PA-mAb in a Rat Model of Anthrax Sepsis

PA-mAb 在炭疽脓毒症大鼠模型中的作用

• 批准号: 7215804
• 负责人: Peter Q Eichacker
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7215804
• 关键词: anthrax toxin; bioterrorism /chemical warfare; disease /disorder model; immunotherapy; laboratory rat; monoclonal antibody; nonhuman therapy evaluation; septicemia

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.

炭疽杆菌引起的败血症是高度致命的，是当今主要的生物恐怖主义威胁。由B释放的致死毒素（LeTx）。炭疽杆菌的保护性抗原（PA）和致死因子（LF）是该病的核心。在采用静脉推注LeTx的常规Fisher 344炭疽脓毒症大鼠模型中，在LeTx注射之前或之时而不是之后给予PA-mAb增加了存活率。然而，该模型没有模拟在实际感染期间发生的LeTx的连续释放，并且由LeTx的推注诱导的快速死亡（即1.5小时）可能已经否定了从随后的mAb治疗中观察到治疗益处的可能性。因此，我们研究了在24小时LeTx输注开始后（0小时）或3、6、9或12小时时在大鼠（n=185）中给予的PA-mAb或安慰剂（非特异性mAb）。安慰剂组动物的平均至死亡时间相似（p=ns），与给药时间无关（中位15 h，范围9 - 152 h，p=ns）。在每个治疗时间，PA-mAb组的生存率（%）均高于安慰剂组，尽管这些差异随着最近的治疗而降低（0 h时100 vs 67，p=0.001; 3 h时90 vs 42，p=0.01; 6 h时100 vs 56，p=0.001; 9 h时73 vs 56，p=0.2; 12 h时79 vs 53，p=0.2）。在接受24小时LeTx输注的大鼠中，其中致死率高，但晚于传统的炭疽模型，PA-mAb给予长达6小时后，最初的LeTx暴露是非常保护性的，并给予9和12小时后，导致有益的趋势的结果。临床上，PA-mAb可降低由于LeTx释放导致的发病率或死亡率，即使在炭疽败血症患者出现后给药。