Deciphering the domain specificity of C. difficile toxin neutralizing antibodies
Deciphering the domain specificity of C. difficile toxin neutralizing antibodies
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DOI：
10.1016/j.vaccine.2019.05.040
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发表时间：
2019-06-27
期刊：
影响因子：
5.5
通讯作者：
Anosova, Natalie G.
中科院分区：
文献类型：
--
作者：
Cole, Leah E.;Li, Lu;Anosova, Natalie G.
艰难梭菌感染（CDI）是抗生素治疗相关的院内腹泻和伪膜性结肠炎的主要原因。CDI的病理作用主要归因于毒素A（TcdA）和B（TcdB）。足够的毒素特异性抗体反应与无症状携带相关，而体液反应不足与复发性CDI相关。虽然支持抗毒素抗体重要性的数据是大量的，但关于这些抗体的毒素结构域特异性的清晰度更有限。为了研究这个问题，使用毒素中和测定来评估靶向TcdB的多个结构域的人mAb的组合。这些数据显示，当与针对一个或两个结构域的相同浓度的单一mAb或mAb组合相比时，对所有主要毒素结构域具有特异性的mAb组合具有改善的中和效力。还评估了通过用类毒素疫苗候选物免疫仓鼠引起的血清抗体的功能和毒素结构域结合特异性。用类毒素疫苗候选物免疫激发对TcdA和TcdB的多个结构域特异性的毒素中和抗体。当在毒素中和试验中进行评估时，多克隆血清显示出比同等浓度的单个mAb更高的抗毒素活性。这些数据表明靶向多个毒素结构域的任何基于抗体的治疗性或预防性治疗的潜在益处。(C)2019年，任作家。爱思唯尔有限公司出版
Clostridium difficile infection (CDI) is the principal cause of nosocomial diarrhea and pseudomembranous colitis associated with antibiotic therapy. The pathological effects of CDI are primarily attributed to toxins A (TcdA) and B (TcdB). Adequate toxin-specific antibody responses are associated with asymptomatic carriage, whereas insufficient humoral responses are associated with recurrent CDI. While the data supporting the importance of anti-toxin antibodies are substantial, clarity about the toxin domain specificity of these antibodies is more limited. To investigate this matter, combinations of human mAbs targeting multiple domains of TcdB were assessed using toxin neutralization assays. These data revealed that a combination of mAbs specific to all major toxin domains had improved neutralizing potency when compared to equivalent concentrations of a single mAb or a combination of mAbs against one or two domains. The function and toxin domain binding specificity of serum antibodies elicited by immunization of hamsters with a toxoid vaccine candidate was also assessed. Immunization with a toxoid vaccine candidate provoked toxin neutralizing antibodies specific to multiple domains of both TcdA and TcdB. When assessed in a toxin neutralization assay, polyclonal sera displayed greater activity against elevated concentrations of toxins than equivalent concentrations of individual mAbs. These data suggest a potential benefit of any antibody based therapeutic or prophylactic treatment that targets multiple toxin domains. (C) 2019 The Authors. Published by Elsevier Ltd.