We used human monoclonal antibodies (humAbs) to study the mechanism of neuron intoxication by tetanus neurotoxin and to evaluate these antibodies as a safe preventive and therapeutic substitute for hyperimmune sera to treat tetanus in mice. By screening memory B cells from immune donors, we selected 2 tetanus neurotoxin–specific mAbs with exceptionally high neutralizing activities and extensively characterized them both structurally and functionally. We found that these antibodies interfered with the binding and translocation of the neurotoxin into neurons by interacting with 2 epitopes, whose identification pinpoints crucial events in the cellular pathogenesis of tetanus. Our observations explain the neutralization ability of these antibodies, which we found to be exceptionally potent in preventing experimental tetanus when injected into mice long before the toxin. Moreover, their Fab derivatives neutralized tetanus neurotoxin in post-exposure experiments, suggesting their potential for therapeutic use via intrathecal injection. As such, we believe these humAbs, as well as their Fab derivatives, meet the requirements to be considered for prophylactic and therapeutic use in human tetanus and are ready for clinical trials.

中文翻译：

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非常有效的人单克隆抗体可有效预防和治疗小鼠破伤风

我们使用人类单克隆抗体 (humAb) 来研究破伤风神经毒素引起神经元中毒的机制，并评估这些抗体作为超免疫血清治疗小鼠破伤风的安全预防和治​​疗替代品。通过从免疫供体中筛选记忆 B 细胞，我们选择了 2 种具有极高中和活性的破伤风神经毒素特异性 mAb，并对它们的结构和功能进行了广泛的表征。我们发现，这些抗体通过与 2 个表位相互作用来干扰神经毒素与神经元的结合和易位，这些表位的鉴定确定了破伤风细胞发病机制中的关键事件。我们的观察解释了这些抗体的中和能力，我们发现在毒素之前很长时间注射到小鼠体内时，它在预防实验性破伤风方面非常有效。此外，他们的 Fab 衍生物在暴露后实验中中和了破伤风神经毒素，这表明它们具有通过鞘内注射治疗用途的潜力。因此，我们相信这些人类抗体及其 Fab 衍生物符合人类破伤风预防和治疗用途的要求，并已准备好进行临床试验。