Characterization and Development of a Cross Spectrum Anti-Dengue Antibody

描述（由申请人提供）：在本授权申请中，我们建议进一步推进泛登革热抗体的开发，以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，世界上一半以上的人口面临感染风险。登革热是由四种遗传上相关但血清学上不同的病毒引起的，称为DV-1至DV-4，它们是黄病毒属的成员。最近的估计表明，每年有3.9亿多人感染，其中9 600万人表现为临床疾病。与登革热病毒感染相关的高发病率对DV流行的人群和国家造成重大的公共卫生、社会和经济影响。登革热被描述为一种新兴疾病，病例数量、疾病严重程度和疾病的地理传播都在增加。目前没有用于预防或治疗登革热的特异性药物，并且正在开发用于登革热的几种候选疫苗，尽管没有一种被批准。鉴于登革热的全球健康影响和扩展性质以及缺乏预防或治疗该疾病的特异性药物，靶向所有DV的有效治疗剂将为满足登革热的大量未满足的临床需求提供显著益处。 为此，我们通过计算化学和结构信息学设计了抗体4 E5 A，其有效地结合并有效地中和DV 1 -4并赋予显著的体内活性。该抗体靶向E蛋白的结构域III上的表位，该表位在病毒体上是高度可接近的并且其突变能力受到限制。鉴于 由于4 E5 A的特性，我们建议进一步表征和开发抗体以进行I期临床试验。我们的研究将旨在（1）通过以下方式检查4 E5 A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中的安全性和有效性，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）活性并鉴定其他备用候选物。总体而言，4 E5 A和相关分子将用于检验临床假设，即通过给予抗体降低病毒滴度将（a）减轻症状和（B）减轻或消除与疾病进展相关的出血性并发症。

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.