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（由申请人提供）：本申请是对PAS-10-151{阿尔茨海默病药物发现拨款（R21）}的响应。为了最大限度地提高被动免疫治疗在治疗、延缓或预防阿尔茨海默病（AD）方面的疗效，目前有150万美国人患有这种疾病，需要新的载体来有效地靶向免疫治疗药物直接递送到大脑。凝集素的结合，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，并通过以下途径促进直接给药：1)吸附或受体介导的内吞作用进入嗅觉感觉神经元（OSN），然后在细胞内运输到嗅球；（ii）非特异性流体期内吞作用进入osn，然后在细胞内转运到嗅球；和/或（iii）细胞外扩散沿嗅间上皮间隙直接到嗅球和/或脑脊液。通过静脉注射A¿单克隆抗体（mAb）进行被动免疫，在阿尔茨海默病转基因小鼠模型的临床前研究和早期人类临床试验中显示出有希望的结果，如降低大脑A¿和稳定或预防认知缺陷。然而，抗体在大脑中的渗透水平受到血脑屏障（BBB）的限制。此外，在患有血管淀粉样蛋白的小鼠和人类中，血液中高水平的抗ass抗体已导致微出血和血管源性水肿。该项目旨在通过使用WGA载体蛋白将抗a¿抗体的鼻内递送途径的功效最大化来克服这些限制。该项目将测试WGA作为一种新型载体的功效，它不仅可以增强抗a¿mAb， 3A1的递送，3A1结合单/二聚体和纤维状Ass（由Lemere-Consultant博士提供），而且由于其鼻粘膜样生化成分，也可以促进3A1的被动扩散，最大化鼻内被动免疫的免疫治疗效果，将在阿尔茨海默氏病5XFAD模型中进行测试。假设：经鼻给药wga偶联的3A1单抗联合未标记的3A1抗体将最大限度地发挥鼻被动免疫的免疫治疗潜力，改善5XFAD转基因小鼠ad样病理认知变化。特异性目的：b[1]野生型小鼠经鼻给药后转运WGA-3A1抗体到大脑，3A1-WGA结合到5XFAD小鼠和人AD的大脑Ass斑块。确定wga偶联3A1单抗联合未标记3A1抗体鼻内被动免疫是否能预防年轻斑块前5XFAD小鼠ad样病理认知改变。[3]测定wga偶联3A1单抗联合未标记3A1抗体鼻内被动免疫是否会减弱老年晚期带斑块5XFAD小鼠ad样病理认知变化。包括转基因小鼠在内的所有资源和所需的专业知识都已准备好开始这项研究。意义：本项目将评估一种新的靶向免疫治疗直接到大脑的递送系统，从而推进一种最有希望延缓或预防阿尔茨海默病进展的治疗方法。