Discovery of potent human antibodies for prevention of (recurrent) HCV infection

描述(由申请人提供)：国立卫生研究院肝病行动计划中强调的研究目标之一是开发包括抗病毒抗体在内的方法，以防止丙型肝炎病毒(丙型肝炎病毒)在肝移植后复发。丙型肝炎病毒相关性肝功能衰竭是肝移植最常见的适应症，但丙型肝炎病毒复发总是发生在肝移植后，并可导致移植物迅速丢失。免疫抑制的肝移植受者对干扰素-a和利巴韦林的副作用耐受性差，因此迫切需要在移植环境中预防和/或治疗丙型肝炎病毒的新策略。这项应用的长期目标是开发一种有效的、可耐受的抗体鸡尾酒，以防止丙型肝炎复发，同样的治疗方法也可能在医疗保健/实验室工作人员意外接触病毒的情况下或在高危人群中预防感染。其具体目的是(I)产生大量的人源性单抗(MAb)，并鉴定针对相对保守的中和病毒表位的中和性单抗；(Ii)设计单抗以最大限度地提高其抗病毒活性，并研究单抗组合在中和不同丙型肝炎病毒分离株方面的好处；以及(Iii)证明最佳单抗组合在保护原代人类肝细胞的小嵌合动物模型中免受多个异种丙型肝炎病毒的攻击的有效性。证明抗体鸡尾酒具有显著的保护作用，将为进一步研究在临床环境中预防丙型肝炎复发的被动抗体方法提供科学基础。公共卫生相关性：丙型肝炎病毒(丙型肝炎病毒)相关性肝功能衰竭是肝移植最常见的适应症。迫切需要一种有效和可耐受的方法来预防丙型肝炎病毒肝移植后的再感染。这项提议的目标是发现一种高效的人类单抗的鸡尾酒，以防止丙型肝炎病毒复发。

DESCRIPTION (provided by applicant): One of the research goals highlighted in the Action Plan for Liver Disease of the National Institutes of Health is to develop means, including anti-viral antibodies, to prevent recurrence of hepatitis C virus (HCV) after liver transplantation. HCV-associated liver failure is the most common indication for liver transplantation but recurrent HCV invariably occurs after transplantation and can lead to rapid graft loss. The immunosuppressed liver transplant recipients tolerate the side effects of IFN-a and ribavirin poorly and therefore new strategies for prevention and/or treatment of HCV in the transplant setting are urgently required. The long-term objective of this application is to develop an effective and tolerable antibody cocktail to prevent recurrent HCV, and the same treatment may also be useful in preventing infection in the cases of accidental virus exposure of healthcare/laboratory workers, or in high risk populations. The specific aims are (i) to generate a large panel of human monoclonal antibodies (MAbs) and to identify neutralizing MAbs targeting relatively conserved neutralizing viral epitopes; (ii) to engineer the MAbs to maximize their antiviral activity and to investigate the benefits of MAb combinations over single MAbs in neutralizing diverse HCV isolates; and (iii) to demonstrate the efficacy of the best MAb combination in protecting a small chimeric animal model bearing primary human hepatocytes against challenges by multiple heterologous HCV. A demonstration of significant protection by the antibody cocktail would provide the scientific foundation for further investigation of this passive antibody approach in the prevention of recurrent HCV in clinical settings. Public Health Relevance: Hepatitis C virus (HCV)-associated liver failure is the most common indication for liver transplantation. An effective and tolerable means to prevent re-infection after liver transplant for HCV is urgently needed. The goal of this proposal is to discover a cocktail of highly potent human monoclonal antibodies to prevent recurrent HCV.