In Vivo Efficacy Testing Core

摘要：核心C 体内药效测试是医学对抗(MCM)发展的重要组成部分。为 出血热病毒(HFV)，在这种情况下，进行人类临床试验是困难的或不道德的， 美国食品和药物管理局(FDA)制定了这项动物规则。通过FDA动物许可证 规则要求在至少两个人类疾病的替代动物模型中进行有效性测试。在支持中 在普罗米修斯的总体目标中，Core C将执行基于抗体的体内疗效测试 在啮齿动物和非人灵长类动物(NHP)模型中，来自项目I、II和III的MCMS 丝状病毒、汉坦病毒和奈罗病毒病。埃博拉病毒、汉坦病毒和 奈罗病毒病将成为向下选择单抗的第一种体内筛选机制 基于抗体(MAb)的MCMS在高等动物模型中的进一步评估。仓鼠模型 将利用汉坦病毒感染和CCHFV感染的小鼠模型来评估新的 从项目I中发现单抗，并向下选择用于NHP测试的前导单抗。核心C将评估 项目II中Fc效应功能改变的单抗在啮齿类动物模型中的体内效应 疾病以确定具有最佳体内效力的mAb修饰。安慰剂的预防作用 将评估表达埃博拉病毒、汉坦病毒和CCHFV特异性单抗的项目III DMAb 首先，在疾病的啮齿动物模型中，将在NHP中测试铅DMAb。体内疗效结果 所有核心C的工作将集中到项目I、II和III以及核心A和B中 用于高级开发的先导单抗鸡尾酒和/或DMAb构建物鉴定 讨论。

Abstract: Core C In vivo efficacy testing is an essential part of medical countermeasure (MCM) development. For hemorrhagic fever viruses (HFV), where human clinical trials are difficult or unethical to conduct, the Food and Drug Administration (FDA) instituted the animal rule. Licensure via the FDA animal rule requires efficacy testing in at least two surrogate animal models of human disease. In support of overall Prometheus objectives, Core C will execute in vivo efficacy testing of antibody-based MCMs derived from Projects I, II, and III in rodent and nonhuman primate (NHP) models of filovirus, hantavirus, and nairovirus disease. Rodent models of ebolavirus, hantavirus, and nairovirus disease will serve as the first in vivo screening mechanism to down-select monoclonal antibody (mAb)-based MCMs for further assessment in higher animal models. Hamster models of hantavirus infection and mouse models of CCHFV infection will be utilized to evaluate newly discovered mAbs from Project I and down-select lead mAbs for NHP testing. Core C will evaluate in vivo efficacy of mAbs with altered Fc effector functions from Project II in rodent models of disease to identify mAb modifications with optimal in vivo potency. The prophylactic efficacy of Project III DMAbs expressing ebolavirus, hantavirus, and CCHFV-specific mAbs will be evaluated first in rodent models of disease and lead DMAbs will be tested in NHPs. In vivo efficacy results from all Core C efforts will be funneled into Projects I, II, and III and Cores A and B for identification of lead mAb cocktails and/or DMAb constructs for advanced development discussions.