Characterization and Development of a Cross Spectrum Anti-Dengue Antibody

跨谱抗登革热抗体的表征和开发

基本信息

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
项目类别：
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

项目摘要

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）：在本拨款申请中，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。登革热是世界范围内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。登革热由四种基因相关但血清学不同的病毒引起，称为 DV-1 至 DV-4，它们属于黄病毒属成员。最近的估计表明，每年发生超过 3.9 亿例感染，其中 9600 万人出现临床疾病。与登革热病毒感染相关的高发病率会对登革热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出现的疾病，其病例数量、疾病严重程度和疾病的地理传播不断增加。目前还没有用于预防或治疗登革热的特定药物，并且正在开发几种针对登革热的候选疫苗，但尚未获得批准。考虑到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该疾病的特异性药物，针对所有 DV 的有效治疗方法将为满足登革热未满足的大量临床需求提供重大益处。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，并赋予显着的体内活性。该抗体针对 E 蛋白结构域 III 上的一个表位，该表位在病毒颗粒上非常容易接近，并且其突变能力受到限制。鉴于鉴于4E5A的属性，我们建议进一步表征和开发该抗体以进行I期临床试验。我们的研究旨在 (1) 通过以下方式检查 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，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）活性并确定其他备用候选者。总体而言，4E5A 和相关分子将用于测试临床假设，即通过施用抗体降低病毒滴度将（a）减轻症状并（b）减轻或消除与疾病进展相关的出血并发症。