Therapeutic antibodies are one of the major classes of medical countermeasures that can protect against potential bioweapons such as botulinum toxin. Although a broad array of antibodies are being evaluated for their ability to neutralize the toxin, there is little information that defines the circumstances under which these antibodies can be used. In the present study, an effort was made to quantify the temporal factors that govern therapeutic antibody use in a post-challenge scenario. Experiments were done involving inhalation administration of toxin to mice, intravenous administration to mice, and direct application to murine phrenic nerve-hemidiaphragm preparations. As part of this study, several pharmacokinetic characteristics of botulinum toxin and of neutralizing antibodies were measured. The core observation that emerged from the work was that the window of opportunity within which post-challenge administration of antibodies exerted a beneficial effect increased as the challenge dose of toxin decreased. The critical factor in establishing the window of opportunity was the amount of time needed for fractional redistribution of a neuroparalytic quantum of toxin from the extra-neuronal space to the intra-neuronal space. This redistribution event was a dose-dependent phenomenon. It is likely that the approach used to identify the factors that govern post-challenge efficacy of antibodies against botulinum toxin can be used to assess the factors that govern post-challenge efficacy of medical countermeasures against any agent of bioterrorism or biological warfare.
- Received February 15, 2011.
- Revision received May 16, 2011.
- Accepted May 16, 2011.
- The American Society for Pharmacology and Experimental Therapeutics