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United States Department of Agriculture

Agricultural Research Service

Research Project: DEVELOPMENT OF DETECTION TECHNOLOGIES FOR TOXINS AND THEIR VALIDATION IN FOOD MATRICES Title: Antibody Protection Against Botulinum Neurotoxin Intoxication In Mice

Authors
item CHENG, LUISA WAI WAI
item STANKER, LARRY
item HENDERSON, THOMAS
item Lou, Jianlong -
item Marks, James -

Submitted to: Infection and Immunity
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: July 25, 2009
Publication Date: October 1, 2009
Citation: Cheng, L.W., Stanker, L.H., Henderson Ii, T.D., Lou, J., Marks, J.D. 2009. Antibody Protection Against Botulinum Neurotoxin Intoxication In Mice. Infection and Immunity. 77(10):4305-4313.

Interpretive Summary: Botulinum neurotoxin (BoNT) serotype A is considered one of the most potent toxins and potential bioterrorist threat agents. However, this toxin is used therapeutically in a wide array of medical conditions. As a result, there is a need to protect against the deadly effects of intoxication and, at the same time, preserve the medical benefits of this toxin. Currently, the only therapies available are intensive hospital care and passive immunization with horse anti-serum or human antibodies against BoNTs, which have the drawbacks of serious side effects and limited supplies, respectively. Intense efforts are focused on the development of better treatments, and better animal models are needed to study the effects of such therapies. Here we have experimentally studied botulism in mice. We compared the effects of different treatment doses and timing. This work will help scientists understand how the toxin and antibody therapy work in an animal, leading to the development of more effective treatments.

Technical Abstract: Adulteration of food or feed with any of the seven serotypes of botulinum neurotoxin (BoNT) is a potential bioterrorism concern. Currently, there is strong interest in the development of detection reagents, vaccines, therapeutics and other countermeasures. A sensitive immunoassay for detecting BoNT/A, based on monoclonal antibodies (mAbs) F1-2 and F1-40, has been developed and used in complex matrices. The epitope for F1-2 has been mapped to peptides in the heavy chain and F1-40 to the light chain of BoNT/A. In this study, the ability of these mAbs to provide therapeutic protection against BoNT/A intoxication in mouse intravenous and oral models was tested. High dosages of individual mAbs protected mice nicely from both pre and post-exposure to BoNT/A holotoxin. A combination therapy consisting of antibodies against both light and heavy chains of the toxin, however, significantly increased protection even at lower dosage of mAbs. In vitro toxin assays showed that these monoclonal antibodies did not block BoNT/A catalytic activity but instead blocked toxin entry into primary and cultured neuronal cells. The timing of antibody rescue in the mouse intoxication models revealed windows of opportunity for antibody therapeutic treatment that correlated well with biologic half-lives of toxin in the sera. Knowledge of BoNT intoxication and antibody clearance in those mouse models and the understanding of the pharmacokinetics of BoNT are invaluable for future development of antibodies and immunotherapeutics against BoNT.

Last Modified: 7/28/2014
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