title: Enhancement of anthrax lethal toxin cytotoxicity: a subset of monoclonal antibodies against protective antigen increases lethal toxin-mediated killing of murine macrophages.
abstract: We investigated the ability of using monoclonal antibodies (MAbs) against anthrax protective antigen (PA), an anthrax exotoxin component, to modulate exotoxin cytotoxic activity on target macrophage cell lines. Anthrax PA plays a critical role in the pathogenesis of Bacillus anthracis infection. PA is the cell-binding component of the two anthrax exotoxins: lethal toxin (LeTx) and edema toxin. Several MAbs that bind the PA component of LeTx are known to neutralize LeTx-mediated killing of target macrophages. Here we describe for the first time an overlooked population of anti-PA MAbs that, in contrast, function to increase the potency of LeTx against murine macrophage cell lines. The results support a possible mechanism of enhancement: binding of MAb to PA on the macrophage cell surface stabilizes the PA by interaction of MAb with macrophage Fcgamma receptors. This results in an increase in the amount of PA bound to the cell surface, which in turn leads to an enhancement in cell killing, most likely due to increased internalization of LF. Blocking of PA-receptor binding eliminates enhancement by MAb, demonstrating the importance of this step for the observed enhancement. The additional significance of these results is that, at least in mice, immunization with PA appears to elicit a poly-clonal response that has a significant prevalence of MAbs that enhance LeTx-mediated killing in macrophages.
authors.affiliation: Elusys Therapeutics, Inc., Pine Brook, New Jersey 07058, USA. Nmohamed@elusys.com
authors.forename: Nehal
authors.initials: N
authors.lastname: Mohamed
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.forename: Claudia S
authors.initials: CS
authors.lastname: Ferreira
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Little
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Friedlander
authors.forename: George L
authors.initials: GL
authors.lastname: Spitalny
authors.forename: Leslie S
authors.initials: LS
authors.lastname: Casey
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000097:blood / Q000276:immunology*; D019067:Antibody-Dependent Enhancement; D000942:Antigens, Bacterial / Q000276:immunology; D001408:Bacillus anthracis / Q000378:metabolism / Q000472:pathogenicity; D001427:Bacterial Toxins / Q000276:immunology / Q000633:toxicity*; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D006801:Humans; D008264:Macrophages / Q000276:immunology* / Q000502:physiology; D051379:Mice; D011961:Receptors, Fc / Q000378:metabolism; D020298:U937 Cells
chemical_list: D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D011961:Receptors, Fc; C030325:anthrax toxin