一种四克隆抗体组合能有效中和多种 C 和 D 型肉毒神经毒素。
A Four-Monoclonal Antibody Combination Potently Neutralizes Multiple Botulinum Neurotoxin Serotypes C and D.
机构信息
Department of Anesthesia & Perioperative Care, University of California, San Francisco, Zuckerberg San Francisco General Hospital and Trauma Center, 1001 Potrero Avenue, San Francisco, CA 94110, USA.
Molecular and Translational Sciences Division, United States Army Medical Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD 21702, USA.
出版信息
Toxins (Basel). 2021 Sep 10;13(9):641. doi: 10.3390/toxins13090641.
Human botulism can be caused by botulinum neurotoxin (BoNT) serotypes A to G. Here, we present an antibody-based antitoxin composed of four human monoclonal antibodies (mAbs) against BoNT/C, BoNT/D, and their mosaic toxins. This work built on our success in generating protective mAbs to BoNT /A, B and E serotypes. We generated mAbs from human immune single-chain Fv (scFv) yeast-display libraries and isolated scFvs with high affinity for BoNT/C, BoNT/CD, BoNT/DC and BoNT/D serotypes. We identified four mAbs that bound non-overlapping epitopes on multiple serotypes and mosaic BoNTs. Three of the mAbs underwent molecular evolution to increase affinity. A four-mAb combination provided high-affinity binding and BoNT neutralization of both serotypes and their mosaic toxins. The mAbs have potential utility as therapeutics and as diagnostics capable of recognizing and neutralizing BoNT/C and BoNT/D serotypes and their mosaic toxins. A derivative of the four-antibody combination (NTM-1634) completed a Phase 1 clinical trial (Snow et al., Antimicrobial Agents and Chemotherapy, 2019) with no drug-related serious adverse events.
人类肉毒中毒可由 A 至 G 型肉毒神经毒素（BoNT）引起。在此，我们介绍了一种基于抗体的解毒剂，它由针对 BoNT/C、BoNT/D 及其嵌合毒素的四种人源单克隆抗体（mAb）组成。这项工作是基于我们在生成针对 BoNT/A、B 和 E 型保护性 mAb 方面的成功。我们从人类免疫酵母展示 scFv 文库中生成 mAb，并分离出对 BoNT/C、BoNT/CD、BoNT/DC 和 BoNT/D 型具有高亲和力的 scFv。我们鉴定出了四种结合多个型别和嵌合 BoNT 的非重叠表位的 mAb。其中三种 mAb 经历了分子进化以提高亲和力。四 mAb 组合可提供高亲和力结合和 BoNT 中和作用，既能中和这两种型别，也能中和它们的嵌合毒素。这些 mAb 具有作为治疗剂和诊断剂的潜在用途，能够识别和中和 BoNT/C 和 BoNT/D 型别及其嵌合毒素。该四抗体组合的一个衍生物（NTM-1634）已完成一项 1 期临床试验（Snow 等人，《抗菌药物和化疗》，2019 年），无与药物相关的严重不良事件。
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