{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T04:25:09Z","timestamp":1760243109569,"version":"build-2065373602"},"reference-count":62,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2015,9,29]],"date-time":"2015-09-29T00:00:00Z","timestamp":1443484800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>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 (&gt;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.<\/jats:p>","DOI":"10.3390\/toxins7103960","type":"journal-article","created":{"date-parts":[[2015,9,29]],"date-time":"2015-09-29T11:05:55Z","timestamp":1443524755000},"page":"3960-3976","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Passive Immunotherapy Protects against Enteric Invasion and Lethal Sepsis in a Murine Model of Gastrointestinal Anthrax"],"prefix":"10.3390","volume":"7","author":[{"given":"Bruce","family":"Huang","sequence":"first","affiliation":[{"name":"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"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tao","family":"Xie","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Rotstein","sequence":"additional","affiliation":[{"name":"Division of Compliance, Center for Veterinary Medicine, U.S. Food and Drug Administration, Rockville, MD 20855, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Fang","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Frucht","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2015,9,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1093\/aje\/155.11.981","article-title":"Bioterrorism: An update with a focus on anthrax","volume":"155","author":"Brachman","year":"2002","journal-title":"Am. J. Epidemiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.3201\/eid0810.020353","article-title":"Investigation of bioterrorism-related anthrax, United States, 2001: Epidemiologic findings","volume":"8","author":"Jernigan","year":"2002","journal-title":"Emerg. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.1056\/NEJMoa012948","article-title":"Index case of fatal inhalational anthrax due to bioterrorism in the United States","volume":"345","author":"Bush","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2689","DOI":"10.1128\/IAI.01875-06","article-title":"Murine aerosol challenge model of anthrax","volume":"75","author":"Loving","year":"2007","journal-title":"Infect. Immun."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1097\/01.LAB.0000080599.43791.01","article-title":"Pathology of inhalation anthrax in cynomolgus monkeys (Macaca fascicularis)","volume":"83","author":"Vasconcelos","year":"2003","journal-title":"Lab. Investig."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4801","DOI":"10.1128\/IAI.72.8.4801-4809.2004","article-title":"Murine model of pulmonary anthrax: Kinetics of dissemination, histopathology, and mouse strain susceptibility","volume":"72","author":"Lyons","year":"2004","journal-title":"Infect. Immun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.mam.2009.08.004","article-title":"Anthrax in animals","volume":"30","author":"Beyer","year":"2009","journal-title":"Mol. Aspects Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.vetmic.2009.08.016","article-title":"Anthrax undervalued zoonosis","volume":"140","author":"Fasanella","year":"2010","journal-title":"Vet. Microbiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.4315\/0362-028X.JFP-12-048","article-title":"Immunomagnetic capture of Bacillus anthracis spores from food","volume":"75","author":"Shields","year":"2012","journal-title":"J. Food Prot."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"691","DOI":"10.4315\/0362-028X-66.4.691","article-title":"Bacillus anthracis: Current knowledge in relation to contamination of food","volume":"66","author":"Erickson","year":"2003","journal-title":"J. Food Prot."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2349","DOI":"10.4315\/0362-028X-66.12.2349","article-title":"Detection and fate of Bacillus anthracis (Sterne) vegetative cells and spores added to bulk tank milk","volume":"66","author":"Perdue","year":"2003","journal-title":"J. Food Prot."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"751","DOI":"10.4315\/0362-028X-68.4.751","article-title":"An assessment of pasteurization treatment of water, media, and milk with respect to Bacillus spores","volume":"68","author":"Novak","year":"2005","journal-title":"J. Food Prot."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4479","DOI":"10.1128\/AEM.00096-06","article-title":"Thermal inactivation of Bacillus anthracis spores in cow\u2019s milk","volume":"72","author":"Xu","year":"2006","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e66943","DOI":"10.1371\/journal.pone.0066943","article-title":"A New Murine Model for Gastrointestinal Anthrax Infection","volume":"8","author":"Xie","year":"2013","journal-title":"PLoS ONE"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"35","DOI":"10.2217\/17460913.4.1.35","article-title":"Anti-toxin antibodies in prophylaxis and treatment of inhalation anthrax","volume":"4","author":"Schneemann","year":"2009","journal-title":"Future Microbiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1093\/infdis\/167.5.1239","article-title":"Postexposure prophylaxis against experimental inhalation anthrax","volume":"167","author":"Friedlander","year":"1993","journal-title":"J. Infect. