Development of therapeutic pan-Alphavirus human monoclonal antibodies

项目摘要 甲病毒是披膜病毒科的正链包膜RNA病毒，在全球引起疾病 在人类身上。例如，基孔肯雅病毒（CHIKV）是一种蚊子传播的甲病毒， 一种在人类中爆发的严重发热性疾病的流行病，其特征是使人虚弱的急性和慢性 多发性关节炎其他致关节炎甲病毒（例如，罗斯河（RRV）、马亚罗河（MAYV）和奥永河（O 'nyong nyong） （ONNV）病毒）正在超越其历史界限，在大洋洲、非洲和非洲爆发， 美洲.委内瑞拉（VEEV）和东方（EEEV）马脑炎病毒是蚊子传播的 有可能在人类中引起致命的神经侵入性疾病的甲病毒。目前，没有抗病毒药物 或许可的疫苗存在用于治疗或预防任何甲病毒感染。这一高度的目标 长期合作者（Diamond、Crowe、Kuhn/Rossmann、Fremont和 Streblow laboratories）和一个新的商业合作伙伴（IDBiologics）正在开发Fc优化的高效力 用于预防和治疗人类中多种甲病毒感染的泛甲病毒人类mAb。 我们的方法是筛选来自受试者的现有和新生成的人类mAb组 既往感染或免疫不同甲病毒（CHIKV、RRV或VEEV）， 广泛的交叉反应性、中和性和与感染细胞表面的结合。经过严格的 过滤和Go/No-Go决策过程，将通过亲和力成熟来改进先导候选mAb， Fc效应子功能的优化和治疗潜力将在以下小鼠模型中进行测试： 甲病毒引起的关节炎和脑炎。两个次要目标是确定结构和 人mAb保护的机制相关性。该信息将为可能的mAb组合提供信息 战略随后，我们将产生用于IND使能研究的CHO细胞系，并对优化的 将在非人灵长类动物（NHP）模型中测试泛甲病毒mAb的治疗活性， 甲病毒感染拟议的研究实现了以下CETR RFA目标：（a）基本 这些发现通过产生具有有效保护作用的泛病毒mAb疗法转化为治疗方法， 功效(b)由于许多甲病毒正在出现并造成大规模流行，该项目将 为临床需求未得到满足的疾病开发治疗方法。(c)这项工作需要一个跨学科的学术 团队和行业合作伙伴，这应该有助于转化为治疗。(d)研究的 项目和CETR提供了一个平台，用于发现针对其他病毒的mAb疗法。一个平底锅- 针对大多数全球相关甲病毒的甲病毒mAb治疗将提供立即的 针对疾病出现或生物恐怖分子引入的对策。

PROJECT SUMMARY Alphaviruses are positive-strand enveloped RNA viruses of the Togaviridae family that globally cause disease in humans. As an example, Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes explosive epidemics in humans of a severe febrile illness characterized by debilitating acute and chronic polyarthritis. Other arthritogenic alphaviruses (e.g., Ross River (RRV), Mayaro (MAYV), and O’nyong nyong (ONNV) viruses) are emerging beyond their historical boundaries with outbreaks in Oceania, Africa, and the Americas. Venezuelan (VEEV) and Eastern (EEEV) equine encephalitis viruses are mosquito-transmitted alphaviruses with the potential to cause fatal neuroinvasive disease in humans. At present, no antiviral agents or licensed vaccines exist for the treatment or prevention of any alphavirus infections. The goal of this highly interactive Project 3 between long-standing collaborators (Diamond, Crowe, Kuhn/Rossmann, Fremont, and Streblow laboratories) and a new commercial partner (IDBiologics) is to develop Fc-optimized, high potency pan-alphavirus human mAbs for the prevention and treatment of multiple alphavirus infections in humans. Our approach is to screen existing and newly generated panels of human mAbs derived from subjects who were infected or immunized previously with different alphaviruses (CHIKV, RRV, or VEEV) for extensive cross-reactivity, neutralization, and binding to the surface of infected cells. After a stringent filtering and Go/No-Go decision process, lead candidate mAbs will be improved by affinity maturation and optimization of Fc effector functions, and therapeutic potential will be tested in murine models of alphavirus-induced arthritis and encephalitis. Two secondary goals are to define the structural and mechanistic correlates of human mAb protection. This information will inform a possible combination mAb strategy. Subsequently, we will generate CHO cell lines for IND enabling studies, and pairs of optimized pan-alphavirus mAbs will be tested for therapeutic activity in non-human primate (NHP) models of alphavirus infection. The proposed research achieves the following CETR RFA goals: (a) Basic discoveries that are translated into treatments by generating pan-virus mAb therapy with potent protective efficacy. (b) Since many alphaviruses are emerging and cause large-scale epidemics, this project will develop a therapy for diseases of unmet clinical need. (c) The work requires an interdisciplinary academic team and industry partner, which should facilitate the translation into therapeutics. (d) Studies in this project and CETR provide a platform for the discovery of mAb therapeutics against other viruses. A pan- alphavirus mAb therapy against the majority of globally relevant alphaviruses will provide an immediate countermeasure against disease emergence or bioterrorist introduction.