WGA as a Novel Vehicle for Intranasal Delivery of an Anti-A-beta Antibody in AD

WGA 作为 AD 中抗 A-β 抗体鼻内递送的新型载体

基本信息

批准号：
8432312
负责人：
NEELIMA CHAUHAN
金额：
$ 7.8万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2014-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8432312
关键词：
Active Immunization Affect Afferent Neurons Alzheimer disease prevention Alzheimer&apos s Disease American Amyloid Anatomy Antibodies Area Asses Attention Attenuated Axon Axonal Transport Basal Cell Binding Biochemical Bipolar Neuron Blood Blood - brain barrier anatomy Blood Vessels Brain Bypass Carrier Proteins Cephalic Cerebrum Characteristics Chitosan Cilia Cleaved cell Clinical Trials Cognitive Cognitive deficits Development Diffusion Disease Edema Endocytosis Epithelial Excision Gel Glucosamine Goals Grant Human Immunization Immunotherapeutic agent Immunotherapy Intracellular Transport Intranasal Administration Lead Lectin Liposomes Liquid substance Mediating Methodology Microspheres Minor Modeling Mono-S Monoclonal Antibodies Mus Nasal cavity Neuraxis Neurodegenerative Disorders Neuroglia Nose Olfactory Epithelium Olfactory tract Passive Immunization Pathway interactions Penetration Peptide Hydrolases Pharmaceutical Preparations Phase Physiological Prevention Process Resources Route Safety Sialic Acids Side Staging Structure of mucous membrane of nose Subarachnoid Space Supporting Cell Surface System Testing Therapeutic Transgenic Mice Translating Wheat Germ Agglutinins Wild Type Mouse absorption amyloid peptide bile salts cognitive change cribriform plate dimer drug candidate drug discovery efficacy testing extracellular improved intravenous injection mouse model novel olfactory bulb preclinical study preference prevent receptor mediated endocytosis response surfactant trafficking uptake

项目摘要

This application is in response to PAS-10-151 {Grants for Alzheimer's Disease Drug Discovery (R21)}. Novel vehicles are needed to effectively target direct delivery of immunotherapeutics to the brain in order to maximize the efficacy of passive immunization for treating, delaying or preventing Alzheimer's disease (AD), a disease that currently afflicts >5 million Americans. Conjugation of the lectin, Wheat Germ Agglutinin (WGA), has been shown to enhance intranasal uptake of candidate drugs and promote direct delivery to brain via (i) Adsorptive or receptor-mediated endocytosis into the olfactory sensory neurons (OSN) followed by intracellular transport to olfactory bulb; (ii) Non-specific fluid phase endocytosis into the OSNs followed by intracellular transport to olfactory bulb; and/or (iii) Extracellular diffusion along the inter-olfactory epithelial clefts directly to the olfactory bulb and/or CSF. Passive immunization by intravenous injection of Ass monoclonal antibodies (mAb) has shown promising results such as lowering of cerebral Ass and stabilization or prevention of cognitive deficits in preclinical studies in transgenic mouse models of AD and in early human clinical trials. However, the level of antibody penetration in the brain is limited by the blood-brain-barrier (BBB). In addition, in mice and humans with vascular amyloid, high levels of anti-Ass antibodies in blood has led to microhemorrhage and vasogenic edema. This project aims to overcome such limitations by maximizing the efficacy of the intranasal route of anti-Ass antibody delivery using a WGA carrier protein. This project will test the efficacy of WGA as a novel vehicle that will not only enhance delivery of anti-Ass mAb, 3A1, that binds to mono/dimers and fibrillar Ass (To be provided by Dr. Lemere-Consultant) by virtue of its endocytic uptake preference, but will also facilitate passive diffusion of 3A1 due to its nasal mucosa-like biochemical composition, maximizing immunotherapeutic efficacy of intranasal passive immunization, to be tested in Alzheimer's 5XFAD model. Hypothesis: Intranasal delivery of WGA-conjugated 3A1 mAb combined with unlabeled 3A1 antibody will maximize the immunotherapeutic potential of intranasal passive immunization ameliorating AD-like patho-cognitive changes in 5XFAD transgenic mice. Specific Aims: [1] Trafficking of WGA-3A1 antibody after intranasal delivery to the brain in wild type mice and binding of 3A1-WGA to Ass plaques in the brains of 5XFAD mice and human AD. [2] Determining if intranasal passive immunization with WGA-conjugated 3A1 mAb combined with unlabeled 3A1 antibody will prevent AD-like patho-cognitive changes in young pre-plaque 5XFAD mice. [3] Determining if intranasal passive immunization with WGA-conjugated 3A1 mAB combined with unlabeled 3A1 antibody will attenuate AD-like patho-cognitive changes in old late-stage plaque-bearing 5XFAD mice. All resources, including transgenic mice, and required expertise are ready to begin this study. Significance: This project will evaluate a novel delivery system to target immunotherapeutics directly to the brain, and thus advance one of the most promising therapies for delaying the progression or prevention of AD.

