Prevention of Immune Reactions Triggered by First-Generation Adenoviral Vectors by Monoclonal Antibodies and CTLA4Ig

Abstract

The therapeutic potential of adenovirus-mediated gene transfer using first-generation vectors is severely limited by the fact that only transient expression is achievable in immunocompetent animals. The loss in transgene expression can be attributed at least in part to the appearance of detrimental immune responses directed toward vector and/or transgene-encoded determinants. FK506 and cyclosporin A both reduced these immune responses. These immunosuppressants, however, may induce many severe side effects during prolonged use. An alternative strategy has been developed to overcome these problems following in vivo transfection of muscles of adult immunocompetent mice with a ΔE₁/E₃ ^a adenoviral vector encoding a β-galactosidase (β-Gal) expression cassette. YTS 177 (an anti-CD4 monoclonal antibody) as well as CTLA4Ig, a recombinant protein, partially controlled the immune responses. They were indeed able to reduce the muscle infiltration by CD4⁺ and CD8⁺ cells but they failed to repress the humoral response. Co-administration of YTS 191 (an anti-CD4), YTS 169 (an anti-CD8), and TIB 213 (an anti-CD11a) was, however, very efficient in blocking both cellular and humoral immune reactions. This combination of monoclonal antibodies allowed strong and stable trans-gene expression over 1 month. These data underline the potential of monoclonal antibodies as immunosuppressive adjunct treatment for adenovirus-mediated gene transfer.

Overview summary

Replication-defective adenoviruses are considered promising candidates for somatic gene therapy in many diseases. However, first-generation adenoviruses trigger immune responses that lead to the elimination of the infected cells. Moreover, even if new generation vectors are not immunogenic, immune responses will likely be raised against some non-self new proteins produced following the expression of non-self transgenes. In this study, we demonstrate that different monoclonal antibodies can be injected separately or in combination to overcome cellular and humoral immune reactions triggered by vector-mediated gene transfer, in some cases allowing strong transgene expression for at least 4 weeks. Our results confirm the immunological problems associated with gene transfer using first-generation adenoviral vectors and demonstrate that adequate immunosuppression using monoclonal antibodies can significantly increase the success of gene transfer.