Broadly Neutralizing MAbs against Hepatitis C Virus

描述(申请人提供)：估计有390万美国人和全球1.7亿人感染了丙型肝炎病毒(HCV)。慢性感染者有发展成严重和危及生命的肝病的风险，丙型肝炎病毒是美国肝移植的主要原因。目前还没有丙型肝炎病毒疫苗，现有的治疗方法是非特异性抗病毒药物，疗效不高，毒性大。因此，迫切需要新的、有针对性的丙型肝炎病毒疗法。进入抑制剂目前被用于治疗其他病毒感染；然而，直到最近，研究丙型肝炎病毒进入和抑制的系统有限。一项重大进展是最近发现丙型肝炎病毒包膜糖蛋白E1E2可以伪型逆转录病毒核心颗粒。这些丙型肝炎病毒假病毒颗粒(HCVpp)准确地概括了丙型肝炎病毒进入的基本生物学过程，并首次提供了一种强大的手段来诱导和筛选具有丙型肝炎病毒中和活性的单抗(MAb)。第二个里程碑式的发展是发现了一种在细胞培养(HCVcc)中有效复制的丙型肝炎病毒毒株，使单抗能够在体外针对真正的病毒进行测试。在这个新的第一阶段项目中，我们寻求利用这些重要发现来开发用于治疗丙型肝炎病毒感染的新型和广泛中和单抗(NtMAbs)。融合基因HCVpp将被用来通过新的方案免疫小鼠。将产生大约25,000个杂交瘤细胞，并使用最先进的筛选技术分析对HCVpp的特异性抑制。最有希望的NtMAb将以纯化形式与代表主要丙型肝炎病毒基因型的=50个HCVpp小组和可用的HCVcc毒株进行测试。此外，将绘制NtMAbs与E1E2结合的图谱，并测试其对无关病毒的活性，以确定它们的特异性。项目的成功需要我们确定一种新的NtMAb，它在效力和抗丙型肝炎病毒活性方面优于所有现有的NtMAb。符合我们严格的开发标准的NtMAb将代表着该领域的重大进步和一个重要的新的丙型肝炎病毒候选药物。在第二阶段项目中，领先的NtMAb将在已建立的丙型肝炎病毒感染的体内模型中进行疗效评估，并将被人性化，以支持作为丙型肝炎病毒治疗的一种新模式的临床测试。 全球约有1.7亿人感染丙型肝炎病毒(丙型肝炎病毒)。慢性感染者有发展成严重和潜在威胁生命的肝病的风险，包括肝硬变和肝细胞癌。目前的治疗方法疗效不高，但毒性很大，迫切需要新的治疗方法来对抗丙型肝炎病毒感染。

DESCRIPTION (provided by applicant): An estimated 3.9 million Americans and 170 million individuals worldwide have been infected with hepatitis C virus (HCV). Chronically infected individuals are at risk of developing severe and life-threatening liver disease, and HCV is the leading cause of liver transplantation in the U.S. No vaccine for HCV is currently available, and the existing therapies are non-specific antiviral agents with modest efficacies and significant toxicities. Therefore, there is an urgent need for new, targeted HCV therapies. Entry inhibitors currently are used to treat other viral infections; however, until recently there were limited systems for studying entry and inhibition of HCV. A major advance was the recent discovery that the HCV envelope glycoproteins E1E2 can pseudotype retroviral core particles. These HCV pseudovirus particles (HCVpp) accurately recapitulate the essential biology of HCV entry and provide for the first time a robust means to elicit and screen panels of monoclonal antibodies (MAbs) for HCV-neutralizing activity. A second landmark development was the discovery of a virulent strain of HCV that replicates efficiently in cell culture (HCVcc), enabling MAbs to be tested against authentic virus in vitro. In this new Phase I project, we seek to leverage these important discoveries for the purposes of developing novel and broadly neutralizing MAbs (NtMAbs) for the treatment of HCV infection. Fusogenic HCVpp will be used to immunize mice using novel regimens. Approximately 25,000 hybridomas will be generated and analyzed for specific inhibition of HCVpp using state-of-the-art screening. The most promising NtMAbs will be tested in purified form against a panel of =50 HCVpp representing the major HCV genotypes and against the available strains of HCVcc. In addition, NtMAbs will be mapped for E1E2 binding and tested for activity against unrelated viruses to establish their specificity. Project success requires that we identify a novel NtMAb that is superior to all existing NtMAbs in terms of potency and spectrum of anti-HCV activity. A NtMAb that meets our stringent criteria for development would represent both a significant advance to this field and an important new HCV drug candidate. In the Phase II project, the lead NtMAb will be evaluated for efficacy in established in vivo models of HCV infection and will be humanized to support clinical testing as a novel mode of HCV therapy. Approximately 170 million individuals worldwide are infected with hepatitis C virus (HCV). Chronically infected individuals are at risk of developing severe and potentially life-threatening liver disease, including cirrhosis and hepatocellular carcinoma. Current therapies have modest efficacies and significant toxicities, and there is an urgent need for new therapies to combat HCV infection.