Growth Factor Receptor Antibody: Immunogene Approach

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Abstract
The “Fab immunogene” is a novel gene transfer vehicle in which the Fab fragment of anti-human epidermal growth factor (EGF) receptor antibody B4G7 is conjugated with poly-l-lysine to form an affinity complex with DNA. It was developed to target delivery of therapeutic genes into EGF receptor-hyperproducing tumor cells. Various characteristic features of the immunogene have been documented (Chen et al., 1998). Here we add further evidence to prove that in vitro transfer of β-galactosidase/Fab immunogene is exclusively to EGF receptor-positive cells and that the herpes simplex virus thymidine kinase (TK)/Fab immunogene induces substantial suicide effects on A431 tumor cells when treated together with ganciclovir. The in vivo specificity of the immunogene transfer was examined using A431 tumor-bearing nude mice. When these nude mice were injected intraperitoneally with the chloramphenicol acetyltransferase (CAT)/Fab immunogene, CAT DNA was detected in the tumors as well as in liver and kidney but not brain, whereas CAT mRNA and enzyme activity were detected only in the tumors. Local and intraperitoneal injection of the TK/Fab immunogene and subsequent administration of ganciclovir effectively suppressed the growth of A431 tumors transplanted on the backs of nude mice. These observations suggest a possible application of the Fab immunogene system in cancer gene therapy. To target the delivery of therapeutic genes into EGF receptor-hyperproducing tumor cells, we developed the “Fab immunogene,” which is a novel gene transfer vehicle consisting of the Fab fragment of anti-human EGF receptor antibody B4G7 and poly-l-lysine, forming an affinity complex with DNA. Here, we provide evidence that the Fab immunogene specifically delivers reporter genes in vitro as well as in vivo. Moreover, delivery of the therapeutic suicide gene TK and subsequent treatment with ganciclovir efficiently suppressed the growth of A431 cell tumors transplanted in nude mice. Thus, the TK/Fab immunogene has potential for use in the in vivo systemic therapy of squamous cell carcinomas.