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e33583","DOI":"10.1371\/journal.pone.0033583","article-title":"Anthrax lethal toxin disrupts intestinal barrier function and causes systemic infections with enteric bacteria","volume":"7","author":"Sun","year":"2012","journal-title":"PLoS ONE"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"8275","DOI":"10.1128\/IAI.73.12.8275-8281.2005","article-title":"Direct inhibition of T-lymphocyte activation by anthrax toxins in vivo","volume":"73","author":"Comer","year":"2005","journal-title":"Infect. Immun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"747","DOI":"10.4049\/jimmunol.172.2.747","article-title":"Cutting edge: Anthrax lethal toxin inhibits activation of IFN-regulatory factor 3 by lipopolysaccharide","volume":"172","author":"Dang","year":"2004","journal-title":"J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/nature01794","article-title":"Impairment of dendritic cells and adaptive immunity by anthrax lethal toxin","volume":"424","author":"Agrawal","year":"2003","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1126\/science.280.5364.734","article-title":"Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor","volume":"280","author":"Duesbery","year":"1998","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3162","DOI":"10.1073\/pnas.79.10.3162","article-title":"Anthrax toxin edema factor: A bacterial adenylate cyclase that increases cyclic AMP concentrations of eukaryotic cells","volume":"79","author":"Leppla","year":"1982","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1084\/jem.20041557","article-title":"Anthrax toxins suppress T lymphocyte activation by disrupting antigen receptor signaling","volume":"201","author":"Paccani","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1172\/JCI17991","article-title":"Bacillus anthracis lethal toxin induces TNF-alpha-independent hypoxia-mediated toxicity in mice","volume":"112","author":"Moayeri","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6155","DOI":"10.4049\/jimmunol.176.10.6155","article-title":"Anthrax lethal toxin has direct and potent inhibitory effects on B cell proliferation and immunoglobulin production","volume":"176","author":"Fang","year":"2006","journal-title":"J. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4966","DOI":"10.4049\/jimmunol.174.8.4966","article-title":"Anthrax lethal toxin blocks MAPK kinase-dependent IL-2 production in CD4+ T cells","volume":"174","author":"Fang","year":"2005","journal-title":"J. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.3390\/toxins3111433","article-title":"Antibodies against anthrax: mechanisms of action and clinical applications","volume":"3","author":"Froude","year":"2011","journal-title":"Toxins"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1146\/annurev.biochem.75.103004.142728","article-title":"Anthrax toxin: receptor binding, internalization, pore formation, and translocation","volume":"76","author":"Young","year":"2007","journal-title":"Annu. Rev. Biochem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/n35101999","article-title":"Identification of the cellular receptor for anthrax toxin","volume":"414","author":"Bradley","year":"2001","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5170","DOI":"10.1073\/pnas.0431098100","article-title":"Human capillary morphogenesis protein 2 functions as an anthrax toxin receptor","volume":"100","author":"Scobie","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"531","DOI":"10.4161\/mabs.1.6.10195","article-title":"Raxibacumab","volume":"1","author":"Mazumdar","year":"2009","journal-title":"MAbs"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"101","DOI":"10.2147\/IDR.S47305","article-title":"Raxibacumab: potential role in the treatment of inhalational anthrax","volume":"7","author":"Kummerfeldt","year":"2014","journal-title":"Infect. Drug Resist."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.3390\/toxins3081004","article-title":"Monoclonal antibody therapies against anthrax","volume":"3","author":"Chen","year":"2011","journal-title":"Toxins"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1056\/NEJMoa0810603","article-title":"Raxibacumab for the treatment of inhalational anthrax","volume":"361","author":"Migone","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1038\/385833a0","article-title":"Crystal structure of the anthrax toxin protective antigen","volume":"385","author":"Petosa","year":"1997","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"120","DOI":"10.3390\/toxins5010120","article-title":"Bacillus anthracis protective antigen kinetics in inhalation spore-challenged untreated or Levofloxacin\/Raxibacumab-treated New Zealand white rabbits","volume":"5","author":"Corey","year":"2013","journal-title":"Toxins"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1128\/AAC.04606-14","article-title":"Added benefit of raxibacumab to antibiotic treatment of inhalational anthrax","volume":"59","author":"Migone","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5463","DOI":"10.4049\/jimmunol.1002471","article-title":"Neutrophil elastase mediates pathogenic effects of anthrax lethal toxin in the murine intestinal tract","volume":"185","author":"Fang","year":"2010","journal-title":"J. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/S0736-4679(03)00079-9","article-title":"The history of anthrax","volume":"24","author":"Sternbach","year":"2003","journal-title":"J. Emerg. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.mam.2009.06.004","article-title":"Dr. Jekyll and Mr. Hyde: A short history of anthrax","volume":"30","author":"Schwartz","year":"2009","journal-title":"Mol. Aspects Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1111\/1469-0691.12706","article-title":"History of biological warfare and bioterrorism","volume":"20","author":"Barras","year":"2014","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_42","first-page":"312","article-title":"Factors associated with human anthrax outbreak in the Chikupo and Ngandu villages of Murewa district in Mashonaland East Province, Zimbabwe","volume":"42","author":"Mwenye","year":"1996","journal-title":"Cent. Afr. J. Med."