An Immunoprotectant for Argentine Hemorrhagic Fever

阿根廷出血热的免疫保护剂

• 批准号: 8692502
• 负责人: Larry Zeitlin
• 金额: $ 120.45万
• 依托单位: MAPP BIOPHARMACEUTICAL, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-21 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8692502
• 关键词: Academia; Acute; Address; Animal Model; Antibodies; Arenavirus; Benchmarking; Binding; Biological Assay; Biological Products; Biological Response Modifier Therapy; Biological Warfare; Categories; Cavia; Centers for Disease Control and Prevention (U.S.); Chemistry; Clinical Management; Clinical Research; Collaborations; Communicable Diseases; Complement; Controlled Study; Coupled; Development; Diagnosis; Disease; Disease Outbreaks; Drug Formulations; Epitopes; Exposure to; FDA approved; Future; Glycoproteins; Goals; Health protection; Human; Individual; Industry; Infection; International; Investigational Drugs; Investigational New Drug Application; Junin virus; Kentucky; Lead; Maps; Medical; Methods; Modeling; Monoclonal Antibodies; Morbidity - disease rate; National Security; Nature; Performance; Pharmaceutical Preparations; Pharmacology and Toxicology; Phase; Plants; Population; Preclinical Testing; Prevention; Preventive; Production; Public Health; Research Institute; Risk; Rodent; Safety; Serum; Symptoms; System; Testing; Texas; Therapeutic; Treatment Efficacy; Universities; Viral Hemorrhagic Fevers; Virus; X-Ray Crystallography; antibody-dependent cell cytotoxicity; bioprocess; cGMP production; cost effective; disorder prevention; drug development; hemorrhagic fever virus; improved; in vivo; manufacturing process development; member; mortality; neutralizing monoclonal antibodies; prevent; product development; public health relevance

DESCRIPTION (provided by applicant): Junin virus, the causative agent of Argentine hemorrhagic fever, is an arenavirus identified by the Centers for Disease Control and Prevention (CDC) as a Category A agent, or "high-priority agent ... that pose(s) a risk to national security." There are currently no FDA approved drugs available for preventing or treating infections with Junin. There is a clear unmet need for a Junin immunoprotectant to address the threat of biowarfare as well as for public health protection during regular naturally occurring outbreaks. We have identified highly potent neutralizing monoclonal antibody (mAbs) that bind the Junin glycoprotein (GP). Clinical studies using polyclonal sera have demonstrated a clear relationship between neutralization and therapeutic efficacy, providing excellent proof-of-concept support for this effort. The goal of this proposed effort is the development of an immunoprotectant for Junin virus, manufactured in a rapid and cost-effective plant system (RAMP: Rapid Antibody Manufacturing Platform), for prevention and post-exposure treatment of infection. The Specific Aims of this proposed effort are: Specific Aim 1. Determine therapeutic window of lead product candidate. The guinea pig model will be used to identify the therapeutic window of the product candidate. Specific Aim 2. Elucidate structural and functional activities of the mAb and Junin virus. The epitope of MJ-01 will be mapped by X-ray crystallography and its potency quantified by neutralization assays (with and without complement), and antibody dependent cellular cytotoxicity (ADCC). An understanding of the mechanism of action is required for the future Investigational New Drug submission (Aim 4). Specific Aim 3. Humanize the Junin immunoprotectant and manufacture drug product using a versatile and inexpensive GMP platform. The lead product candidate will be humanized and then produced using the RAMP system. A stable formulation will be identified, and Good Manufacturing Practices (GMP) performed to supply the drug product for IND-enabling studies. Specific Aim 4. Complete Investigational New Drug (IND) enabling studies All IND-enabling pharmacology, toxicology, and Chemistry, Manufacturing and Controls (CMC) studies will be performed, with a final goal of filing an IND application to support a Phase 1 human safety trial.

描述（由申请人提供）：胡宁病毒是阿根廷出血热的病原体，是一种沙粒病毒，被美国疾病控制和预防中心 (CDC) 认定为 A 类病原体，或“高优先级病原体……对国家造成风险”。 目前尚无 FDA 批准的药物可用于预防或治疗胡宁感染。对于胡宁免疫保护剂的需求显然尚未得到满足，以解决生物战的威胁以及在定期自然发生的疫情期间保护公众健康。我们已经确定了与胡宁糖蛋白 (GP) 结合的高效中和单克隆抗体 (mAb)。临床研究使用 多克隆血清已证明中和与治疗功效之间存在明确的关系，为这项工作提供了极好的概念验证支持。这项工作的目标是开发胡宁病毒的免疫保护剂，在快速且经济高效的植物系统（RAMP：快速抗体制造平台）中生产，用于感染的预防和暴露后治疗。 这项拟议工作的具体目标是： 具体目标 1. 确定先导产品候选物的治疗窗。 豚鼠模型将用于确定候选产品的治疗窗口。 具体目标 2. 阐明 mAb 和胡宁病毒的结构和功能活性。 MJ-01 的表位将通过 X 射线晶体学绘制，并通过中和测定（有或没有补体）和抗体依赖性细胞毒性 (ADCC) 量化其效力。未来的研究性新药提交（目标 4）需要了解作用机制。 具体目标 3. 使用多功能且廉价的 GMP 平台将 Junin 免疫保护剂人性化并生产药品。主要候选产品将被人性化，然后使用 RAMP 系统生产。将确定稳定的配方，并执行良好生产规范 (GMP)，为 IND 支持研究提供药品。 具体目标 4. 完成研究性新药 (IND) 支持研究 所有支持 IND 的药理学、毒理学以及化学、制造和控制 (CMC) 研究都将进行，最终目标是提交 IND 申请以支持一期人体安全试验。