神经毒性
脑脊液
免疫疗法
淀粉样蛋白(真菌学)
抗体
体内
转基因小鼠
生物标志物
化学
转基因
体外
重组DNA
医学
药理学
病理
内科学
免疫学
生物化学
免疫系统
生物
毒性
生物技术
基因
作者
Stina Tucker,Christer Möller,Karin Tegerstedt,Anna Lord,Hanna Laudon,Johan Sjödahl,Linda Söderberg,Erika Spens,Charlotte Sahlin,Erik Rollman Waara,Andrew Satlin,Pär Gellerfors,Gunilla Osswald,Lars Lannfelt
摘要
Amyloid-β (Aβ) immunotherapy for Alzheimer's disease (AD) has good preclinical support from transgenic mouse models and clinical data suggesting that a long-term treatment effect is possible. Soluble Aβ protofibrils have been shown to exhibit neurotoxicity in vitro and in vivo, and constitute an attractive target for immunotherapy. Here, we demonstrate that the humanized antibody BAN2401 and its murine version mAb158 exhibit a strong binding preference for Aβ protofibrils over Aβ monomers. Further, we confirm the presence of the target by showing that both antibodies efficiently immunoprecipitate soluble Aβ aggregates in human AD brain extracts. mAb158 reached the brain and reduced the brain protofibril levels by 42% in an exposure-dependent manner both after long-term and short-term treatment in tg-ArcSwe mice. Notably, a 53% reduction of protofibrils/oligomers in cerebrospinal fluid (CSF) that correlated with reduced brain protofibril levels was observed after long-term treatment, suggesting that CSF protofibrils/oligomers could be used as a potential biomarker. No change in native monomeric Aβ42 could be observed in brain TBS extracts after mAb158-treatment in tg-ArcSwe mice. By confirming the specific ability of mAb158 to selectively bind and reduce soluble Aβ protofibrils, with minimal binding to Aβ monomers, we provide further support in favor of its position as an attractive new candidate for AD immunotherapy. BAN2401 has undergone full phase 1 development, and available data indicate a favorable safety profile in AD patients.
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