title: Human monoclonal antibodies against anthrax lethal factor and protective antigen act independently to protect against Bacillus anthracis infection and enhance endogenous immunity to anthrax.
abstract: 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-mug 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.
authors.affiliation: Biological Defense Research Directorate, Naval Medical Research Center, 12300 Washington Ave., Silver Spring, MD 20910-7500, USA. albrechtm@nmrc.navy.mil
authors.forename: Mark T
authors.initials: MT
authors.lastname: Albrecht
authors.forename: Han
authors.initials: H
authors.lastname: Li
authors.forename: E Diane
authors.initials: ED
authors.lastname: Williamson
authors.forename: Chris S
authors.initials: CS
authors.lastname: LeButt
authors.forename: Helen C
authors.initials: HC
authors.lastname: Flick-Smith
authors.forename: Conrad P
authors.initials: CP
authors.lastname: Quinn
authors.forename: Hans
authors.initials: H
authors.lastname: Westra
authors.forename: Darrell
authors.initials: D
authors.lastname: Galloway
authors.forename: Alfred
authors.initials: A
authors.lastname: Mateczun
authors.forename: Stanley
authors.initials: S
authors.lastname: Goldman
authors.forename: Herman
authors.initials: H
authors.lastname: Groen
authors.forename: Les W J
authors.initials: LW
authors.lastname: Baillie
mesh_terms: D000818:Animals; D000881:Anthrax / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control*; D000907:Antibodies, Bacterial / Q000097:blood; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000942:Antigens, Bacterial / Q000276:immunology*; D000992:Antitoxins / Q000494:pharmacology*; D001408:Bacillus anthracis / Q000276:immunology*; D001427:Bacterial Toxins / Q000276:immunology*; D005260:Female; D006801:Humans; D006825:Hybridomas; D007116:Immunization, Passive; D007074:Immunoglobulin G / Q000097:blood; D020128:Inhibitory Concentration 50; D051379:Mice; D016019:Survival Analysis
chemical_list: D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D000942:Antigens, Bacterial; D000992:Antitoxins; D001427:Bacterial Toxins; D007074:Immunoglobulin G; C030325:anthrax toxin