title: Passive Immunotherapy Protects against Enteric Invasion and Lethal Sepsis in a Murine Model of Gastrointestinal Anthrax.
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.
authors.affiliation: 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. bruce.huang@fda.hhs.gov.
authors.forename: Bruce
authors.initials: B
authors.lastname: Huang
authors.affiliation: 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. tao.xie@fda.hhs.gov.
authors.forename: Tao
authors.initials: T
authors.lastname: Xie
authors.affiliation: Division of Compliance, Center for Veterinary Medicine, U.S. Food and Drug Administration, Rockville, MD 20855, USA. david.rotstein@fda.hhs.gov.
authors.forename: David
authors.initials: D
authors.lastname: Rotstein
authors.affiliation: 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. hui.fang@fda.hhs.gov.
authors.forename: Hui
authors.initials: H
authors.lastname: Fang
authors.affiliation: 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. david.frucht@fda.hhs.gov.
authors.forename: David M
authors.initials: DM
authors.lastname: Frucht
mesh_terms: D000818:Animals; D000881:Anthrax / Q000276:immunology / Q000382:microbiology / Q000628:therapy*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000627:therapeutic use*; D000942:Antigens, Bacterial; D001408:Bacillus anthracis / Q000187:drug effects / Q000276:immunology / Q000472:pathogenicity; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005260:Female; D005759:Gastroenteritis / Q000276:immunology / Q000382:microbiology / Q000628:therapy*; D007116:Immunization, Passive / Q000379:methods*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008815:Mice, Inbred Strains; D018805:Sepsis / Q000276:immunology / Q000517:prevention & control*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C030325:anthrax toxin
keywords: anthrax toxin; edema factor; gastrointestinal anthrax; lethal factor; monoclonal antibody; protective antigen; raxibacumab