RT Journal Article
SR Electronic
T1 Identification of the Factors that Govern the Ability of Therapeutic Antibodies to Provide Post-Challenge Protection Against Botulinum Toxin: A Model for Assessing Post-Challenge Efficacy of Medical Countermeasures Against Agents of Bioterrorism and Biological Warfare
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.111.180653
DO 10.1124/jpet.111.180653
A1 Fetweh H. Al-Saleem
A1 Zidoon Nasser
A1 Rebecca M. Olson
A1 Linsen Cao
A1 Lance L. Simpson
YR 2011
UL http://jpet.aspetjournals.org/content/early/2011/05/17/jpet.111.180653.abstract
AB 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.