HighIn VivoProduction of a Model Monoclonal Antibody on Adenoviral Gene Transfer

Abstract

The therapeutic potential of monoclonal antibodies (MAbs) for treating a variety of severe or life-threatening diseases is high. Although intravenous infusion appears to be the simplest and most obvious mode of administration, it is not applicable in many long-term treatments. It might, however, be advantageously replaced by gene/cell therapies, rendering treatments cost-effective and eliminating the short- and long-term side effects associated with injection of massive doses of antibodies. Grafting of ex vivo genetically modified cells of various types has already been used for in vivo production and systemic delivery of MAbs in mice. However, although sustained for long periods of time, serum levels of ectopic MAbs were low. We show here that in vivo administration to mice of a first-generation adenoviral vector expressing a model MAb also permits achievement of the same goal, but with 100 to 200 times better efficiency that in any other case of gene transfer described thus far. We also investigated for possible anti-idiotypic response against the ectopic MAb. None was detected in the animals expressing the lowest levels of ectopic MAb production; a response was detected among the highest producers. In the latter case, however, the response was low and could not exert any significant neutralizing activity. In conclusion, our work indicates that high levels of circulating ectopic MAb can be obtained on direct in vivo gene transfer without inducing an anti-idiotypic response sufficiently robust to exert a neutralizing effect. This observation is encouraging in the perspective of clinical applications of this technology.