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

项目摘要/摘要 克里米亚-刚果出血热病毒(CCHFV)是一种由壁虱传播的新出现的病原体，可引起严重和 通常致命的出血热在广泛的地理范围内，包括30多个 国家。NIAID将CCHFV列为A类优先病原体，这是一种构成最高 对国家安全和公共健康构成威胁。CCHF对公共卫生特别重要，因为没有 获得许可的疫苗或治疗方法可用于人类，并因为担心病毒可能 被用作生物恐怖主义的代理人。本项目的目标是开发一种基于单抗的 暴露后治疗作为一种潜在的医学对策，可以为所有六个人提供保护 CCHFV在基因上的不同分支。单抗将在体外进行比较，以选择符合以下条件的候选抗体 防御代表所有主要M段分支的CCHFV。最有希望的抗体将是 使用STAT-1基因敲除小鼠模型测试它们抵御疾病的能力 是在CCHFV挑战之后给出的。然后，剂量和治疗方案将得到优化。领头羊 候选抗体将被评估其保护非人类灵长类动物免受CCHFV疾病的能力 在暴露后给药。这项提案将汇集开发铅反兴奋剂所需的专业知识 CCHFV小鼠单抗与人恒定区嵌合，以及研制和 全面优化人源性抗CCHF单抗。

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.