Late treatment with a protective antigen-directed monoclonal antibody improves hemodynamic function and survival in a lethal toxin-infused rat model of anthrax sepsis

Background. In animal models, treatment with 5H3, a fully human protective antigen-directed monoclonal antibody (PA-MAb), improved survival when administered close to the time of Bacillus anthracis lethal toxin (LeTx) bolus or live bacterial challenge. However, treatment with PA-MAb would be most valuable clinically if it were beneficial even when administered after the onset of shock and lethality due to LeTx. Methods. We investigated the effects of PA-MAb versus placebo administered in rats (n = 324) at the time of or 3, 6, 9, or 12 h after the initiation of a 24-h LeTx infusion. Results. In rats receiving placebo, mean arterial blood pressure (MBP) and heart rate (HR) were decreased in nonsurvivors, compared with those in survivors, at 6 h and then worsened further, with lethality first evident at 8 h (median, 16 h; range, 8-152 h). At each treatment time, survival rates were greater for PA-MAb than for placebo, although improvement was decreased at later treatment times (P = .001, for the effect of time). Compared with placebo, PA-MAb significantly increased MBP during the 12 h after the initiation of treatment, but the increase was greatest for treatment at 3 h; similarly, PA-MAb significantly increased HR at all treatment times. Conclusion. In this rat model, improvements in outcome due to PA-MAb were significant when it was administered up to 6 h (and approached significance when administered up to 12 h) after initial exposure to LeTx. Clinically, PA-MAb may be beneficial even when administered after the onset of shock and lethality due to LeTx.