Disease-modifying passive immunotherapies focused on reducing amyloid-beta (Aβ) deposition are a potential therapeutic strategy for Alzheimer's disease (AD). However, the results of Aβ passive immunotherapy clinical trials were unsatisfactory, largely due to the low efficacy of whole antibodies due to their relatively large molecular weight and low blood-brain barrier transmittance. Furthermore, the constant region fragments of whole antibodies can trigger inflammatory reactions, which raises safety concerns. Single chain fragment variables (scFvs), containing only the variable region of the heavy and light chains of antibodies, show great potential for the treatment of AD. With the aim of generating a safe and effective AD passive immunotherapy, we designed and successfully prepared scFvs targeting Aβ and investigated their activity in vitro. The results showed that both the 10D5-scFv and 12B4-scFv have high affinities for Aβ monomers, oligomers, and fibers. Moreover, scFvs could prevent the formation of Aβ oligomers and fibers, and block their cellular toxicity. In addition, 10D5-scFv and 12B4-scFv could bind to Aβ plaques on the sections of mice brains in the in vitro study, indicating potential for the treatment of AD.

专注于减少淀粉样蛋白 β (Aβ) 沉积的疾病修饰被动免疫疗法是阿尔茨海默病 (AD) 的潜在治疗策略。然而，Aβ被动免疫治疗临床试验的结果并不理想，主要是由于全抗体分子量较大，血脑屏障透光率低，疗效低。此外，整个抗体的恒定区片段会引发炎症反应，这引发了安全问题。仅包含抗体重链和轻链可变区的单链片段变量 (scFvs) 显示出治疗 AD 的巨大潜力。为了产生安全有效的 AD 被动免疫疗法，我们设计并成功制备了靶向 Aβ 的 scFv，并在体外研究了它们的活性。结果表明，10D5-scFv 和 12B4-scFv 对 Aβ 单体、低聚物和纤维都具有高亲和力。此外，scFvs 可以阻止 Aβ 寡聚体和纤维的形成，并阻断它们的细胞毒性。此外，在体外研究中，10D5-scFv 和 12B4-scFv 可以与小鼠大脑切片上的 Aβ 斑块结合，表明其具有治疗 AD 的潜力。