Characterization and Development of a Cross Spectrum Anti-Dengue Antibody

跨谱抗登革热抗体的表征和开发

• 批准号: 9115535
• 负责人: RAM SASISEKHARAN
• 金额: $ 75万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9115535
• 关键词: Address; Advanced Development; Affinity; Animal Model; Antibodies; Antibody-Dependent Enhancement; Applications Grants; Area; Attenuated Live Virus Vaccine; Binding; Biochemical; Clinical; Country; Culicidae; Dengue; Dengue Infection; Development; Disease; Disease Progression; E protein; Emerging Communicable Diseases; Engineering; Epitopes; Escape Mutant; Flavivirus; Genotype; Goals; Health; Human; In Vitro; Incidence; Infection; Informatics; Japanese Encephalitis; Japanese encephalitis virus; Licensing; Life; Monoclonal Antibodies; Morbidity - disease rate; Mosquito Control; Mutate; Mutation; Nature; Network-based; Passive Immunization; Phase; Phase I Clinical Trials; Population; Population Growth; Populations at Risk; Prevention; Protein Engineering; Proteus; Public Health; Reporting; Risk; Role; Safety; Series; Severity of illness; Site; Specificity; Structure; Testing; Therapeutic; Tick-Borne Encephalitis; Tissues; Travel; Urbanization; Vaccines; Viral; Virion; Virus; Virus Diseases; West Nile virus; World Health Organization; Yellow Fever; antibody engineering; combat; computational chemistry; cross reactivity; design; economic impact; global health; improved; in vivo; meetings; member; mouse model; neutralizing antibody; novel; pathogen; prevent; reduce symptoms; safety study; social; therapeutic target; vaccine candidate

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.

描述（由申请人提供）：在本赠款申请中，我们建议进一步开发泛登角抗体，以用于被动免疫和治疗策略。 登革热是世界范围内最重要的蚊子传播病毒疾病，世界上有一半以上的人口处于感染风险。登革热是由四个遗传相关但在血清学不同的病毒中引起的，该病毒称为FLAVIVIRUS属的成员DV-1至DV-4。最近的估计表明，每年发生超过3.9亿次感染，其中9600万例表现出临床疾病。与登革热病毒感染相关的高发病率会导致对DVS流行的人群和人口的重大公共卫生，社会和经济影响。登革热被描述为一种新兴疾病，病例越来越多，疾病的严重程度和疾病的地理传播。目前尚无针对登革热的预防或治疗的特定代理，尽管没有批准，但仍在开发登革热的几种疫苗。鉴于登革热的全球健康影响和扩大的性质以及缺乏预防或治疗疾病的特定药物，针对所有DVS的有效治疗方法将为满足巨大的未满足登革热的临床需求提供巨大的好处。 为此，我们通过计算化学和结构信息学设计了抗体4E5A，该抗体可有效地结合并有效地中和DV1-4并赋予体内活性显着。该抗体靶向E ProteI的域III的表位，该抗体在病毒粒子上高度可访问，并且在其突变的能力上受到约束。鉴于 4E5A的属性，我们建议进一步表征和发展I期临床试验的抗体。我们的研究将针对（1）检查4E5A的安全性和活动 一系列机械性研究以及登革热动物模型中的安全性和功效，（2）利用我们的基于结构的网络和蛋白质工程方法来探测探针结构（表位） - 并识别额外的备份候选者。总体而言，4E5A和相关分子将用于测试临床假设，即通过抗体减少病毒滴度，将（a）减少症状，（b）减少或消除与疾病进展相关的出血并发症。