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A novel neutralizing human monoclonal antibody broadly abrogates hepatitis C virus infection in vitro and in vivo
Antiviral Research ( IF 4.5 ) Pub Date : 2017-10-23 , DOI: 10.1016/j.antiviral.2017.10.015
Isabelle Desombere 1 , Ahmed Atef Mesalam 2 , Richard A Urbanowicz 3 , Freya Van Houtte 1 , Lieven Verhoye 1 , Zhen-Yong Keck 4 , Ali Farhoudi 1 , Koen Vercauteren 1 , Karin E Weening 1 , Thomas F Baumert 5 , Arvind H Patel 6 , Steven K H Foung 4 , Jonathan Ball 3 , Geert Leroux-Roels 1 , Philip Meuleman 1
Affiliation  

Infections with hepatitis C virus (HCV) represent a worldwide health burden and a prophylactic vaccine is still not available. Liver transplantation (LT) is often the only option for patients with HCV-induced end-stage liver disease. However, immediately after transplantation, the liver graft becomes infected by circulating virus, resulting in accelerated progression of liver disease. Although the efficacy of HCV treatment using direct-acting antivirals has improved significantly, immune compromised LT-patients and patients with advanced liver disease remain difficult to treat. As an alternative approach, interfering with viral entry could prevent infection of the donor liver. We generated a human monoclonal antibody (mAb), designated 2A5, which targets the HCV envelope. The neutralizing activity of mAb 2A5 was assessed using multiple prototype and patient-derived HCV pseudoparticles (HCVpp), cell culture produced HCV (HCVcc), and a human-liver chimeric mouse model. Neutralization levels observed for mAb 2A5 were generally high and mostly superior to those obtained with AP33, a well-characterized HCV-neutralizing monoclonal antibody. Using humanized mice, complete protection was observed after genotype 1a and 4a HCV challenge, while only partial protection was achieved using gt1b and 6a isolates. Epitope mapping revealed that mAb 2A5 binding is conformation-dependent and identified the E2-region spanning amino acids 434 to 446 (epitope II) as the predominant contact domain. Conclusion: mAb 2A5 shows potent anti-HCV neutralizing activity both in vitro and in vivo and could hence represent a valuable candidate to prevent HCV recurrence in LT-patients. In addition, the detailed identification of the neutralizing epitope can be applied for the design of prophylactic HCV vaccines.



中文翻译:

一种新的中和人单克隆抗体在体外和体内广泛消除丙型肝炎病毒感染

丙型肝炎病毒 (HCV) 感染是世界范围内的健康负担,目前还没有预防性疫苗。肝移植 (LT) 通常是 HCV 诱发的终末期肝病患者的唯一选择。然而,移植后,肝脏移植物立即被循环病毒感染,导致肝脏疾病加速进展。尽管使用直接作用抗病毒药物治疗 HCV 的疗效已显着提高,但免疫受损的 LT 患者和晚期肝病患者仍然难以治疗。作为一种替代方法,干扰病毒进入可以防止供体肝脏的感染。我们生成了一种人单克隆抗体 (mAb),命名为 2A5,它靶向 HCV 包膜。mAb 2A5 的中和活性使用多个原型和患者来源的 HCV 假颗粒 (HCVpp)、细胞培养产生的 HCV (HCVcc) 和人肝嵌合小鼠模型进行了评估。观察到 mAb 2A5 的中和水平通常较高,并且大多优于使用 AP33(一种充分表征的 HCV 中和单克隆抗体)获得的水平。使用人源化小鼠,在基因型 1a 和 4a HCV 攻击后观察到完全保护,而使用 gt1b 和 6a 分离株仅获得部分保护。表位作图显示 mAb 2A5 结合是构象依赖性的,并将跨越氨基酸 434 至 446(表位 II)的 E2 区确定为主要的接触结构域。观察到 mAb 2A5 的中和水平通常较高,并且大多优于使用 AP33(一种充分表征的 HCV 中和单克隆抗体)获得的水平。使用人源化小鼠,在基因型 1a 和 4a HCV 攻击后观察到完全保护,而使用 gt1b 和 6a 分离株仅获得部分保护。表位作图显示 mAb 2A5 结合是构象依赖性的,并将跨越氨基酸 434 至 446(表位 II)的 E2 区确定为主要的接触结构域。观察到 mAb 2A5 的中和水平通常较高,并且大多优于使用 AP33(一种充分表征的 HCV 中和单克隆抗体)获得的水平。使用人源化小鼠,在基因型 1a 和 4a HCV 攻击后观察到完全保护,而使用 gt1b 和 6a 分离株仅获得部分保护。表位作图显示 mAb 2A5 结合是构象依赖性的,并将跨越氨基酸 434 至 446(表位 II)的 E2 区确定为主要的接触结构域。结论:mAb 2A5在体外体内均显示出有效的抗 HCV 中和活性,因此可以成为预防 LT 患者 HCV 复发的有价值的候选药物。此外,中和表位的详细鉴定可用于设计预防性HCV疫苗。

更新日期:2017-10-23
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