Development of therapeutic pan-Alphavirus human monoclonal antibodies

项目总结 甲型病毒是Togaviridae家族的正链包膜RNA病毒，可在全球范围内引起疾病 在人类身上。例如，基孔肯雅病毒(CHIKV)是一种蚊子传播的甲型病毒，它会导致 一种以衰弱、急性和慢性为特征的严重发热性疾病在人类中的爆炸性流行 多发性关节炎。其他致关节炎的甲型病毒(例如罗斯河(RRV)、马亚罗(MAYV)和O‘nyong Nyong (ONNV)病毒正在超越其历史边界，在大洋洲、非洲和 美洲。委内瑞拉(VEEV)和东部(EEEV)马脑炎病毒通过蚊子传播 有可能导致人类致命神经侵袭性疾病的甲型病毒。目前，还没有抗病毒药物 或有许可的疫苗用于治疗或预防任何甲型病毒感染。这一高度的目标是 长期合作伙伴(钻石、克劳、库恩/罗斯曼、弗里蒙特和 Strelow实验室)和一个新的商业合作伙伴(IDBiologics)将开发FC优化的高效 用于预防和治疗人类多发性甲型病毒感染的泛甲病毒人单抗。 我们的方法是筛选现有的和新产生的来自受试者的人类mAb板 之前感染或免疫过不同甲型病毒(CHIKV、RRV或VEEV)的人 广泛的交叉反应、中和和与感染细胞表面的结合。在经历了严格的 筛选和通过/不通过决策过程，主要候选单抗将通过亲和力成熟和 Fc效应器功能的优化和治疗潜力将在小鼠模型中进行测试 甲型病毒引起的关节炎和脑炎。两个次要目标是定义结构和 人源单抗保护的机制关联。此信息将通知可能的组合mAb 策略。随后，我们将生成用于IND使能研究的CHO细胞系，并优化成对 泛甲病毒单抗将在非人灵长类动物(NHP)模型中进行治疗活性测试 甲型病毒感染。拟议的研究实现了CETRRFA的以下目标：(A)基本 通过产生具有强大保护力的泛病毒mAb疗法而转化为治疗的发现 功效。(B)由于许多甲型病毒正在出现并造成大规模流行，本项目将 开发一种治疗未得到满足的临床需求的疾病的方法。(C)这项工作需要跨学科的学术研究 团队和行业合作伙伴，这应该有助于转化为治疗学。(D)这方面的研究 Project和CETR为发现抗其他病毒的单抗治疗药物提供了一个平台。平底锅- 针对大多数全球相关甲型病毒的甲型病毒单抗治疗将立即提供 防止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.