Broadly Neutralizing MAbs against Hepatitis C Virus

描述（由申请人提供）：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脏疾病的风险，HCV是美国肝移植的主要原因。目前没有针对HCV的疫苗，现有的治疗方法是非特异性抗病毒药物，疗效适中，毒性显著。因此，迫切需要新的靶向HCV治疗方法。进入抑制剂目前用于治疗其他病毒感染；然而，直到最近才有有限的系统来研究HCV的进入和抑制。最近的一项重大进展是发现HCV包膜糖蛋白E1E2可以假型逆转录病毒核心颗粒。这些HCV假病毒颗粒（HCVpp）准确地概括了HCV进入的基本生物学，并首次提供了一种强大的方法来诱导和筛选单克隆抗体（mab），以获得HCV中和活性。第二个具有里程碑意义的进展是发现了一种能在细胞培养物中有效复制的HCV毒株（HCVcc），使单克隆抗体能够在体外对真正的病毒进行检测。在这个新的I期项目中，我们寻求利用这些重要发现来开发用于治疗HCV感染的新型和广泛中和的单克隆抗体（ntmab）。融合性HCVpp将用于使用新方案免疫小鼠。将产生大约25,000个杂交瘤，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将以纯化形式针对代表主要HCV基因型的50个HCVpp和现有HCVcc菌株进行测试。此外，将绘制ntmab与E1E2结合的图谱，并测试其对不相关病毒的活性，以确定其特异性。项目的成功需要我们鉴定出一种新型NtMAb，该NtMAb在抗hcv活性的效力和谱方面优于所有现有的NtMAb。一个符合我们严格的开发标准的NtMAb将代表这一领域的重大进步和一个重要的新的HCV候选药物。在II期项目中，主要的NtMAb将在已建立的HCV感染体内模型中进行疗效评估，并将作为HCV治疗的新模式进行人源化以支持临床试验。

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.