阿尔茨海默病中抗 Aβ mAbs 对可溶性 Aβ 动力学和脑内靶点结合的机制建模。

Mechanistic Modeling of Soluble Aβ Dynamics and Target Engagement in the Brain by Anti-Aβ mAbs in Alzheimer's Disease.

机构信息

Department of Translational & Systems Pharmacology, Genentech Research & Early Development, Genentech, Inc., South San Francisco, California, CA 94048, United States.

出版信息

Curr Alzheimer Res. 2020;17(4):393-406. doi: 10.2174/1567205017666200302122307.

DOI:10.2174/1567205017666200302122307

PMID:32116192

Abstract

BACKGROUND

Anti-amyloid-β (Aβ) monoclonal antibodies (mAbs) are currently in development for treating Alzheimer's disease.

OBJECTIVES

To address the complexity of Aβ target engagement profiles, improve the understanding of crenezumab Pharmacokinetics (PK) and Aβ Pharmacodynamics (PD) in the brain, and facilitate comparison of anti-Aβ therapies with different binding characteristics.

METHODS

A mechanistic mathematical model was developed describing the distribution, elimination, and binding kinetics of anti-Aβ mAbs and Aβ (monomeric and oligomeric forms of Aβ1-40 and Aβ1-42) in the brain, Cerebrospinal Fluid (CSF), and plasma. Physiologically meaningful values were assigned to the model parameters based on the previous data, with remaining parameters fitted to clinical measurements of Aβ concentrations in CSF and plasma, and PK/PD data of patients undergoing anti-Aβ therapy. Aβ target engagement profiles were simulated using a Monte Carlo approach to explore the impact of biological uncertainty in the model parameters.

RESULTS

Model-based estimates of in vivo affinity of the antibody to monomeric Aβ were qualitatively consistent with the previous data. Simulations of Aβ target engagement profiles captured observed mean and variance of clinical PK/PD data.

CONCLUSION

This model is useful for comparing target engagement profiles of different anti-Aβ therapies and demonstrates that 60 mg/kg crenezumab yields a significant increase in Aβ engagement compared with lower doses of solanezumab, supporting the selection of 60 mg/kg crenezumab for phase 3 studies. The model also provides evidence that the delivery of sufficient quantities of mAb to brain interstitial fluid is a limiting step with respect to the magnitude of soluble Aβ oligomer neutralization.

摘要

背景

抗淀粉样蛋白-β（Aβ）单克隆抗体（mAb）目前正在开发用于治疗阿尔茨海默病。

目的

为了解决 Aβ 靶向结合特征的复杂性，深入了解 crenezumab 的药代动力学（PK）和大脑中的 Aβ 药效动力学（PD），并促进比较具有不同结合特征的抗 Aβ 疗法。

方法

开发了一个机械数学模型，用于描述抗 Aβ mAb 和 Aβ（Aβ1-40 和 Aβ1-42 的单体和寡聚形式）在大脑、脑脊液（CSF）和血浆中的分布、消除和结合动力学。根据先前的数据为模型参数分配了具有生理意义的值，并用剩余的参数拟合 CSF 和血浆中 Aβ 浓度的临床测量值，以及接受抗 Aβ 治疗的患者的 PK/PD 数据。使用蒙特卡罗方法模拟 Aβ 靶向结合特征，以探索模型参数中生物学不确定性的影响。

结果

基于抗体对单体 Aβ 的体内亲和力的模型估计与先前的数据定性一致。Aβ 靶向结合特征的模拟捕获了临床 PK/PD 数据的均值和方差。

结论

该模型可用于比较不同抗 Aβ 疗法的靶向结合特征，并表明 60 mg/kg crenezumab 与较低剂量的 solanezumab 相比，可显著增加 Aβ 结合，支持选择 60 mg/kg crenezumab 进行 3 期研究。该模型还提供了证据表明，将足够数量的 mAb 递送到脑间质液是限制可溶性 Aβ 寡聚物中和程度的一个限制步骤。