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

描述（由申请人提供）：美国国立卫生研究院肝病行动计划强调的研究目标之一是开发包括抗病毒抗体在内的手段，以防止肝移植后丙型肝炎病毒（HCV）的复发。HCV相关的肝功能衰竭是肝移植最常见的指征，但复发性HCV总是在移植后发生，并可导致移植物迅速丧失。免疫抑制的肝移植受者对IFN-a和利巴韦林的副作用耐受较差，因此迫切需要在移植环境中预防和/或治疗HCV的新策略。这项应用的长期目标是开发一种有效的和可耐受的抗体鸡尾酒来预防复发性HCV，同样的治疗也可以用于预防意外暴露于病毒的卫生保健/实验室工作人员或高危人群的感染。具体目的是：(i)产生大量的人单克隆抗体（mab），并鉴定针对相对保守的中和病毒表位的中和mab；（ii）设计MAb以最大限度地发挥其抗病毒活性，并研究MAb组合在中和多种HCV分离株方面优于单一MAb的益处；（iii）证明最佳单抗组合在保护携带原代人肝细胞的小型嵌合动物模型免受多种异种HCV攻击方面的有效性。证明抗体鸡尾酒具有显著的保护作用，将为进一步研究这种被动抗体方法在临床环境中预防复发性HCV提供科学基础。公共卫生相关性：丙型肝炎病毒（HCV）相关的肝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手段来预防丙肝移植后的再感染。本提案的目标是发现一种高效的人单克隆抗体鸡尾酒来预防复发性HCV。

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.