An Immunoprotectant for Argentine Hemorrhagic Fever

描述（由申请人提供）：阿根廷出血热的病原体朱宁病毒是一种沙粒病毒，由疾病控制和预防中心（CDC）确定为A类病原体，或“高优先级病原体.对国家安全构成危险 安全“目前没有FDA批准的药物可用于预防或治疗朱宁感染。对于朱宁免疫保护剂存在明显未满足的需求，以解决生物战的威胁以及在常规自然发生的爆发期间保护公共卫生。我们已经鉴定了结合朱宁糖蛋白（GP）的高效中和性单克隆抗体（mAb）。使用多克隆血清的临床研究已经证明了中和和治疗功效之间的明确关系，为这一努力提供了极好的概念验证支持。这项工作的目标是开发一种用于朱宁病毒的免疫保护剂，在快速和具有成本效益的工厂系统（RAMP：快速抗体制造平台）中制造，用于预防和暴露后治疗感染。 这一拟议努力的具体目标是： 具体目标1。确定先导候选产品的治疗窗。 豚鼠模型将用于确定候选产品的治疗窗。 具体目标2。阐明mAb和朱宁病毒的结构和功能活性。 MJ-01的表位将通过X射线晶体学进行定位，其效力通过中和试验（有和无补体）和抗体依赖性细胞毒性（ADCC）进行定量。在未来的研究性新药申报（目标4）中，需要了解作用机制。 具体目标3。人源化朱宁免疫保护剂并使用通用且廉价的GMP平台制造药物产品。将对先导候选产品进行人源化，然后使用RAMP系统生产。将确定一种稳定的制剂，并执行药品生产质量管理规范（GMP），以提供用于IND使能研究的制剂。 具体目标4。完成新药临床试验（IND）启动研究 将进行所有IND使能药理学、毒理学和化学、生产和控制（CMC）研究，最终目标是提交IND申请，以支持1期人体安全性试验。

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.