该应用是对PAS-10-151 {阿尔茨海默氏病药物发现（R21）}的赠款。需要新颖的车辆有效地针对直接输送免疫疗法到大脑最大化被动免疫对治疗，延迟或预防阿尔茨海默氏病（AD）的功效，A 目前遭受500万美国人的疾病。凝集素，小麦胚芽凝集素（WGA）的结合，已被证明可以增强鼻内吸收候选药物，并通过（i）促进直接递送到大脑吸附性或受体介导的内吞作用到嗅觉感觉神经元（OSN），然后是细胞内运输到嗅球；（ii）非特异性液相内吞作用到OSN，然后是细胞内运输到嗅球；和/或（iii）沿着高野战道上皮裂缝直接到达的细胞外扩散嗅球和/或CSF。通过静脉注射屁股单克隆抗体的被动免疫（mAb）显示出令人鼓舞的结果，例如降低脑屁股和稳定或预防认知 AD的转基因小鼠模型和人类早期临床试验中的转基因小鼠模型中的缺陷。但是，大脑中抗体渗透水平受血脑屏障（BBB）的限制。另外，在小鼠中血管淀粉样蛋白，血液中高水平抗体抗体的人类导致微含量和血管浮肿。该项目旨在通过最大化鼻内的功效来克服此类限制使用WGA载体蛋白递送抗体抗体的途径。该项目将测试WGA的功效新型车辆不仅会增强与单二聚体和纤维屁股结合的抗Ass MAB 3A1的递送（由Lemere-Counsultant博士提供）凭借其内吞吸收偏好，但也将有助于 3A1由于其鼻粘膜样生化组成而被动扩散，最大化免疫治疗性鼻内被动免疫的功效，将在阿尔茨海默氏症的5XFAD模型中进行测试。假设：鼻内 WGA偶联的3A1 mAb与未标记的3A1抗体的递送将最大化鼻内被动免疫的免疫治疗潜力可以改善类似广告样的病原体认知变化在5xFAD转基因小鼠中。具体目的：[1]鼻内递送后WGA-3A1抗体的运输野生型小鼠中的大脑以及3A1-WGA与5xFAD小鼠和人类AD的大脑中的屁股斑块结合。 [2] 确定鼻内被动免疫是否用WGA偶联的3A1 mAb与未标记的3A1结合抗体将防止年轻的Pre-Phaque 5XFAD小鼠的AD样病原认知变化。 [3]确定是否用WGA偶联的3A1 mAb与未标记的3A1抗体结合使用的鼻内无源免疫免疫衰减旧的后期斑块5xFAD小鼠的类似AD的病原体认知变化。所有资源，包括转基因小鼠以及所需的专业知识，准备开始这项研究。意义：这个项目将评估一种新型的输送系统，将免疫疗法直接靶向大脑，从而促进了其中之一延迟AD进展或预防的最有希望的疗法。