An Immunoprotectant for Argentine Hemorrhagic Fever

描述(申请人提供)：朱宁病毒，阿根廷出血热的病原体，是一种被疾病控制和预防中心鉴定为A类病原体的新冠病毒，或称“高优先级病原体……对国家(S)构成风险” 安全措施。“目前还没有FDA批准的药物来预防或治疗Junin感染。显然，对Junin免疫保护剂的需求尚未得到满足，以应对生物武器的威胁，以及在定期自然发生的疫情期间提供公共卫生保护。我们已经鉴定出结合Junin糖蛋白(GP)的高效中和单抗(MAbs)。使用多克隆血清的临床研究已经证明了中和和治疗效果之间的明确关系，为这一努力提供了极好的概念验证支持。这项拟议工作的目标是开发一种针对Junin病毒的免疫保护剂，该保护剂在快速且具有成本效益的植物系统(RAMP：快速抗体制造平台)中生产，用于预防感染和暴露后治疗。 这项拟议工作的具体目标是： 具体目标1.确定候选先导产品的治疗窗口。 豚鼠模型将被用来确定产品候选的治疗窗口。 具体目的2.阐明单抗和Junin病毒的结构和功能活性。 今后的研究新药提交工作需要了解行动机制(目标4)。 具体目标3.将聚宁免疫保护剂人性化，并利用通用、廉价的GMP平台制造药物产品。主要候选产品将被人性化，然后使用坡道系统生产。将确定稳定的配方，并执行良好制造规范(GMP)，为IND研究提供药物产品。 具体目标4.完成研究性新药(IND)促进研究 将进行所有支持IND的药理学、毒理学和化学、制造和控制(CMC)研究，最终目标是提交IND申请，以支持第一阶段人类安全试验。

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.