Modulation of IgG blood-brain barrier permeability by surface-accessible glycan moieties

通过表面可及的聚糖部分调节 IgG 血脑屏障通透性

• 批准号: 9069723
• 负责人: WILLIAM A BANKS
• 金额: $ 7.29万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9069723
• 关键词: Address; Alzheimer' s Disease; Amyloid beta-Protein; Antibodies; Blood - brain barrier anatomy; Brain; Carbohydrates; Central Nervous System Diseases; Clinical Trials; Detection; Ensure; Face; Galactose; Glycoproteins; Health; Human; Immune; Immunoglobulin G; In Vitro; Infusion procedures; Intravenous Immunoglobulins; Iodine; Lectin; Measures; Methodology; Methods; Modeling; Monoclonal Antibodies; Mus; Neurodegenerative Disorders; Outcome; Pathway interactions; Patients; Penetration; Peripheral; Permeability; Pharmaceutical Preparations; Polysaccharides; Radiolabeled; Role; Sialic Acids; Surface; Surface Plasmon Resonance; Testing; Therapeutic antibodies; Tissues; Transgenic Mice; Work; functional decline; in vitro Model; peptide A; radiotracer; response; sialylation; therapeutic target

 DESCRIPTION (provided by applicant): Here, we will test the hypothesis that IgG antibody blood-brain barrier permeability will increase in response to elevated surface sialic acid levels. Increasing the blood-brain barrier permeability of antibodies is important because antibody drugs for Alzheimer's Disease and other neurodegenerative disorders remain largely outside the brain after administration. Increasing antibody concentrations in the brain will help the antibodies access their primary therapeutic targets and may also tap into new immune pathways that benefit patients. The project consists of two aims that each address a question below: (1) Does the average IgG blood-brain barrier permeability increase upon addition of IgG sialic acid? (2) Is the blood-brain barrier permeability specific for sialylated IgG higher than fo desiaylated IgG? Both aims will use in vitro blood-brain barrier models to ensure that blood-brain barrier permeability is measured in the absence of other influx and efflux pathways. Aim 1 uses a standard radiolabelling methodology for IgG detection. Aim 2 uses a glycan-specific Surface Plasmon Resonance method to specifically track IgG with surface exposed sialic acid or galactose moieties. Support for this hypothesis will open new avenues for antibody treatment of Alzheimer's Disease and other diseases of the central nervous system.

 描述（由申请人提供）：在这里，我们将检验以下假设：IgG 抗体血脑屏障通透性会随着表面唾液酸水平升高而增加，因为治疗阿尔茨海默病的抗体药物，增加抗体的血脑屏障通透性很重要。和其他神经退行性疾病在给药后主要保留在大脑之外。增加大脑中的抗体浓度将有助于抗体达到其主要治疗靶点，并且还可能利用新的免疫途径来造福患者。该项目包括两个目标。每个都解决了以下问题：（1）添加 IgG 唾液酸后，平均 IgG 血脑屏障通透性是否会增加？（2）唾液酸化 IgG 的血脑屏障通透性是否高于去酰化 IgG？使用体外血脑屏障模型确保在没有其他流入和流出途径的情况下测量血脑屏障渗透性。目标 1 使用标准放射性标记方法进行 IgG 检测。 Aim 2 使用聚糖特异性表面等离子共振方法来特异性追踪具有表面暴露的唾液酸或半乳糖部分的 IgG，这一假设的支持将为阿尔茨海默病和其他中枢神经系统疾病的抗体治疗开辟新途径。