Multimodal imaging of antibody-mediated therapy during acute viral encephalitides

描述(由申请人提供)：治疗嗜神经病毒面临巨大挑战，因为在向中枢神经系统(CNS)输送有效的生物药物方面受到限制，而且在不断变化的疾病状态下难以确定相关的治疗剂量。在感染的某个阶段有用的化合物可能在以后毫无用处，甚至是有害的。使情况进一步复杂化的是，可能减轻中枢神经系统感染的一些直接后果的药物或抗体，由于其作用方式或对血脑屏障通透性的影响，可能会间接加重疾病。因此，了解潜在治疗药物的分布与中枢神经系统疾病进展相一致是至关重要的。这只能通过使用适当的动物模型来实现。我们的目标是利用体内多模式成像方法在这两条链之间建立一座桥梁：(I)定义两种高神经致病性生物防御相关因子尼帕病毒(Nipah Virus)和日本脑炎病毒(JEV)的疾病进展；(Ii)评估高度中和重组人单抗(RhMAbs)在中枢神经系统的生物分布和疗效。支持这项工作计划的三个基本要素是：获得现有的重组人单抗并具备生成新型治疗性重组人单抗的专业知识；能够建立急性中枢神经系统感染的小动物模型和大脑中的显微和宏观图像病毒；以及临床培训，以便根据治疗各种神经疾病患者的情况进行实验观察。在该项目的探索和开发阶段提出了四个协同目标：1.修改现有的和鉴定新的用于CNS体内抗体成像的rhMAb：我们将从微观和宏观上评估已经连接到荧光染料或MRI造影剂Gd的静脉递送的现有rhMAb的时间CNS生物分布。同时，将使用相同的多模式成像平台来生成、纯化、衍生化、交付和可视化乙脑病毒特异性重组人单抗。2.确定是否有可能增强向大脑输送重组人单抗：我们将使用两种互补的方法来探索是否有可能增强重组人单抗进入中枢神经系统的摄取。使用超声波和静脉输液的短暂物理破坏血脑屏障或非典型的鼻腔给药途径将被用于给药结合的重组人单抗。3.确定在感染期间是否可以检测到中枢神经系统传递的重组人单抗，并评估治疗益处：在开发阶段定义了非疾病状态下的生物分布后，我们将使用多模式成像来评估重组人单抗的分布以及感染后治疗人员对临床结果的影响。4.确定治疗窗口的长度和暴露后治疗所需的最小剂量：我们将评估是否有可能在整个疾病过程中使用重组人单抗进行治疗，并确定达到最大临床益处所需的最小治疗剂量。

DESCRIPTION (provided by applicant): Treating neurotropic viruses presents significant challenges due to the constraints imposed in delivering efficacious biopharmaceuticals to the central nervous system (CNS) and the difficulties determining relevant therapeutic doses during constantly changing disease states. Compounds which are useful at one stage of the infection may be useless or even detrimental later on. Complicating matters further, drugs or antibodies which may mitigate some of the direct consequences of CNS infection may indirectly exacerbate disease due to their mode of action or their effects on blood brain barrier permeability. Therefore it is vital to understand both the distribution of potential therapeutics i concert with disease progression in the CNS. This can only be achieved using appropriate animal models. Our goal is to build a bridge between these two strands using in vivo multimodal imaging approaches (i) to define the disease progression for two highly neuropathogenic biodefense-relevant agents, Nipah virus (NiV) and Japanese encephalitis virus (JEV); and (ii) to assess the CNS biodistribution and efficacy of highly neutralizing recombinant human monoclonal antibodies (rhMAbs). Three essential elements underpin this program of work: access to existing rhMAbs and expertise in the generation of novel therapeutic rhMAbs; the ability to establish small animal models of acute CNS infections and microscopically and macroscopically image viruses in the brain; and the clinical training to contextualize experimental observations based on treating patients with a diversity of neurological conditions. Four synergistic aims are proposed in the exploratory and the developmental phases of this project: 1. Modify existing and identify new rhMAbs for in vivo antibody imaging in the CNS: We will micro- and macroscopically assess the temporal CNS biodistribution of an intravenously delivered existing rhMAb that has been conjugated to fluorescent dyes or the MRI-contrast agent gadolinium. Concurrently, JEV-specific rhMAbs will be generated, purified, derivatized, delivered and visualized using the same multimodal imaging platforms. 2. Determine if it is possible to enhance delivery of rhMAbs to the brain: We will use two complementary approaches to explore if it is possible to enhance the uptake of rhMAbs into the CNS. Either transient, physical disruption of the blood brain barrier using ultrasound followed by intravenous infusion or the atypical intranasal route will be used to administer conjugated rhMAbs. Biodistribution will be assessed temporally as in Aim 1. 3. Determine if CNS-delivered rhMAbs can be detected during infection and assess the therapeutic benefits: Having defined biodistribution in non-diseased states during the development phase we will use multimodal imaging to assess rhMAb distribution and the impact the therapeutics have on clinical outcome after infection. 4. Determine the length of the therapeutic window and the minimal dose needed for post-exposure treatment: We will assess if it is possible to use rhMAbs therapeutically throughout the disease process and we will determine the minimal therapeutic dose required to achieve the maximum clinical benefit.