Consortium for Immunotherapeutics Against Viral Hemorrhagic Fevers

描述（由申请方提供）：A类丝状病毒和沙粒病毒引起严重和快速进展的出血热，对此没有特定的治疗方法或疫苗。在可能的暴露前和暴露后治疗中，单克隆抗体目前被认为是最有效的，为暴露后治疗提供了最长的窗口，并且由于安全性，可用性和有效性的原因，最有可能获得FDA的批准。在过去的一年里，我们的团队成员首先确定了特异性抗体和抗体混合物，这些抗体和抗体混合物在多种动物模型中提供了有效的暴露后保护，以对抗埃博拉病毒和拉沙病毒。我们将翻译这些疗法，并填补针对其他致病性丝状病毒（苏丹、马尔堡和本迪布焦）和沙粒病毒（卢霍、马丘波、朱宁等）的抗体的关键资源缺口。该提案描述了一个由学术和工业研究人员组成的大型多学科联盟。我们有 收集了约315个针对丝状病毒的单克隆抗体和约100个针对沙粒病毒的单克隆抗体。这是有史以来为这些病毒组装的最大的抗体库，包括已知的最有效的抗体。该联合会包括三个BSL 4实验室的主任-接触后治疗开发和评估专家;高通量和人类抗体发现和分析方面的其他领导人，他们可以接触到2012年爆发的独特的大型人类幸存者队列;结构生物学家对丝状病毒和沙粒病毒糖蛋白有深入的了解，能够在免疫过程中绘制池中几乎每种抗体的表位。该项目的过程中;和工业科学家谁是大规模生产和评估的治疗人类使用的专家。我们的联盟对所有研究者和他们希望贡献的所有抗体开放。我们将提供一个公开的，全面的和明确的分析，哪些抗体对这些抗体最有效，为什么，哪些抗体可以组合最大的协同作用，为什么，以及哪些表位导致广谱反应性。该计划的目标是推进基于单克隆抗体的免疫产品，以满足对这些病毒家族的治疗需求，并在第5年前提交一份或多份研究性新药申请。 相关性：该项目将对病毒性出血热抗体进行前所未有的全领域分析，并将最有效的抗体鸡尾酒转化为临床应用。这些产品将提供急需的暴露前或暴露后治疗，以对抗世界上一些最致命的病毒。

DESCRIPTION (provided by applicant): Category A filoviruses and arenaviruses cause severe and rapidly progressing hemorrhagic fever, for which no specific treatments or vaccines are available. Among the possible pre- and post-exposure treatments vetted, monoclonal antibodies are currently thought to be the most effective, provide the longest window for post-exposure treatment, and be most likely to achieve FDA approval for reasons of safety, availability and efficacy. In the last year, members of our team were first to identify specific antibodies and cocktails of antibodies that confer effective post-exposure protection against Ebola virus and Lassa virus in multiple animal models. We will translate these therapies and fill critical resource gaps in antibodies against other pathogenic filoviruses (Sudan, Marburg and Bundibugyo) and arenaviruses (Lujo, Machupo, Junin, etc.). This proposal describes a large, multidisciplinary consortium from academic and industrial investigators. We have gathered ~315 monoclonal antibodies against the filoviruses and ~100 monoclonal antibodies against the arenaviruses. These are the largest antibody pools ever assembled for these viruses and include the most potent antibodies known. The consortium includes directors of three BSL4 laboratories - experts in post exposure therapeutic development and evaluation; other leaders in high-throughput and human antibody discovery and analysis with access to unique, large cohorts of human survivors of outbreaks in 2012; structural biologists with intimate knowledge of the filovirus and arenavirus glycoproteins able to map the epitope of nearly every antibody in the pools during the course of the project; and industrial scientists who are experts in large-scale production and evaluation of therapeutics for human use. Our consortium is open to all investigators and to all antibodies they wish to contribute. We will provide a public, comprehensive and definitive analysis of which antibodies are most effective against these antibodies and why, which antibodies can be combined for greatest synergy and why, and which epitopes lead to broad-spectrum reactivity. The over-arching goal is to advance mAb-based immunotherapeutic products to fill the need for treatments against these families of viruses and to file one or more Investigational New Drug applications by year 5. RELEVANCE: This project will perform an unprecedented, field-wide analysis of antibodies against viral hemorrhagic fevers and will translate the most effective antibody cocktails to clinical use. These products will provide a much needed pre- or post-exposure therapy against some of the world's most lethal viruses.