Safety and Pharmacokinetics of Chimeric Anti-Shiga Toxin 1 and Anti-Shiga Toxin 2 Monoclonal Antibodies in Healthy Volunteers
Safety and Pharmacokinetics of Chimeric Anti-Shiga Toxin 1 and Anti-Shiga Toxin 2 Monoclonal Antibodies in Healthy Volunteers
复制标题
DOI：
10.1128/aac.01661-08
复制
发表时间：
2009-07-01
影响因子：
4.9
通讯作者：
Riviere, Marc
中科院分区：
文献类型：
--
作者：
Bitzan, Martin;Poole, Ruth;Riviere, Marc
产志贺毒素（Stx）的大肠杆菌（STEC）引起出血性结肠炎和溶血性尿毒症综合征（HUS）。产志贺毒素大肠杆菌感染和并发症（包括死亡）的发生率在幼儿和老年人中最高。没有因果疗法。由于Stx是导致产志贺毒素大肠杆菌患者器官损伤的主要病理因子，因此正在开发治疗性抗体，以在感染的早期阶段中和全身吸收的毒素。进行了两项I期、单剂量、开放标签、非随机研究，以评估抗Stx1和Stx2（分别为c α Stx1和c α Stx2）的嵌合单克隆抗体（抗毒素）的安全性和药代动力学。在第一项研究中，16名志愿者接受了1或3mg /kg体重的c α Stx1或c α Stx2单次短时间静脉输注（每组n = 4）。在第二项研究中，10名志愿者接受c α Stx1和c α Stx2以1或3 mg/kg的剂量联合输注1小时（每组n = 5）。治疗后出现的不良事件是轻微的，自发消退，并且通常与抗体输注无关。未观察到严重不良事件。在第57天采集的单个血液样本中检测到人抗嵌合抗体。c α Stx1的抗体清除率（0.38 +/- 0.16 ml/h/kg[平均+/-标准差]）略高于c α Stx2 (0.20 +/- 0.07 ml/h/kg) （P = 0.0013， t检验）。清除率低与c α Stx1 （190.4 +/- 140.2 h）和c α Stx2 （260.6 +/- 112.4 h, P = 0.151）的消除半衰期长一致。小体积分布（0.08 +/- 0.05升/kg，综合数据）表明抗体保留在循环中。结论：单独或联合短时间静脉输注c α Stx1和c α Stx2均具有良好的耐受性。这些结果为未来针对产志贺毒素大肠杆菌感染患者的安全性和有效性试验奠定了基础，以改善或预防溶血性尿毒综合征和其他并发症。
Shiga toxin (Stx)-producing Escherichia coli (STEC) causes hemorrhagic colitis and hemolytic-uremic syndrome (HUS). The rates of STEC infection and complications, including death, are highest among young children and elderly individuals. There are no causal therapies. Because Stx is the primary pathological agent leading to organ injury in patients with STEC disease, therapeutic antibodies are being developed to neutralize systemically absorbed toxin during the early phase of the infection. Two phase I, single-dose, open-label, nonrandomized studies were conducted to evaluate the safety and pharmacokinetics of the chimeric monoclonal antibodies (antitoxins) against Stx 1 and 2 (c alpha Stx1 and c alpha Stx2, respectively). In the first study, 16 volunteers received 1 or 3 mg/kg of body weight of c alpha Stx1 or c alpha Stx2 as a single, short (1-h) intravenous infusion (n = 4 per group). In a second study, 10 volunteers received a 1-h infusion of c alpha Stx1 and c alpha Stx2 combined at 1 or 3 mg/kg (n = 5 per group). Treatment-emergent adverse events were mild, resolved spontaneously, and were generally unrelated to the antibody infusion. No serious adverse events were observed. Human antichimeric antibodies were detected in a single blood sample collected on day 57. Antibody clearance was slightly greater for c alpha Stx1 (0.38 +/- 0.16 ml/h/kg [mean +/- standard deviation]) than for c alpha Stx2 (0.20 +/- 0.07 ml/h/kg) (P = 0.0013, t test). The low clearance is consistent with the long elimination half-lives of c alpha Stx1 (190.4 +/- 140.2 h) and c alpha Stx2 (260.6 +/- 112.4 h; P = 0.151). The small volume of distribution (0.08 +/- 0.05 liter/kg, combined data) indicates that the antibodies are retained within the circulation. The conclusion is that c alpha Stx1 and c alpha Stx2, given as individual or combined short intravenous infusions, are well tolerated. These results form the basis for future safety and efficacy trials with patients with STEC infections to ameliorate or prevent HUS and other complications.