Learning from the Ebola success: Can a mAb also save lives after yellow fever infection?

摘要 项目概述/摘要最近使用单一中和单克隆抗体（nmAb）降低埃博拉病毒（EBOV）感染个体死亡率的开创性实验突出了这类药物在治疗传染病中的重要性。2019年8月，Anthony Fauci博士宣布，mAb 114的施用将EBOV感染患者的死亡率从70%降低到约35%。EBOV感染不再被认为是一种统一的致命疾病。与EBOV感染类似，野生型黄热病病毒（wtYFV）感染导致高病毒载量，住院患者的死亡率高达50%。一旦感染，目前没有可用的治疗方法。虽然YFV 17 D疫苗通常是有效的，但它具有一些潜在的严重副作用，这降低了其覆盖率。不幸的是，世界卫生组织（世卫组织）报告了巴西大规模疫苗接种运动造成的约100例严重不良反应，使许多人放弃接种疫苗。尽管开展了疫苗接种运动，但免疫覆盖率仍然很低，使大量人面临风险。世界上大多数国家，包括美国，由于两种相关的黄病毒登革热（DENV）和寨卡病毒（ZIKV）的出现，人类很容易受到蚊子传播的疾病的影响。在Mabloc LLC，通过我们与Watkins，Kallas和Burton实验室以及Adimab LLC的合作，我们已经组装了大量黄病毒特异性中和单克隆抗体（nmAbs）。事实上，沃特金斯实验室已经表明，这些单克隆抗体可用于预防和治疗黄病毒感染。Watkins和Burton实验室以及最近的其他实验室已经证明，可以通过使用nmAb鸡尾酒或单一nmAb在印度恒河猴中预防ZIKV感染。此外，沃特金斯和伯顿实验室还表明，这种混合物可以将感染ZIKV的怀孕猕猴的病毒载量降低到无法检测到的水平。这些数据首次证明，在相关非人灵长类动物（NHP）模型中，暴露后用nmAbs治疗可减少黄病毒复制。在本申请的I期中，我们计划使用体外测定和在叙利亚金黄仓鼠中的体内筛选从我们现有的mAb库中鉴定至少五种nmAb用于wtYFV治疗。在第二阶段，我们将使用我们最好的YFV特异性nmAbs进行组织交叉反应性研究。然后，我们将测试最好的三种nmAb在治疗wtYFV感染的猴子中的功效。在完成该快速通道I/II期申请后，我们计划至少获得一种商业上可行的混合物或单一nmAb，其可以有效抑制wtYFV攻击的NHP中的病毒复制，从而使其免于wtYFV感染的后遗症，即死亡。

Abstract PROJECT SUMMARY/ABSTRACT The recent groundbreaking experiment using a single neutralizing monoclonal antibody (nmAb) to reduce the death rate in Ebola virus (EBOV)-infected individuals highlights the importance of this class of drug in the treatment of infectious disease. In August 2019, Dr. Anthony Fauci announced that administration of mAb114 had reduced the death rate from 70% to approximately 35% in EBOV-infected patients. EBOV infection is no longer considered a uniformly fatal disease. Similar to EBOV infection, wild-type yellow fever virus (wtYFV) infection results in high viral loads and a death rate of up to 50% in hospitalized patients. Once infected, there is no current treatment available. While the YFV17D vaccine is generally efficacious, it has some potentially severe side effects which diminish its coverage. Unfortunately, the World Health Organization (WHO) reported approximately 100 cases of severe adverse effects due to mass vaccination campaigns in Brazil, dissuading many people from receiving the vaccine. Even though vaccination campaigns were launched, immunization coverage remains low, leaving a significant number of people at risk. Most of the world, including the U.S., is vulnerable to mosquito-transmitted diseases, as shown by the emergence of two related flaviviruses dengue (DENV) and Zika (ZIKV). At Mabloc LLC, through our collaborations with the Watkins, Kallas and Burton laboratories, and Adimab LLC, we have assembled a large collection of flavivirus-specific neutralizing monoclonal antibodies (nmAbs). Indeed, the Watkins laboratory has already shown that these mAbs can be used for the prevention and treatment of flavivirus infections. The Watkins and Burton laboratories, and more recently others, have demonstrated that ZIKV infection can be prevented in Indian rhesus macaques by using either a nmAb cocktail or a single nmAb. Additionally, the Watkins and Burton laboratories have also shown that this cocktail can reduce viral load to undetectable levels in ZIKV-infected pregnant macaques. These data demonstrated, for the first time, that post-exposure treatment with nmAbs can reduce flavivirus replication in a relevant non- human primate (NHP) model. In Phase I of this application, we plan to identify at least five nmAbs from our existing pool of mAbs for wtYFV treatment using in vitro assays and in vivo screening in Syrian golden hamsters. In Phase II, we will perform tissue cross reactivity studies using our best YFV-specific nmAbs. We will then test the efficacy of the best three nmAbs in treating wtYFV-infected monkeys. After the completion of this Fast-Track Phase I/II application, we plan to have at least a commercially viable cocktail or a single nmAb that can efficaciously suppress viral replication in wtYFV-challenged NHPs, and thereby save them from the sequelae of wtYFV infection, namely death.