B. anthracis as an agent of bioterrorism that continues to be a potential health problem in the United States today. Systemic B. anthracis resulting in shock is almost 100% lethal despite conventional supportive therapies. Developing effective adjunctive treatments that work with conventional ones is important. B. anthracis produces 2 toxins; lethal toxin (LeTx) comprised of lethal factor (LF) and protective antigen (PA), and edema toxin (ETx) comprised of edema factor (EF) and PA. Protective antigen mediates cellular uptake of the toxic moieties LF and EF. In this process, seven PA molecules form a heptamer on the host cell surface that three molecules of LF or EF bind with. The affinity of LF and EF for PA appears similar. Lethal factor is an endopeptidase that cleaves mitogen activated protein kinase kinases (MAPKK) and disrupts intracellular signaling. ETx is an adenyl cyclase that transforms ATP to cAMP and can alter hemodynamic and immune function in the host. Although LeTx has been strongly implicated in the pathogenesis of B. anthracis, growing evidence suggests that ETx may also have an important pathogenic role. In experiments we conducted, although ETx was approximately 10 times less lethal than LeTx, in similar doses it produced earlier and greater levels of shock. Together LeTx and ETx had additive effects on lethality and shock.
Several lines of evidence now indicate that inhibiting the toxins produced by B. anthracis may have beneficial effects during this infection ). In this regard agents that target PA may have an advantage since they can inhibit the effects of both LF and EF. However, such agents have been tested primarily in models employing LeTx challenge alone as opposed to ETx or the two toxins together. Furthermore, whether treatment with PA inhibitor will be beneficial if treatment has been delayed until after shock related to the two toxins has started has received little study.
Dr. Robert Purcells group from NIAID in collaboration with the Bacterial Toxins and Therapeutic Section has now developed a chimpanzee monoclonal antibody against PA which has been designated W1. Pre-treatment with W1 was protective in mice challenged with LeTx and ETx both alone and in combination. Post-treatment with lower doses of W1 was effective up to 6 h with LeTx and ETx both alone and together. Higher doses of W1 are now being studied to evaluate treatment effects when started as late as 12h.
