An Immunoprotectant for Marburg Virus

描述(由申请人提供)：与马尔堡病毒(Marv)暴发有关的死亡率从20%到90%以上不等。MARV被美国疾病控制和预防中心列为A类药物，即“对国家安全构成风险的高优先级药物。”MARV病毒不仅引起急性和可怕的疾病，而且在潮湿或干燥的气雾剂中相对稳定；无论是非肠道感染还是通过气雾剂感染，它都具有高度传染性--1 LD50约为1个斑块形成单位；它容易被医院和医源性传播给卫生保健人员和由卫生保健人员传播；作为一种非洲地方性病毒，它可能由足智多谋的个人或群体通过反复自然暴发感染。目前还没有预防或治疗Marv感染的药物。显然，对Marv免疫保护剂的需求尚未得到满足，以解决生物武器威胁以及自然发生的疫情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。由于其良好的安全性和有效性，单抗是一类迅速增长的治疗药物。我们已经证明，在非人灵长类动物(NHP)模型(即最具人类代表性的模型)中，mAbs的鸡尾酒可以提供暴露后和治疗后的保护，以抵御另一种丝状病毒(埃博拉)的致命攻击。随着我们第一阶段SBIR工作的成功完成，我们已经确定了六种有效的抗MARV单抗，可以保护小鼠免受致命挑战。此外，在这项提案中，我们将与综合生物疗法公司(Kelly Warfield博士；马里兰州盖瑟斯堡)和加拿大公共卫生局(PHAC；Gary Kobinger博士)联合起来，他们的团队已经通过单独的资金确定了更多的保护性单抗。我们将与Tom Geisbert博士(UTMB；德克萨斯州加尔维斯顿)一起确定这些单抗组合中的哪一种最适合继续开发。该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。在具体目标1中，现有的保护性单抗将使用具有良好特性的瞬时烟草生产系统来生产。在啮齿动物身上的实验将被用来选择一种领先的mAb鸡尾酒，以促进对非人类灵长类(NHP)的测试。在具体目标2中，鸡尾酒将在NHPS中进行评估，以对抗致命的MARV挑战。在具体目标3中，将完成启用IND的测试，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.