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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, Maryland 20910-7500,¹ MPIR Laboratory, Meningitis & Vaccine Preventable Diseases Branch, Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control & Prevention, Atlanta, Georgia,² Defense Science Technology Laboratories, Porton Down, Salisbury, Wiltshire SP4 0JQ, United Kingdom,³ IQ Corporation, Rozenburglaan 13a, 9727 DL Groningen, The Netherlands,⁴ The Ohio State University, Department of Microbiology, Columbus, Ohio 43210,⁵ University of Groningen, University Medical Center, Department of Pathology and Laboratory Medicine, Medical Biology Section, Laboratory for Tumor Immunology, Groningen, The Netherlands,⁶ Cardiff University, Welsh School of Pharmacy, Cardiff CF10 3NB, Wales, United Kingdom⁷

Received 16 February 2007/ Returned for modification 6 April 2007/ Accepted 7 June 2007

The unpredictable nature of bioterrorism and the absence of real-time detection systems have highlighted the need for an efficient postexposure therapy for Bacillus anthracis infection. One approach is passive immunization through the administration of antibodies that mitigate the biological action of anthrax toxin. We isolated and characterized two protective fully human monoclonal antibodies with specificity for protective antigen (PA) and lethal factor (LF). 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 IQNLF neutralized the same amount of toxin. When combined, the antibodies had additive neutralization efficacy. IQNPA binds to domain IV of PA containing the host cell receptor binding site, while IQNLF recognizes domain I containing the PA binding region in LF. A single 180-µg dose of either antibody given to A/J mice 2.5 h before challenge conferred 100% protection against a lethal intraperitoneal spore challenge with 24 50% lethal doses [LD₅₀s] of B. anthracis Sterne and against rechallenge on day 20 with a more aggressive challenge dose of 41 LD₅₀s. Mice treated with either antibody and infected with B. anthracis Sterne developed detectable murine anti-PA and anti-LF immunoglobulin G 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.

Published ahead of print on 23 July 2007.

Editor: D. L. Burns