Antibody semorinemab reduces tau pathology in a transgenic mouse model and engages tau in patients with Alzheimer's disease
Antibody semorinemab reduces tau pathology in a transgenic mouse model and engages tau in patients with Alzheimer's disease
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DOI：
10.1126/scitranslmed.abb2639
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发表时间：
2021-05-12
影响因子：
17.1
通讯作者：
Kerchner, Geoffrey A.
中科院分区：
文献类型：
--
作者：
Ayalon, Gai;Lee, Seung-Hye;Kerchner, Geoffrey A.
Tau蛋白已成为阿尔茨海默病（AD）被动免疫治疗的一个有吸引力的替代靶点。迄今为止，与其他疾病标志物相比，tau病理的解剖分布和程度与病程和严重程度的相关性更好。我们在这里描述了semorinemab的产生、临床前鉴定和1期临床鉴定，semorinemab是一种人源抗tau单克隆抗体，具有免疫球蛋白G4 （igG4）同型主干。Semorinemab结合所有六种人类tau亚型，并在神经元和小胶质细胞共培养中保护神经元免受tau寡聚物的神经毒性。此外，每周腹腔注射一次semorinemab，持续13周，小鼠版本的semorinemab减少了tau病变转基因小鼠模型中的tau病理积累，与抗体效应功能状态无关。Semorinemab在体内也显示了明确的靶标作用证据，在tau转基因小鼠、非人灵长类动物和人类中观察到系统性tau浓度的增加。与健康对照组相比，在给药后，AD参与者观察到更高浓度的系统性tau。在1期临床试验中，单次给药至16800 mg和多次给药至33600 mg，一个月未观察到有关安全信号。
Tau has become an attractive alternative target for passive immunotherapy efforts for Alzheimer's disease (AD). The anatomical distribution and extent of tau pathology correlate with disease course and severity better than other disease markers to date. We describe here the generation, preclinical characterization, and phase 1 clinical characterization of semorinemab, a humanized anti-tau monoclonal antibody with an immunoglobulin G4 (igG4) isotype backbone. Semorinemab binds all six human tau isoforms and protects neurons against tau oligomer neurotoxicity in cocultures of neurons and microglia. In addition, when administered intraperitoneally once weekly for 13 weeks, murine versions of semorinemab reduced the accumulation of tau pathology in a transgenic mouse model of tauopathy, independent of antibody effector function status. Semorinemab also showed clear evidence of target engagement in vivo, with increases in systemic tau concentrations observed in tau transgenic mice, nonhuman primates, and humans. Higher concentrations of systemic tau were observed after dosing in AD participants compared to healthy control participants. No concerning safety signals were observed in the phase 1 clinical trial at single doses up to 16,800 mg and multiple doses totaling 33,600 mg in a month.