Immunotherapeutics for Treatment of Flavivirus Infection

治疗黄病毒感染的免疫疗法

• 批准号: 7276679
• 负责人: Erol Fikrig
• 金额: $ 127.92万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7276679
• 关键词: Antibodies; Antigens; Appearance; Bacteriophages; Binding; Birds; Blood-Borne Pathogens; Cause of Death; Clinical; Data; Dengue; Dengue Virus; Development; Dose; Drug or chemical Tissue Distribution; E protein; Elderly; Encephalitis; Enhancing Antibodies; Epitopes; Equus caballus; Escape Mutant; Flavivirus; Flavivirus Infections; Goals; Half-Life; Human; Immune; Immune response; Immunity; Immunization; Immunocompromised Host; Immunotherapeutic agent; In Vitro; Infection; Kinetics; Maps; Modeling; Nature; Numbers; Pan Genus; Phage Display; Procedures; Prophylactic treatment; Reagent; Recombinant Antibody; Recombinants; Research Personnel; Safety; Serotyping; Tertiary Protein Structure; Therapeutic; Therapeutic Effect; United States; Vaccines; Vero Cells; Virulent; Virus; Virus Diseases; West Nile virus; Yellow fever virus; cross reactivity; env Gene Products; human disease; human monoclonal antibodies; in vitro Assay; in vivo; macrophage; mouse model; novel; pre-clinical; prevent; programs; treatment effect; vector; virus envelope

DESCRIPTION (provided by applicant): Since its appearance in the United States in 1999, West Nile virus (WNV) has caused the deaths of large numbers of birds and horses and close to 1000 humans. There is currently no effective therapy available, and a potent therapy is urgently needed. The goal of this project is to develop and evaluate the efficacy of recombinant human monoclonal antibodies for the prophylaxis and treatment of lethal WNV infection. We have produced recombinant human monoclonal single chain variable fragments (scFv) against the WNV envelope protein using a phage display screen, and characterized these antibodies both in vitro and in vivo. This procedure does not require immune selection, and can identify novel epitopes that are not normally recognized during infection or immunization with antigen - something that is not possible with other antibody development strategies. We have shown that these antibodies - particularly scFv #11, our model antibody for development - neutralize WNV and related flaviviruses in vitro, and are both protective before infection and therapeutic after infection in the mouse model of WNV. Here we propose to produce scFv#11 as a complete antibody and demonstrate its efficacy against WNV, as well as its cross-protective neutralization of dengue virus and other flaviviruses. In addition, we will produce and characterize additional recombinant antibodies to develop a synergistic combination of two antibodies for enhanced neutralization and therapy against WNV and other flavivirus infections. The recombinant antibodies will be fully human, produced rapidly and in high titer, free of blood-borne pathogens, and will be promising candidates for further development as a clinical reagent to combat flaviviral infection.

描述（申请人提供）：自 1999 年在美国出现以来，西尼罗河病毒（WNV）已导致大量鸟类和马匹以及近 1000 人死亡。目前尚无有效的治疗方法，迫切需要有效的治疗方法。该项目的目标是开发和评估重组人单克隆抗体预防和治疗致命性西尼罗河病毒感染的功效。我们使用噬菌体展示筛选生产了针对 WNV 包膜蛋白的重组人单克隆单链可变片段 (scFv)，并在体外和体内表征了这些抗体。该过程不需要免疫选择，并且可以识别在感染或抗原免疫过程中通常无法识别的新表位 - 这是其他抗体开发策略不可能实现的。我们已经证明，这些抗体 - 特别是我们开发的模型抗体 scFv #11 - 在体外中和 WNV 和相关黄病毒，并且在 WNV 小鼠模型中在感染前具有保护作用，在感染后具有治疗作用。在这里，我们建议生产 scFv#11 作为完整抗体，并证明其对抗西尼罗河病毒的功效，以及对登革热病毒和其他黄病毒的交叉保护性中和作用。此外，我们将生产并表征其他重组抗体，以开发两种抗体的协同组合，以增强针对西尼罗河病毒和其他黄病毒感染的中和和治疗。重组抗体将是完全人源的、快速产生、高滴度、不含血源性病原体，并且将成为进一步开发作为对抗黄病毒感染的临床试剂的有希望的候选者。