PA-mAb in a Rat Model of Anthrax Sepsis

炭疽芽孢杆菌引起的败血症具有高度致命性，是当今主要的生物恐怖主义威胁。由炭疽芽胞杆菌释放的由保护性抗原（PA）和致死因子（LF）组成的致死毒素（LeTx）是炭疽芽胞杆菌疾病的核心。在采用静脉注射LeTx的传统Fisher 344大鼠炭疽败血症模型中，在注射LeTx之前或同时（而不是之后）给药PA-mAb可提高生存率。然而，该模型并未模拟LeTx在实际感染期间的持续释放，并且大量注射LeTx诱导的快速死亡（即1.5 h）可能否定了观察到后续单抗治疗的治疗益处的可能性。因此，我们研究了大鼠（n=185）在开始24小时LeTx输注后（0小时）或3、6、9或12小时给予的PA-mAb或安慰剂（非特异性mAb）。与治疗时间无关，安慰剂动物的平均死亡时间相似（p=ns）（中位15小时，范围9至152小时，p=ns）。在每个治疗时间，与安慰剂相比，PA-mAb的生存率（%）更高，尽管这些差异在最新治疗中有所下降（0小时100 vs 67， p=0.001； 3小时90 vs 42， p=0.01； 6小时100 vs 56， p=0.001； 9小时73 vs 56， p=0.2； 12小时79 vs 53， p=0.2）。在接受24小时LeTx输注的大鼠中，其致死率很高，但比传统炭疽模型晚，在初始LeTx暴露后6小时给予PA-mAb具有很强的保护作用，在9和12小时后给予PA-mAb会产生有益的结果趋势。临床上，即使在出现炭疽败血症的患者后给予PA-mAb，也可能降低LeTx释放引起的发病率或死亡率。

Sepsis due to Bacillus anthracis is highly lethal and a major bioterrorism threat today. Lethal toxin (LeTx) released by B. anthracis and comprised of protective antigen (PA) and lethal factor (LF) is central to this disease. In a conventional Fisher 344 rat model of anthrax sepsis employing a intravenous bolus of LeTx, administration of PA-mAb prior to or at the time of LeTx injection, but not later, increased survival. However, this model does not simulate the continuous release of LeTx that occurs during actual infection and the rapid death (i.e. 1.5 h) induced by bolus injection of LeTx may have negated the possibility of observing therapeutic benefit from later mAb treatment. Therefore we investigated PA-mAb or placebo (nonspecific mAb) administered in rats (n=185) at the time of (0 h) or 3, 6, 9, or 12 h after the start of a 24 h infusion of LeTx. Mean time to death was similar (p=ns) in placebo animals independent of treatment time (median 15 h, range 9 to 152 h, p=ns). At each treatment time, survival rates (%) were greater with PA-mAb compared to placebo although these differences decreased with the latest treatments (100 vs 67, p=0.001 at 0 h; 90 vs 42, p=0.01 at 3 h; 100 vs 56, p=0.001 at 6 h; 73 vs 56, p=0.2 at 9 h; and 79 vs 53, p=0.2 at 12 h). In rats receiving a 24 h LeTx infusion in which lethality was high but later than in conventional anthrax models, PA-mAb given up to 6 h after initial LeTx exposure was very protective and given 9 and 12 h after caused beneficial trends in outcome. Clinically, PA-mAb may reduce morbidity or mortality due to LeTx release even if administered after patients present with anthrax sepsis.