A Tetraspecific VHH-Based Neutralizing Antibody Modifies Disease Outcome in Three Animal Models of Clostridium difficile Infection.
A Tetraspecific VHH-Based Neutralizing Antibody Modifies Disease Outcome in Three Animal Models of Clostridium difficile Infection.
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DOI：
10.1128/cvi.00730-15
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发表时间：
2016-09
期刊：
影响因子：
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通讯作者：
Tzipori S
中科院分区：
文献类型：
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作者：
Schmidt DJ;Beamer G;Tremblay JM;Steele JA;Kim HB;Wang Y;Debatis M;Sun X;Kashentseva EA;Dmitriev IP;Curiel DT;Shoemaker CB;Tzipori S
艰难梭菌感染（CDI）是医院感染的主要原因，是北美、欧洲和亚洲的一种严重疾病。CDI从无症状携带到危及生命的腹泻、中毒性巨结肠和毒血症差别很大。由于出现了高毒力耐药菌株，社区获得性感染的发生率有所增加。这些新菌株导致疾病频繁复发，治疗复杂化，住院时间延长，患者发病率和死亡率增加。因此，开发新的治疗方法绕过抗菌素耐药性的发展并避免肠道微生物群的破坏是至关重要的。在这里，我们描述了一种基于vhh的单一异聚体中和剂（VNA）的构建，该中和剂针对艰难梭菌的两个主要毒力因子，毒素a （TcdA）和B （TcdB）。命名为VNA2-Tcd，这种药物在细胞检测中对艰难梭菌毒素具有亚纳摩尔毒素中和能力。当系统外给药时，VNA2-Tcd在非生物仔猪和小鼠中对CDI有保护作用，在仓鼠中有较小程度的保护作用。用腺病毒基因治疗仔猪，可促进VNA2-Tcd的表达，对CDI也有保护作用。
Clostridium difficile infection (CDI), a leading cause of nosocomial infection, is a serious disease in North America, Europe, and Asia. CDI varies greatly from asymptomatic carriage to life-threatening diarrhea, toxic megacolon, and toxemia. The incidence of community-acquired infection has increased due to the emergence of hypervirulent antibiotic-resistant strains. These new strains contribute to the frequent occurrence of disease relapse, complicating treatment, increasing hospital stays, and increasing morbidity and mortality among patients. Therefore, it is critical to develop new therapeutic approaches that bypass the development of antimicrobial resistance and avoid disruption of gut microflora. Here, we describe the construction of a single heteromultimeric VHH-based neutralizing agent (VNA) that targets the two primary virulence factors of Clostridium difficile, toxins A (TcdA) and B (TcdB). Designated VNA2-Tcd, this agent has subnanomolar toxin neutralization potencies for both C. difficile toxins in cell assays. When given systemically by parenteral administration, VNA2-Tcd protected against CDI in gnotobiotic piglets and mice and to a lesser extent in hamsters. Protection from CDI was also observed in gnotobiotic piglets treated by gene therapy with an adenovirus that promoted the expression of VNA2-Tcd.