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当代阿耳茨海默病研究

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ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

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Research Article

阿尔茨海默病中可溶性A分子动力学和脑内抗A羟丙基单克隆抗体作用的机制建模

卷 17, 期 4, 2020

页: [393 - 406] 页: 14

弟呕挨: 10.2174/1567205017666200302122307

价格: $65

摘要

背景:抗淀粉样蛋白-羟色胺(A羟色胺)单克隆抗体(mAbs)目前正在开发中，用于治疗阿尔茨海默病。 目的:解决羟甲基苯丙氨酸靶向药物参与情况的复杂性，提高对crenezumab在大脑中的药代动力学(PK)和药代动力学(PD)的理解，并促进具有不同结合特性的抗A羟甲基苯丙氨酸靶向药物治疗的比较。 方法:建立了一个机械数学模型来描述抗A单克隆抗体和单聚体(单聚体和寡聚体形式的双甲基单抗和双甲基单甲基单抗)在脑、脑脊液(CSF)和血浆中的分布、消除和结合动力学。根据之前的数据，将有生理意义的值分配给模型参数，剩下的参数与临床测量的脑脊液和血浆中的浓度和接受抗A疗法的患者的PK/PD数据相吻合。利用蒙特卡罗方法模拟了一种寡糖目标的接触情况，以探讨模型参数中生物不确定性的影响。 结果:基于模型的抗体对单分子A的体内亲和力的估计与之前的数据定性一致。模拟了一个目标与临床PK/PD数据的均值和方差。 结论:该模型可用于比较不同抗a药物的靶向作用，并证明60 mg/kg crenezumab与低剂量的solanezumab相比，显著提高了抗a药物的靶向作用，支持在3期研究中选择60 mg/kg crenezumab。该模型还提供了证据，证明运送足够数量的单克隆抗体到脑组织间液是一个限制步骤，相对于可溶性a低聚物中和的大小。

关键词: 阿尔兹海默症

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