Preclinical Development of Human Monoclonal Antibodies for Postexposure Treatment of Crimean-Congo Hemorrhagic Fever

项目总结/摘要 克里米亚-刚果出血热病毒（CCHFV）是一种蜱传的新兴病原体，可引起严重的 通常是致命的出血热在人类跨越广泛的地理范围，包括超过30个 国家NIAID将CCHFV列为A类优先病原体， 危害国家安全和公共健康。CCHF对公共卫生特别重要，因为没有 由于担心这种病毒可能会在人类中传播， 被用作生物恐怖主义的工具。本项目的目标是开发一种基于单克隆抗体的 作为一种潜在的医疗对策，可以在所有六个方面提供保护 CCHFV的遗传上不同的分支。将在体外比较单克隆抗体，以选择 防止代表所有主要M片段进化枝的CCHFV。最有希望的抗体将是 使用STAT-1基因敲除小鼠模型测试了它们在抗体 在用CCHFV攻击后给予。然后将优化给药和治疗方案。率先 候选抗体将评估其保护非人灵长类动物免受CCHFV疾病的能力， 暴露后服用。该提案将汇集开发铅抗- 与人恒定区嵌合的CCHFV小鼠单克隆抗体，以及开发和 优化全人源抗CCHF单克隆抗体。

PROJECT SUMMARY/ABSTRACT Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne emerging pathogen that causes severe and often fatal hemorrhagic fever in humans across a broad geographic range that includes more than 30 countries. The NIAID lists CCHFV as a Category A priority pathogen, a biological agent that poses the highest risk to national security and public health. CCHF is of particular importance to public health as there are no licensed vaccines or treatments available for use in humans, and because of the concern that the virus could be used as an agent of biological terrorism. The goal of this project is to develop a monoclonal antibody-based postexposure treatment as a potential medical countermeasure that can provide protection across all six genetically distinct clades of CCHFV. Monoclonal antibodies will be compared in vitro to select candidates that protect against CCHFVs representing all major M segment clades. The most promising antibodies will then be tested using the STAT-1 knockout mouse model for their ability to protect against disease when the antibodies are given following challenge with CCHFV. Dosing and treatment regimens will then be optimized. The lead candidate antibody will be evaluated for its ability to protect nonhuman primates from CCHFV disease when administered after exposure. This proposal will draw together the expertise needed to develop lead anti- CCHFV mouse monoclonal antibodies chimerized with human constant regions, as well as to develop and optimize fully human anti-CCHF monoclonal antibodies.