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Toxins 2015, 7(10), 3960-3976; doi:10.3390/toxins7103960

Passive Immunotherapy Protects against Enteric Invasion and Lethal Sepsis in a Murine Model of Gastrointestinal Anthrax

1
Division of Biotechnology Review and Research II, Office of Biotechnology Products, Office of Product Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993-0002, USA
2
Division of Compliance, Center for Veterinary Medicine, U.S. Food and Drug Administration, Rockville, MD 20855, USA
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Shihui Liu
Received: 19 August 2015 / Accepted: 19 August 2015 / Published: 29 September 2015
(This article belongs to the Collection Anthrax Toxins)
View Full-Text   |   Download PDF [3006 KB, uploaded 29 September 2015]   |  

Abstract

The principal portal for anthrax infection in natural animal outbreaks is the digestive tract. Enteric exposure to anthrax, which is difficult to detect or prevent in a timely manner, could be exploited as an act of terror through contamination of human or animal food. Our group has developed a novel animal model of gastrointestinal (GI) anthrax for evaluation of disease pathogenesis and experimental therapeutics, utilizing vegetative Bacillus anthracis (Sterne strain) administered to A/J mice (a complement-deficient strain) by oral gavage. We hypothesized that a humanized recombinant monoclonal antibody (mAb) * that neutralizes the protective antigen (PA) component of B. anthracis lethal toxin (LT) and edema toxin (ET) could be an effective treatment. Although the efficacy of this anti-anthrax PA mAb has been shown in animal models of inhalational anthrax, its activity in GI infection had not yet been ascertained. We hereby demonstrate that passive immunotherapy with anti-anthrax PA mAb, administered at the same time as gastrointestinal exposure to B. anthracis, prevents lethal sepsis in nearly all cases (>90%), while a delay of up to forty-eight hours in treatment still greatly reduces mortality following exposure (65%). Moreover, passive immunotherapy protects against enteric invasion, associated mucosal injury and subsequent dissemination by gastrointestinal B. anthracis, indicating that it acts to prevent the initial stages of infection. * Expired raxibacumab being cycled off the Strategic National Stockpile; biological activity confirmed by in vitro assay. View Full-Text
Keywords: gastrointestinal anthrax; anthrax toxin; protective antigen; monoclonal antibody; raxibacumab; lethal factor; edema factor gastrointestinal anthrax; anthrax toxin; protective antigen; monoclonal antibody; raxibacumab; lethal factor; edema factor
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Huang, B.; Xie, T.; Rotstein, D.; Fang, H.; Frucht, D.M. Passive Immunotherapy Protects against Enteric Invasion and Lethal Sepsis in a Murine Model of Gastrointestinal Anthrax. Toxins 2015, 7, 3960-3976.

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