An Immunoprotectant for Marburg Virus

描述（由申请人提供）：马尔堡病毒（MARV）暴发相关的死亡率从20%到90%以上不等。MARV被疾病控制和预防中心列为A类药物，或“高优先级药物”。这对国家安全构成了威胁。”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；无论是通过肠外感染还是通过气溶胶感染，它都具有高度传染性——1个LD50大约是1个斑块形成单位；它受到医院和医源性传播的影响，并由卫生保健人员传播；作为一种非洲地方性病毒，它可以由足智多谋的个人或群体从反复发生的自然疫情中获得。目前没有药物可用于预防或治疗MARV感染。对MARV免疫保护剂的需求显然未得到满足，以应对生物战威胁以及自然发生的疫情引起的公共卫生关切。抗体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，单克隆抗体是一种快速增长的治疗药物。我们已经证明，在非人灵长类动物（NHP）模型（即最具代表性的人类模型）中，单克隆抗体鸡尾酒可以提供暴露后和治疗性保护，抵御另一种丝状病毒（埃博拉）的致命攻击。由于我们的1期SBIR工作的成功完成，我们已经确定了六种有效的抗marv单克隆抗体，可以保护小鼠免受致命的挑战。此外，在这项建议中，我们正在与综合生物治疗公司（Kelly Warfield博士；Gaithersburg医学博士）和加拿大公共卫生署（PHAC； Gary Kobinger博士）联合，他们的团队已经通过单独的资金确定了额外的保护性单克隆抗体。与Tom Geisbert博士（UTMB; Galveston， TX）一起，我们将确定这些单克隆抗体组合中哪一种最适合继续发展。该项目的长期目标是研制一种安全有效的马尔堡病毒免疫保护剂。在Specific Aim 1中，现有的保护性单克隆抗体将使用一种具有良好特征的瞬时烟草生产系统来生产。啮齿类动物实验将用于选择单克隆抗体先导鸡尾酒，用于非人灵长类动物（NHP）测试。在特异性目标2中，将在NHPs中评估鸡尾酒对抗致命MARV挑战的效果。在具体目标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.