Human monoclonal antibodies directed against toxins A and B prevent Clostridium difficile-induced mortality in hamsters
Human monoclonal antibodies directed against toxins A and B prevent Clostridium difficile-induced mortality in hamsters
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DOI：
10.1128/iai.00982-06
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发表时间：
2006-11-01
影响因子：
3.1
通讯作者：
Thomas, William D., Jr.
中科院分区：
文献类型：
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作者：
Babcock, Gregory J.;Broering, Teresa J.;Thomas, William D., Jr.
艰难梭菌（Clostridium difficile）是院内抗生素相关性腹泻的主要原因，最近爆发的毒力增加的菌株强调了寻找治疗和预防艰难梭菌相关性腹泻（CDAD）复发的新方法的重要性。CDAD病理是由两种外毒素，毒素A和毒素13引起的，这两种外毒素已被证明具有细胞毒性，在毒素A的情况下，具有肠毒性。在本报告中，我们描述了完全人单克隆抗体（HuMAbs），可以中和这些毒素并预防仓鼠疾病。在体外细胞中和实验中，利用携带人免疫球蛋白基因的转基因小鼠分离出能中和毒素A或毒素B细胞毒作用的HuMAbs。3种抗A毒素的HuMAbs （3H2、CDA1和1B11）均能抑制A毒素在小鼠肠袢内的肠毒性和小鼠全身模型的体内毒性。四种抗毒素B HuMAbs （MDX-1388、103-174、1G10和2A11）在体外可以中和细胞毒性，但小鼠的全身毒性不能中和。在建立的艰难梭菌病仓鼠模型中检测了抗毒素A HuMAb CDA1和抗毒素B HuMAb MDX-1388。单独使用CDA1可显著降低仓鼠的死亡率；然而，联合治疗提供了增强的保护。与对照组相比，在原发疾病仓鼠模型中，联合治疗将死亡率从100%降低到45% (P < 0.0001)，在不太严格的复发模型中，死亡率从78%降低到32% （P < 0.0001）。
Clostridium difficile is the leading cause of nosocomial antibiotic-associated diarrhea, and recent outbreaks of strains with increased virulence underscore the importance of identifying novel approaches to treat and prevent relapse of Clostridium difficile-associated diarrhea (CDAD). CDAD pathology is induced by two exotoxins, toxin A and toxin 13, which have been shown to be cytotoxic and, in the case of toxin A, enterotoxic. In this report we describe fully human monoclonal antibodies (HuMAbs) that neutralize these toxins and prevent disease in hamsters. Transgenic mice carrying human immunoglobulin genes were used to isolate HuMAbs that neutralize the cytotoxic effects of either toxin A or toxin B in cell-based in vitro neutralization assays. Three anti-toxin A HuMAbs (3H2, CDA1, and 1B11) could all inhibit the enterotoxicity of toxin A in mouse intestinal loops and the in vivo toxicity in a systemic mouse model. Four anti-toxin B HuMAbs (MDX-1388, 103-174, 1G10, and 2A11) could neutralize cytotoxicity in vitro, although systemic toxicity in the mouse could not be neutralized. Anti-toxin A HuMAb CDA1 and anti-toxin B HuMAb MDX-1388 were tested in the well-established hamster model of C. difficile disease. CDA1 alone resulted in a statistically significant reduction of mortality in hamsters; however, the combination treatment offered enhanced protection. Compared to controls, combination therapy reduced mortality from 100% to 45% (P < 0.0001) in the primary disease hamster model and from 78% to 32% (P < 0.0001) in the less stringent relapse model.