Immunotherapeutics to prevent HCV reinfection

描述（由申请人提供）：全世界有多达1.7亿人慢性感染丙型肝炎病毒（HCV），使感染者面临肝硬化、肝衰竭和肝癌的重大风险。在美国，由HCV引起的终末期肝病是肝移植（LT）的主要指征。然而，HCV感染的再感染是普遍存在的，再感染导致的移植失败是HCV感染的LT受者再次移植和死亡的最常见原因。LT后不久，HCV再感染是普遍的，目前的抗病毒治疗控制不佳。虽然最近FDA批准的两种直接作用的抗病毒药物DAA，telaprevir和boceprevir在治疗慢性HCV感染方面有新的乐观情绪，但由于可能的不良药物相互作用，不建议在移植环境中治疗HCV。累积的证据表明，病毒中和（Vn）抗体对HCV的保护作用，这可能是一种替代方法，以防止肝移植受者的HCV再感染。该项目的目标是开发一种高效的免疫抑制剂，以预防肝移植患者中的HCV再感染，该免疫抑制剂基于限制病毒通过突变逃逸的能力的抗体。在特定目标1中，针对HCV包膜糖蛋白的广泛中和人单克隆抗体（HMAb）将通过亲和力成熟产生，与病毒逃逸无关。酵母展示系统将用于亲和成熟HMAb，以改善不同基因型的真实细胞培养感染性HCV病毒体（HCVRNA）的结合和中和。将评估先导抗体限制多重感染性HCV病毒逃逸的能力。将选择具有最高效价和针对不同HCV基因型沿着的可接受稳定性特征的抗体及其wt克隆，用于使用uPA/SCID模型进行检测。在特定目标2中，将在急性HCV感染的uPA/SCID嵌合人肝小鼠模型中评价亲和力成熟的HCV HMAb，该抗体对不同基因型HCV具有最大中和效力，且与病毒逃逸无关。后续和未来的工作将进一步评价导致最终候选产品的主要候选产品，在HCV人-小鼠肝脏嵌合动物模型中进行关键的额外有效性研究，建立临床开发所需的试验，并开发所需的细胞库和可扩展的生产工艺，用于生产临床批次，用于在I期安全性和免疫原性人体临床试验中进行检测。

DESCRIPTION (provided by applicant): Up to 170 million people worldwide are chronically infected with HCV Hepatitis C virus (HCV) putting the infected individuals at significant risk for cirrhosis, liver failure and liver cancer. End- stage liver disease caused by HCV is the leading indication of liver transplantation (LT) in the United States. However, reinfection with HCV occurs universally and allograft failure because of reinfection is the most common cause for retransplantation and death among HCV-infected LT recipients. Shortly after LT, HCV reinfection is universal and poorly controlled by current antiviral treatments. While there is new optimism in the treatment of chronic HCV infection with two recent FDA approved direct acting antivirals DAA, telaprevir and boceprevir, they are not recommended for treating HCV in the transplant setting due to likely adverse drug-drug interaction. Cumulative evidence indicates a protective role for virus neutralizing (Vn) antibodies for HCV, which could be used as an alternative approach to prevent HCV reinfection in liver transplant recipients. The goal of this project is to develop a highly effective immunotherapeutic to prevent HCV reinfection in liver transplant patients based on antibodies that limit the ability of the virus to escape via mutations In Specific Aim 1, broadly neutralizing human monoclonal antibodies (HMAb) to HCV envelope glycoprotein will be produced via affinity maturation that are not associated with viral escape. A yeast display system will be used to affinity mature HMAbs for improved binding and neutralization authentic cell culture infectious HCV virion (HCVcc) of different genotypes. The lead antibodies will be assessed for the ability to limit viral escape with multiple infectious HCVcc. The antibody with the highest potencies and an acceptable stability profile against different HCVcc genotypes along with its wt clone will be selected for testing using the uPA/SCID model. In Specific Aim 2, the affinity matured HCV HMAb having greatest neutralizing potencies against diverse genotype HCVcc, and not associated with viral escape, will be evaluated in the uPA/SCID chimeric human liver mouse model of acute HCV infection. Subsequent and future work will further evaluate the lead candidate(s) leading to a final candidate product, conduct the crucial, additional efficacy studies in a HCV human-mouse liver chimeric animal model, establish the required assays for clinical development, and develop the required cell banks and a scalable manufacturing process for production of a clinical lot for testing in a phase 1 safety and immunogenicity human clinical trial.