Passive immunotherapy is used to treat intoxication by a variety of biological toxins. Exposure to toxigenic bacteria or purified toxin preparations in a bioterrorism event would necessitate administration of therapeutic antibodies in a mass response setting. The standard practice of intravenous infusion of antibodies to exposed individuals as well as the expense associated with large preparations of purified antibodies would not be practical in this situation. Therefore, a strategy is presented for rapid protection against a bacterial boxin with adenovirus (Ad)-based vectors that express neutralizing single chain antibodies. Shigatoxin was selected for these proof-of-principle experiments due to the availability of specific reagents and the classification of shigatoxin and E. coli O157, a shigatoxin-producing bacterial strain, as potential biowarfare threats. The general principle is that Ad-based gene transfer vectors expressing neutralizing single chain antibodies can elicit rapid passive immunity against shigatoxin by a convenient route of administration and that this technology can be applied to other potential toxin threats. The proposal is based on our experience in the development of Ad-based anti-bacterial vaccines and the ability of Ad vectors to deliver single chain antibodies against specific pathogens. The 3 specific aims outline studies to achieve these goals by developing Ad vectors that express a shigatoxin-specific single chain antibody and optimizing the binding and neutralization characteristics of the single chain antibodies through genetic manipulation and evaluation in an in vivo challenge system.
Aim 1 : To evaluate the hypothesis that shigatoxin-specific single chain antibodies expressed by Ad vectors can neutralize shigatoxin.
Aim 2 : To refine the technology of Ad-expressed antishigatoxin single chain antibodies, modifications known to increase the stability, avidity, and molecular weight of anti-shigatoxin single chain antibodies to enhance their protective efficacy will be examined.
Aim 3 : Evaluate the ability of Ad-delivered anti-shigatoxin antibodies to protect experimental animals from challenge with shigatoxin and toxigenic bacteria.
| Boyer, Julie L; Kobinger, Gary; Wilson, James M et al. (2005) Adenovirus-based genetic vaccines for biodefense. Hum Gene Ther 16:157-68 |
