Plant-derived MAb therapeutics for west nile virus

针对西尼罗病毒的植物源性单克隆抗体疗法

基本信息

批准号：
7917303
负责人：
Qiang Chen
金额：
$ 37.82万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7917303
关键词：
Advanced Development American Antibodies Arizona Avidity Binding Biochemical Blood Blood - brain barrier anatomy Capital Cells Central Nervous System Diseases Cessation of life Characteristics Chimeric Proteins Clinical Clinical Trials Communicable Diseases Cyclic GMP Development Diamond Disadvantaged Disease Outbreaks Dose Elderly Emerging Communicable Diseases Encephalitis Ensure Epidemic Epitopes Future Generations Globulins Hamsters Human Immune Immunotherapeutic agent In Vitro Infection Infectious Agent Inflammatory Intravenous Immunoglobulins Investments Lateral Left Licensing Meningitis Molecular Biology Monoclonal Antibodies Mus Neuraxis Nicotiana North America Permeability Pharmaceutical Preparations Phase Plantibodies Plants Process Production Proteins Rattus Reagent Recombinants Regulation Research Risk Rodent Safety Supportive care Technology Testing Therapeutic Therapeutic Agents Therapeutic Monoclonal Antibodies Therapeutic antibodies Transferrin Receptor Transgenic Plants Treatment Efficacy Universities Vaccines Variant Vertebrates Virus Diseases Washington West Nile virus bioprocess comparative efficacy cost env Gene Products expression vector improved in vitro activity infected vector rodent large scale production medical schools mortality mouse model neoplastic nervous system disorder neutralizing monoclonal antibodies novel novel therapeutics preclinical study prototype scale up vector virus pathogenesis

项目摘要

DESCRIPTION (provided by applicant): The outbreaks of West Nile Virus (WNV) in North America over the last decade indicate its establishment and continued spread throughout the Western hemisphere. At present, no therapeutic or vaccine is available for human use. The continued expanding WNV epidemic demands effective therapeutics and new production technologies that can rapidly transfer them into the clinical setting. The proposed research will advance the development of immunotherapeutics, with an emphasis on technology that allows cost-saving scale-up capability through the use of transgenic plants. The proposed research exploits the facile capability of plant cells to rapidly express and accumulate post-translationally modified proteins, and builds upon our ongoing research to use plant-derived monoclonal antibodies (MAbs) and MAb fusion proteins as therapeutics for viral infections. Recent research has shown that a humanized murine MAb (hu-E16) has promising therapeutic potential. A single dose of hu-E16 protected mice and hamsters against WNV-induced mortality even 5 days after infection. In addition to creating a plant-derived hu-E16 mAb with equivalent activity, this project intends to create a novel blood-brain barrier (BBB) permeable variant to enhance potency and prolong the window of opportunity for treatment. Prototype plant-derived proteins will be produced in quantities sufficient for preclinical trials. We will also develop scale-up and purification technology for subsequent production under cGMP conditions. Transgenic plants are ideal for MAb production since plant-derived MAb and MAb fusion proteins can be rapidly expanded in commercial production without high-capital cost investments for traditional MAb facilities. Thus, in addition to generating novel therapeutic reagents for WNV, this study will provide proof-of-principle for the rapid development and use of "plantibodies" against human infectious diseases. Such technology can then be readily applied in the future to other emerging infectious diseases or bioterrorist threats.

描述（由申请人提供）：过去十年来，西尼罗河病毒（WNV）在北美爆发，表明该病毒已在西半球建立并持续传播。目前，尚无可供人类使用的治疗方法或疫苗。持续扩大的西尼罗河病毒流行需要有效的治疗方法和新的生产技术，以将其迅速转移到临床环境中。拟议的研究将推动免疫治疗的发展，重点是通过使用转基因植物实现节省成本的扩大规模能力的技术。拟议的研究利用植物细胞快速表达和积累翻译后修饰蛋白的简便能力，并建立在我们正在进行的使用植物源单克隆抗体 (MAb) 和 MAb 融合蛋白作为病毒感染治疗药物的研究基础上。最近的研究表明，人源化鼠 MAb (hu-E16) 具有良好的治疗潜力。即使在感染后 5 天，单剂量的 hu-E16 也能保护小鼠和仓鼠免受西尼罗河病毒引起的死亡。除了创建具有同等活性的植物源 hu-E16 mAb 外，该项目还打算创建一种新型血脑屏障 (BBB) 可渗透变体，以增强效力并延长治疗机会。原型植物源蛋白的生产量将足以进行临床前试验。我们还将开发放大和纯化技术，以便在 cGMP 条件下进行后续生产。转基因植物是单克隆抗体生产的理想选择，因为植物来源的单克隆抗体和单克隆抗体融合蛋白可以在商业生产中快速扩展，而无需对传统单克隆抗体设施进行高资本成本投资。因此，除了产生针对西尼罗河病毒的新型治疗试剂外，这项研究还将为快速开发和使用“植物体”对抗人类传染病提供原理验证。这样的技术将来可以很容易地应用于其他新出现的传染病或生物恐怖威胁。