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Infect. Immun. doi:10.1128/IAI.00261-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Human monoclonal antibodies against anthrax lethal factor and protective antigen act independently to protect against Bacillus anthracis infection and enhance endogenous immunity to anthrax

Biological Defense Research Directorate, Naval Medical Research Center, Silver Spring, MD 20910-7500, USA; MPIR Laboratory, Meningitis & Vaccine Preventable Diseases Branch, Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control & Prevention (CDC); Defense Science Technology Laboratories, Porton Down, Salisbury, Wiltshire, SP4 0JQ, UK; IQ Corporation, Rozenburglaan 13a, 9727 DL Groningen, Netherlands; The Ohio State University, Department of Microbiology, Columbus, OH 43210, USA; University of Groningen, University Medical Center, Department of Pathology and Laboratory Medicine, Medical Biology Section, Laboratory for Tumor Immunology, Groningen, Netherlands; Cardiff University, Welsh School of Pharmacy, Cardiff CF10 3NB, Wales, UK

^* To whom correspondence should be addressed. Email: bailliel{at}cardiff.ac.uk.

	Abstract

The unpredictable nature of bio-terrorism and the absence of real-time detection systems have highlighted the need for an efficient post-exposure therapy for Bacillus anthracis infection. One approach is passive immunization through the administration of antibodies that mitigate the biological action of anthrax toxin. We have isolated and characterized two fully human protective monoclonal antibodies with specificity for Protective Antigen and Lethal Factor. These antibodies, designated IQNPA (anti-PA) and IQNLF (anti-LF), were developed as hybridomas from individuals immunized with licensed anthrax vaccine. The effective concentration of IQNPA that neutralized 50% of the toxin in anthrax toxin neutralization assays was 0.3 nM while 0.1 nM of IQNLF neutralized the same amount of toxin. When combined, the antibodies had an additive neutralization efficacy. IQNPA binds to domain 4 of PA containing the host cell receptor binding site while IQNLF recognizes domain 1 containing the PA binding region in LF. A single 180 µg dose of either antibody given to A/J mice 2.5 hours before challenge conferred 100% protection against a lethal intraperitoneal spore challenge (24 times the 50% lethal dose of B. anthracis Sterne) and against re-challenge on day 20 with a more aggressive challenge dose of 41 times the 50% lethal dose. Mice treated with either antibody and infected with B. anthracis Sterne developed detectable murine anti-PA and anti-LF IgG antibody responses by day 17 that were dependent on which antibody the mice had received. Based on these results, IQNPA and IQNLF act independently during prophylactic anthrax treatment and do not interfere with the establishment of endogenous immunity.

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