Broadly Neutralizing MAbs against Hepatitis C Virus

广泛中和抗丙型肝炎病毒的单克隆抗体

• 批准号: 7408604
• 负责人: WILLIAM C OLSON
• 金额: $ 28.73万
• 依托单位: PROGENICS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7408604
• 关键词: Adjuvant; American; Animals; Antigens; Antiviral Agents; Arts; Automation; Binding; Biochemical; Biological Assay; Biology; Blood; Cell Line; Cells; Chronic; Cirrhosis; Class; Clinical; Cultured Cells; Development; Dose; Evaluation; Genotype; Glycoproteins; Goals; HCV Vaccine; HIV-1; Hepatitis C; Hepatitis C virus; Hepatocyte; Human; Hybridomas; Immunization; In Vitro; Inbred BALB C Mice; Individual; Infection; Inhibitory Concentration 50; Lead; Licensing; Life; Liver diseases; Maps; Mediating; Medicine; Methods; Monoclonal Antibodies; Multiple Myeloma; Mus; Neutralization Tests; Nucleosome Core Particle; Palivizumab; Pathway interactions; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Population; Primary carcinoma of the liver cells; Purpose; Range; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Ribavirin; Risk; Screening procedure; Serum; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Specificity; Splenocyte; Staging; System; Technology; Testing; Time; Toxic effect; Treatment Protocols; Vaccines; Vesicular stomatitis Indiana virus; Viral; Virulent; Virus; Virus Diseases; Virus Replication; World Health Organization; anti-hepatitis C; base; college; concept; hepatoma cell; high throughput screening; humanized monoclonal antibodies; in vivo Model; inhibitor/antagonist; innovation; interferon therapy; liver transplantation; milligram; neutralizing monoclonal antibodies; novel; particle; receptor; research clinical testing; response; scale up; success; virus envelope

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.

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HCV疫苗，现有的治疗方法是非特异性抗病毒药物，具有适度的疗效和显著的毒性。因此，迫切需要新的靶向HCV疗法。进入抑制剂目前用于治疗其他病毒感染;然而，直到最近，研究HCV进入和抑制的系统有限。一个主要的进展是最近发现HCV包膜糖蛋白E1 E2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，并首次提供了一个强大的手段来引发和筛选单克隆抗体（MAb）的HCV中和活性。第二个具有里程碑意义的发展是发现了一种在细胞培养中有效复制的HCV强毒株，使单克隆抗体能够在体外针对真实病毒进行测试。在这个新的I期项目中，我们试图利用这些重要的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（NtMAbs）。融合HCVpp将用于使用新方案免疫小鼠。将产生约25，000个杂交瘤，并使用最新技术筛选分析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的组和针对HCVpp的可用菌株进行测试。此外，将对NtMAb进行E1 E2结合图谱分析，并检测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确定一种新的NtMAb，在抗HCV活性的效力和谱方面上级所有现有的NtMAb。符合我们严格的开发标准的NtMAb将代表该领域的重大进展和重要的新HCV候选药物。在II期项目中，将在已建立的HCV感染体内模型中评价先导NtMAb的疗效，并将其人源化以支持作为HCV治疗新模式的临床试验。 全世界约有1.7亿人感染丙型肝炎病毒（HCV）。慢性感染者有发生严重和可能危及生命的肝病的风险，包括肝硬化和肝细胞癌。目前的治疗方法具有适度的疗效和显著的毒性，迫切需要新的治疗方法来对抗HCV感染。