Characterization and Development of a Cross Spectrum Anti-Dengue Antibody

描述(申请人提供)：在这项拨款申请中，我们建议进一步推进泛登革热抗体的开发，以潜在地用于被动免疫和治疗策略。 登革热是世界上最重要的蚊媒病毒性疾病，世界上超过一半的人口面临感染的风险。登革热是由四种在基因上有关联但在血清学上不同的病毒引起的，它们被称为DV-1至DV-4，属于黄病毒属。最近的估计表明，每年有超过3.9亿人感染，其中9600万人表现为临床疾病。与登革热病毒感染相关的高发病率对登革热流行的人群和国家造成了重大的公共卫生、社会和经济影响。登革热被描述为一种新出现的疾病，病例数量、疾病严重性和疾病的地理传播都在增加。目前还没有预防或治疗登革热的具体药物，几种登革热候选疫苗正在开发中，尽管没有一种疫苗获得批准。鉴于登革热对全球健康的影响和不断扩大的性质，以及缺乏预防或治疗这种疾病的特定药物，针对所有登革热患者的有效治疗方法将为满足大量未得到满足的登革热临床需求提供重大好处。 为此，我们通过计算化学和结构信息学设计了抗体4E5A，它能有效结合并有效中和DV1-4，并在体内具有显著的活性。该抗体针对E蛋白III区域上的一个表位，该表位在病毒粒子上很容易获得，并且其突变能力受到限制。给定 针对4E5A的特性，我们建议进一步鉴定和开发针对I期临床试验的抗体。我们的研究将旨在(1)通过以下途径检查4E5A的安全性和活性 一系列体外机制研究以及登革热动物模型的安全性和有效性研究，以及(2)利用我们基于结构的网络和蛋白质工程方法来探测结构(表位)活性，并确定更多的备用候选。总体而言，4E5A和相关分子将用于测试临床假设，即通过注射抗体降低病毒滴度将(A)减轻症状，(B)减轻或消除与疾病进展相关的出血并发症。

DESCRIPTION (provided by applicant): In this grant application, we propose to further advance the development of a pan-dengue antibody for potential use in passive immunization and therapeutic strategies. Dengue is the most important world-wide mosquito-borne viral disease, with over half of the world's population at risk for infection. Dengue is caused by four genetically related but serologically distinct viruses termed DV-1 to DV-4 that are members of the flavivirus genus. Recent estimates suggest that over 390 million infections occur per year, of which 96 million manifest clinical diseases. The high morbidity associated with dengue virus infection leads to significant public health, social, and economic impact on populations and countries where DVs are endemic. Dengue has been described as an emerging disease, with an increasing number of cases, disease severity, and geographical spread of the disease. There are currently no specific agents for the prevention or treatment of dengue, and several vaccine candidates are in development for dengue though none that are approved. Given the global health impact and expanding nature of dengue as well as a lack of specific agents to prevent or treat the disease, a potent therapeutic that targets all DVs would provide significant benefit towards meeting the large unmet clinical need for dengue. To this end, we have engineered, through computational chemistry and structural informatics, the antibody 4E5A, which efficiently binds and potently neutralizes DV1-4 and confers significant in vivo activity. The antibody targets an epitope on domain III of the E protei that is highly accessible on the virion and that is constrained in its ability to mutate. Given the attributes of 4E5A, we propose to further characterize and develop the antibody to Phase I clinical trials. Our studies will be aimed at (1) examining the safety and activity of 4E5A through a series of mechanistic in vitro studies and safety and efficacy in animal models of dengue, and (2) utilizing our structure-based network and protein engineering approach to probe structure (epitope)-activity and to identify additional backup candidates. Overall, 4E5A and related molecules will be used to test the clinical hypothesis that reducing viral titer through administration of an antibody will (a) reduce symptoms and (b) lessen or eliminate hemorrhagic complications associated with disease progression.