Kinetic fingerprints differentiate the mechanisms of action of anti-Aβ antibodies
Kinetic fingerprints differentiate the mechanisms of action of anti-Aβ antibodies
复制标题
DOI：
10.1038/s41594-020-0505-6
复制
发表时间：
2020-09-28
影响因子：
16.8
通讯作者：
Hansson, Oskar
中科院分区：
文献类型：
--
作者：
Linse, Sara;Scheidt, Tom;Hansson, Oskar
通过深入的动力学方法检查了四种抗体对 Aβ 聚集途径的影响，揭示了每种抗体影响的特定分子步骤。淀粉样蛋白级联假说认为，淀粉样蛋白 -β 肽 (Aβ) 的自组装是阿尔茨海默病的致病过程，在过去 20 年中，该假说推动了许多治疗工作。研究 A β 靶向疗法的临床试验的失败已被解释为反对这一假设的证据，无论治疗药物的特性和作用机制如何，评估起来都极具挑战性。在这里，我们将动力学分析与定量结合测量相结合，以解决四种临床阶段抗 Aβ 抗体（aducanumab、gantenerumab、bapineuzumab 和 solanezumab）的作用机制。我们量化了这些抗体对聚集动力学和寡聚聚集体产生的影响，并将这些影响与每种抗体对 Aβ 单体和纤维形式的亲和力和化学计量联系起来。我们的结果表明，在这四种抗体中，aducanumab 显着降低了 Aβ 寡聚物的通量。
The effects of four antibodies on the aggregation pathway of A beta are examined via an in-depth kinetics approach, revealing the specific molecular steps affected by each antibody.The amyloid cascade hypothesis, according to which the self-assembly of amyloid-beta peptide (A beta) is a causative process in Alzheimer's disease, has driven many therapeutic efforts for the past 20 years. Failures of clinical trials investigating A beta-targeted therapies have been interpreted as evidence against this hypothesis, irrespective of the characteristics and mechanisms of action of the therapeutic agents, which are highly challenging to assess. Here, we combine kinetic analyses with quantitative binding measurements to address the mechanism of action of four clinical stage anti-A beta antibodies, aducanumab, gantenerumab, bapineuzumab and solanezumab. We quantify the influence of these antibodies on the aggregation kinetics and on the production of oligomeric aggregates and link these effects to the affinity and stoichiometry of each antibody for monomeric and fibrillar forms of A beta. Our results reveal that, uniquely among these four antibodies, aducanumab dramatically reduces the flux of A beta oligomers.