Multimodal imaging of antibody-mediated therapy during acute viral encephalitides

急性病毒性脑炎期间抗体介导治疗的多模态成像

• 批准号: 8366739
• 负责人: Katharine Nina Bossart
• 金额: $ 19.85万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-06 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8366739
• 关键词: Acute; Address; Animal Model; Antibodies; Antiviral Agents; Biodistribution; Biological Products; Blood - brain barrier anatomy; Brain; Cells; Central Nervous System Agents; Central Nervous System Infections; Child; Clinical; Containment; Contrast Media; Development; Disease; Disease Outcome; Disease Progression; Dose; Drug Delivery Systems; Drug Kinetics; Dyes; Elements; Encephalitis; Exhibits; Ferrets; Fluorescent Dyes; Gadolinium; Generations; Genome; Goals; Human; Image; Individual; Infection; Inflammatory Response; Intravenous; Intravenous infusion procedures; Japanese Encephalitis Viruses; Japanese encephalitis virus; Lead; Length; Libraries; Magnetic Resonance Imaging; Mediating; Mesocricetus auratus; Methods; Modeling; Multimodal Imaging; Nervous System Trauma; Neuraxis; Neurologic; Nipah Virus; Outcome; Patients; Permeability; Pharmaceutical Preparations; Phase; Process; Protocols documentation; Recombinants; Relapse; Route; Staging; Structure; System; Therapeutic; Therapeutic Agents; Therapeutic antibodies; Time; Training; Ultrasonography; Vaccinated; Viral Antibodies; Viral Encephalitis; Virion; Virus; Virus Diseases; Virus Replication; Work; base; biodefense; design; disability; effective therapy; efficacy trial; gadolinium oxide; human monoclonal antibodies; improved; in vivo; mortality; nervous system disorder; neurotropic virus; nonhuman primate; novel therapeutics; prevent; programs; research study; uptake

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. PUBLIC HEALTH RELEVANCE: Japanese encephalitis virus and Nipah virus cause very severe brain infections in humans and most people who survive these infections suffer long term problems in the central nervous system. Currently, there are no effective treatments to overcome these short and long-term problems. By designing new therapeutic agents and enhancing their entry into the brain we hope to reduce the replication of these viruses. This may in turn prevent, or even eliminate the severe disease in the brain, reduce the number of people who die following infection and limit the long term complications observed in the central nervous system.

描述（由申请人提供）：由于在不断变化的疾病状态下，在不断变化的疾病状态下确定相关的治疗剂量的困难，治疗神经旋转病毒提出了重大挑战。在感染的一个阶段有用的化合物可能是无用的，甚至以后有害。使事情进一步复杂化，可能会减轻中枢神经系统感染的某些直接后果的药物或抗体可能会间接加剧由于其作用方式或对血液脑屏障渗透性的影响。因此，重要的是要了解中枢神经系统中潜在的治疗剂I音乐会的分布。这只能使用适当的动物模型来实现。我们的目标是使用体内多模式成像方法（i）在这两条链之间建造一座桥，以定义两种高度神经病生物发育性生物脱硫药物，NIPAH病毒（NIV）和日本脑炎病毒（JEV）的疾病进展； （ii）评估高度中和重组人单克隆抗体（RHMABS）的CNS生物分布和功效。这项工作计划的三个基本要素是：获得现有的RHMAB和专业知识，从而产生了新型治疗性Rhmabs；在大脑中建立急性中枢神经系统感染以及显微镜和宏观图像病毒的小动物模型的能力；以及基于治疗具有多种神经系统疾病的患者的实验观察的临床培训。 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.同时，将使用相同的多模式成像平台生成，纯化，衍生，交付和可视化JEV特异性RHMAB。 2。确定是否有可能增强RHMAB向大脑的递送：我们将使用两种补充方法探索是否可以增强RHMAB的摄取，以增强RHMAB的摄取。使用超声进行静脉输注，或非典型鼻内途径的瞬时，身体破坏的血液屏障，将用于管理共轭RHMAB。与目标1。3中的生物分布将进行时间评估。确定在感染过程中是否可以检测到CNS分配的RHMAB并评估治疗益处：在开发阶段定义了未诊断状态的生物分布，我们在开发阶段我们将使用多模态成像来评估RHMAB分布以及对治疗疗法的影响以及对临床感染的影响。 4。确定暴露后治疗所需的治疗窗口的长度和最小剂量：我们将在整个疾病过程中评估是否可以在治疗过程中使用RHMABS，我们将确定最小的治疗剂量以实现最大的临床益处。 公共卫生相关性：日本脑炎病毒和NIPAH病毒在人类中引起非常严重的大脑感染，而大多数在中枢神经系统中生存的人会遇到长期问题。目前，没有有效的治疗方法来克服这些短期和长期问题。通过设计新的治疗剂并增强他们进入大脑的进入，我们希望减少这些病毒的复制。反过来，这可能会阻止甚至消除大脑中的严重疾病，减少感染后死亡的人数，并限制中枢神经系统中观察到的长期并发症。