},{"key":"ref_43","first-page":"15","article-title":"Ecology and epidemiology of anthrax in cattle and humans in Zambia","volume":"54","author":"Siamudaala","year":"2006","journal-title":"Jpn. J. Vet. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.molmed.2014.12.003","article-title":"New insights into gastrointestinal anthrax infection","volume":"21","author":"Owen","year":"2015","journal-title":"Trends Mol. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"575","DOI":"10.4269\/ajtmh.1988.39.575","article-title":"Serological studies of patients with cutaneous and oral-oropharyngeal anthrax from northern Thailand","volume":"39","author":"Sirisanthana","year":"1988","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2527","DOI":"10.1001\/archinte.163.20.2527","article-title":"Gastrointestinal anthrax: Review of the literature","volume":"163","author":"Beatty","year":"2003","journal-title":"Arch. Intern. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1111\/j.1863-2378.2008.01135.x","article-title":"A review of management practices for the control of anthrax in animals: The 2005 anthrax epizootic in North Dakota\u2014Case study","volume":"55","author":"Dyer","year":"2008","journal-title":"Zoonoses Public Health"},{"key":"ref_48","first-page":"1644","article-title":"From the Centers for Disease Control and Prevention. Human ingestion of Bacillus anthracis-contaminated meat\u2014Minnesota, August 2000","volume":"284","author":"Kassenborg","year":"2000","journal-title":"JAMA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1001\/jama.286.11.1307","article-title":"From the Centers for Disease Control and Prevention. Human anthrax associated with an epizootic among livestock\u2014North Dakota, 2000","volume":"286","author":"Shireley","year":"2001","journal-title":"JAMA"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1001\/jama.1997.03550050051033","article-title":"A large community outbreak of salmonellosis caused by intentional contamination of restaurant salad bars","volume":"278","author":"Torok","year":"1997","journal-title":"JAMA"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"498","DOI":"10.3201\/eid0504.990406","article-title":"Historical trends related to bioterrorism: An empirical analysis","volume":"5","author":"Tucker","year":"1999","journal-title":"Emerg. Infect. Dis."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2236","DOI":"10.1001\/jama.287.17.2236","article-title":"Anthrax as a biological weapon, 2002: Updated recommendations for management","volume":"287","author":"Inglesby","year":"2002","journal-title":"JAMA"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1056\/NEJM199909093411107","article-title":"Anthrax","volume":"341","author":"Dixon","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e130687","DOI":"10.3201\/eid2002.130687","article-title":"Centers for Disease Control and Prevention expert panel meetings on prevention and treatment of anthrax in adults","volume":"20","author":"Hendricks","year":"2014","journal-title":"Emerg. Infect. Dis."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e100532","DOI":"10.1371\/journal.pone.0100532","article-title":"Colonic immune suppression, barrier dysfunction, and dysbiosis by gastrointestinal Bacillus anthracis infection","volume":"9","author":"Lightfoot","year":"2014","journal-title":"PLoS ONE"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"e1000325","DOI":"10.1371\/journal.ppat.1000325","article-title":"The adenylate cyclase toxins of Bacillus anthracis and Bordetella pertussis promote Th2 cell development by shaping T cell antigen receptor signaling","volume":"5","author":"Benagiano","year":"2009","journal-title":"PLoS Pathog."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.biocel.2006.08.010","article-title":"Bacillus anthracis: A multi-faceted role for anthrax lethal toxin in thwarting host immune defenses","volume":"39","author":"Xu","year":"2007","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"G705","DOI":"10.1152\/ajpgi.2001.281.3.G705","article-title":"Neutrophil-mediated epithelial injury during transmigration: Role of elastase","volume":"281","author":"Ginzberg","year":"2001","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"591","DOI":"10.3390\/toxins3060591","article-title":"The effects of anthrax lethal toxin on host barrier function","volume":"3","author":"Xie","year":"2011","journal-title":"Toxins"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e4755","DOI":"10.1371\/journal.pone.0004755","article-title":"Lung epithelial injury by B. anthracis lethal toxin is caused by MKK-dependent loss of cytoskeletal integrity","volume":"4","author":"Lehmann","year":"2009","journal-title":"PLoS ONE"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e62576","DOI":"10.1371\/journal.pone.0062576","article-title":"Anthrax lethal toxin downregulates claudin-5 expression in human endothelial tight junctions","volume":"8","author":"Williams","year":"2013","journal-title":"PLoS ONE"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.3390\/toxins3101278","article-title":"Anthrax lethal toxin-mediated disruption of endothelial VE-cadherin is attenuated by inhibition of the Rho-associated kinase pathway","volume":"3","author":"Warfel","year":"2011","journal-title":"Toxins"}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/7\/10\/3960\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T20:49:27Z","timestamp":1760215767000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/7\/10\/3960"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,9,29]]},"references-count":62,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2015,10]]}},"alternative-id":["toxins7103960"],"URL":"https:\/\/doi.org\/10.3390\/toxins7103960","relation":{},"ISSN":["2072-6651"],"issn-type":[{"type":"electronic","value":"2072-6651"}],"subject":[],"published":{"date-parts":[[2015,9,29]]}}}