Targeted adenovirus vectors for genetic anti-cancer immunization

Anti-cancer immunization is limited by the poor immunogenicity of tumor-associated antigens (TAAs) normally used for vaccination. This problem may be overcome by direct adenovirus-mediated delivery of TAAs to dendritic cells (DCs), which play a centralrole in the generation of the immune response. The specificity and efficiency of this vaccination strategy may be improved by specifically targeting the vectors to DCs. Therefore, we propose to develop an Ad vector targeted to CD40 molecules expressed onthe surface of DCs. In one approach, CD40-specific ligands, the natural CD40 ligand (CD40L) and an anti-CD40 single chain antibody, will be cross-linked to TAA-expressing Ad vectors by peptide zippers genetically incorporated into both the Ad capsid andthe ligand. In an alternative approach, the human immunoglobulin Fc domain and the Z domain of S. aureus protein A will be incorporated into the ligand and the Ad fiber protein, respectively. In both cases, the entire targeting complex is designed toself-assemble during the propagation of the Ad vector. We hypothesize that this vector design will result in more efficient antigen presentation by DCs, thereby leading to significant improvements in anti-cancer immunization-based treatment strategies.The prostate-specific membrane antigen will be employed as a model TAA.