An Immunoprotectant for Marburg Virus

描述（由申请方提供）：与马尔堡病毒（MARV）暴发相关的死亡率范围为20%至90%以上。MARV被疾病控制和预防中心列为A类药物，或“高优先级药物”。对国家安全构成威胁“MARV不仅引起急性和可怕的疾病，而且在湿或干气溶胶中相对稳定;无论是通过肠胃外感染还是通过气溶胶感染，它都具有高度传染性- 1 LD 50约为1个噬菌斑形成单位;它易于向保健人员和由保健人员进行医院内和医源性传播;作为一种非洲地方性病毒，它可能是由一个足智多谋的个人或群体从反复发生的自然爆发中获得的。目前没有药物可用于预防或治疗MARV感染。对于MARV免疫保护剂存在明显的未满足的需求，以解决生物战威胁以及由自然发生的爆发引起的公共卫生问题。用抗体进行被动免疫已被证明对多种病毒有效。由于其优异的安全性和功效，mAb是一类快速增长的治疗药物。我们已经证明，mAb的混合物可以在非人灵长类动物（NHP）模型（即最能代表人类的模型）中提供针对另一种丝状病毒（埃博拉病毒）致命攻击的暴露后和治疗保护。由于我们成功完成了1期SBIR工作，我们已经鉴定出6种有效的抗MARV mAb，可保护小鼠免受致命攻击。此外，在本提案中，我们与Integrated Biotherapeutics（Kelly沃菲尔德博士;盖瑟斯堡，MD）和加拿大公共卫生署（PHAC;加里科宾格博士）联合，其团队已经通过单独的资金确定了额外的保护性mAb。我们将与Tom Geisbert博士（UTMB;加尔维斯顿，TX）一起确定哪种mAb组合最适合继续开发。本项目的长期目标是开发一种安全有效的马尔堡病毒免疫保护剂。在特定目标1中，将使用充分表征的瞬时烟草生产系统生产现有的保护性mAb。啮齿动物实验将用于选择主要mAb混合物，以推进非人灵长类动物（NHP）测试。在特定目标2中，将在NHP中评价混合物对致死性MARV攻毒的影响。在特定目标3中，将完成IND启用测试并提交IND。

DESCRIPTION (provided by applicant): Mortality rates associated with Marburg virus (MARV) outbreaks range from 20% to over 90%. MARV is included by the Centers for Disease Control and Prevention as among the Category A agents, or "high- priority agents ... that pose a risk to national security." MARV not only causes acute and terrifying disease, but it is relatively stable in wet or dry aerosols; it is highly infectious whether infection occurs parenterally or by aerosol-- 1 LD50 is approximately 1 plaque-forming unit; it is subject to nosocomial and iatrogenic spread to and by health care personnel; and as an endemic African virus it could be acquired from recurrent natural outbreaks by a resourceful individual or group. There are currently no drugs available for preventing or treating infections with MARV. There is a clear unmet need for a MARV immunoprotectant to address biowarfare threats as well as public health concerns raised by naturally occurring outbreaks. Passive immunization with antibodies has been shown to be effective against a wide variety of viruses. Because of their excellent safety profile and efficacy mAbs are a rapidly growing class of therapeutic drug. We have shown that a cocktail of mAbs can provide post-exposure and therapeutic protection against lethal challenge with another filovirus (Ebola) in the non-human primate (NHP) model (i.e. the model most representative of humans). As a result of successful completion of our Phase 1 SBIR efforts, we have identified six potent anti-MARV mAbs that protect mice from lethal challenge. Further, in this proposal we are combining forces with Integrated Biotherapeutics (Dr. Kelly Warfield; Gaithersburg, MD) and the Public Health Agency of Canada (PHAC; Dr. Gary Kobinger), whose teams have identified additional protective mAbs via separate funding. Together with Dr. Tom Geisbert (UTMB; Galveston, TX) we will determine which of these combinations of mAbs is the most appropriate for continued development. The Long Range Objective of this project is to develop a safe and effective immunoprotectant for Marburg virus. In Specific Aim 1, the existing protective mAbs will be produced using a well-characterized transient Nicotiana production system. Experiments in rodents will be used to select a lead mAb cocktail for advancement to non-human primate (NHP) testing. In Specific Aim 2, the cocktail will be evaluated in NHPs against lethal MARV challenge. In Specific Aim 3 IND-enabling testing will be completed and an IND submitted.