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Infection and Immunity, October 2009, p. 4305-4313, Vol. 77, No. 10
0019-9567/09/$08.00+0     doi:10.1128/IAI.00405-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Antibody Protection against Botulinum Neurotoxin Intoxication in Mice{triangledown}

Luisa W. Cheng,1* Larry H. Stanker,1 Thomas D. Henderson II,1 Jianlong Lou,2 and James D. Marks2

Foodborne Contaminants Research Unit, Western Regional Research Center, USDA Agricultural Research Service, 800 Buchanan Street, Albany, California 94710,1 Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco General Hospital, Room 3C-38, 1001 Potrero Avenue, San Francisco, California 941102

Received 10 April 2009/ Returned for modification 21 May 2009/ Accepted 25 July 2009

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 serotype A (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 the heavy chain of BoNT/A, and the epitope of F1-40 has been mapped to the light chain. The ability of these MAbs to provide therapeutic protection against BoNT/A intoxication in mouse intravenous and oral intoxication models was tested. High dosages of individual MAbs protected mice well both pre- and postexposure to BoNT/A holotoxin. A combination therapy consisting of antibodies against both the light and heavy chains of the toxin, however, significantly increased protection, even at a lower MAb dosage. An in vitro peptide assay for measuring toxin activity showed that pretreatment of toxin with these MAbs did not block 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 the biologic half-life of the toxin in the serum. Knowledge of BoNT intoxication and antibody clearance in these mouse models and understanding of the pharmacokinetics of BoNT are invaluable for future development of antibodies and therapeutics against intoxication by BoNT.

* Corresponding author. Mailing address: Foodborne Contaminants Research Unit, Western Regional Research Center, USDA Agricultural Research Service, 800 Buchanan Street, Albany, CA 94710. Phone: (510) 559-6337. Fax: (510) 559-5880. E-mail: luisa.cheng{at}ars.usda.gov

{triangledown} Published ahead of print on 3 August 2009.

Editor: S. R. Blanke

Infection and Immunity, October 2009, p. 4305-4313, Vol. 77, No. 10
0019-9567/09/$08.00+0     doi:10.1128/IAI.00405-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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