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

• 批准号: 8246405
• 负责人: NEELIMA CHAUHAN
• 金额: $ 13.39万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 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/8246405
• 关键词: Active Immunization; Affect; Afferent Neurons; Alzheimer disease prevention; Alzheimer' 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; public health relevance; receptor mediated endocytosis; response; surfactant; trafficking; uptake

DESCRIPTION (provided by applicant): 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 A¿ monoclonal antibodies (mAb) has shown promising results such as lowering of cerebral A¿ 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-A¿ 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-A¿ 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. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) affects >5 million Americans and yet there is no long-term prevention or treatment to slow the progression or cure this devastating neurodegenerative disease. The goal of this project is to improve the efficacy and safety of Ass immunotherapy for AD by enhancing direct delivery of Ass antibodies to brain via the nose-brain barrier. If successful in mice, this non-invasive methodology could be translated to human clinical trials.

描述（通过应用程序提供）：此应用是对PAS-10-151 {阿尔茨海默氏病药物发现（R21）}的响应。需要新颖的车辆有效地靶向直接递送免疫疗法向大脑传递，以最大程度地提高被动免疫抑制对治疗，延迟或预防阿尔茨海默氏病（AD）的有效性，这种疾病目前遭受了500万美国人的影响。讲座的结合，小麦胚芽凝集素（WGA）已被证明可以增强候选药物的鼻内摄取，并通过（i）吸附或接收器介导的内吞作用直接递送到大脑中，然后进入嗅觉传感神经元（OSN），然后是细胞内转运到细胞内传输到酚类甘露的情况下； （ii）非特异性液相内吞作用到OSNS，然后细胞内转运到嗅球；和/或（iii）沿着菲尔菲利式上皮裂缝的细胞外扩散，直接直接向嗅球和/或CSF。通过静脉注射A单克隆抗体（MAB）通过静脉注射（MAB）的被动免疫已显示出希望的结果，例如在AD的转基因小鼠模型中，在临床前研究中，在临床前研究中，在临床前研究中降低了脑抗体，稳定或预防认知缺陷。然而，大脑中抗体渗透水平受到血脑屏障（BBB）的限制。此外，在具有血管淀粉样蛋白的小鼠和人类中，血液中高水平的抗体抗体导致了微毛发和血管性水肿。该项目旨在通过使用WGA载体蛋白最大化抗A抗体递送的鼻内途径的有效性来克服这种局限性。 This project will test the efficiency of WGA as a novel vehicle that will not only enhance delivery of anti-A¿ 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, maximising鼻内被动免疫抑制的免疫治疗效率，将在阿尔茨海默氏症的5XFAD模型中进行测试。假设：与未标记的3A1抗体结合使用WGA偶联的3A1 MAB的鼻内递送将最大程度地提高5xFAD转基因小鼠的鼻内无源免疫抑制的免疫治疗潜力。具体目的：[1]在野生型小鼠中向大脑递送到大脑后WGA-3A1抗体的运输以及3A1-WGA与5xFAD小鼠和人类AD的大脑中的Ass斑块结合。 [2]确定鼻内被动免疫抑制是否用WGA偶联的3A1 mAb与未标记的3A1抗体结合在一起，是否会防止年轻的Pre-Plaquque 5xFAD小鼠中的AD样病情认知变化。 [3]确定鼻内被动免疫抑制是否具有WGA偶联的3A1 MAB与未标记的3A1抗体结合使用，会减轻旧的含有晚期斑块的5xFAD小鼠的AD样病情认知变化。包括转基因小鼠在内的所有资源和所需的专业知识都准备开始这项研究。意义：该项目将评估一种新型的输送系统，以将免疫治疗剂直接靶向大脑，从而促进延迟AD进展或预防的最有希望的疗法之一。 公共卫生相关性：阿尔茨海默氏病（AD）影响> 500万美国人，但没有长期的预防或治疗可以减缓或治愈这种毁灭性的神经退行性疾病。该项目的目的是通过通过鼻脑屏障将屁股抗体直接递送到大脑，提高AS免疫疗法的效率和安全性。如果在小鼠中成功，则这种非侵入性方法可以转化为人类临床试验。