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ABBV-8E12,一种人源化抗 Tau 抗体的临床前和临床开发,用于治疗阿尔茨海默病和其他 Tau 病。

Preclinical and Clinical Development of ABBV-8E12, a Humanized Anti-Tau Antibody, for Treatment of Alzheimer's Disease and Other Tauopathies.

机构信息

Tim West, PhD, C2N Diagnostics, 20 S Sarah St, Saint Louis, MO 63108, Email:

出版信息

J Prev Alzheimers Dis. 2017;4(4):236-241. doi: 10.14283/jpad.2017.36.

Abstract

Tau neurofibrillary tangles are found in the brains of patients suffering from Alzheimer's disease and other tauopathies. The progressive spreading of tau pathology from one brain region to the next is believed to be caused by extracellular transsynaptic transmission of misfolded tau between neurons. Preclinical studies have shown that antibodies against tau can prevent this transfer of misfolded tau between cells. Thus, antibodies against tau have the potential to stop or slow the progression of tau pathology observed in human tauopathies. To test this hypothesis, a humanized anti-tau antibody (ABBV-8E12) was developed and a phase 1 clinical trial of this antibody has been completed. The double-blind, placebo-controlled phase 1 study tested single doses of ABBV-8E12 ranging from 2.5 to 50 mg/kg in 30 patients with progressive supranuclear palsy (PSP). ABBV-8E12 was found to have an acceptable safety profile with no clinically concerning trends in the number or severity of adverse events between the placebo and dosed groups. Pharmacokinetic modelling showed that the antibody has a plasma half-life and cerebrospinal fluid:plasma ratio consistent with other humanized antibodies, and there were no signs of immunogenicity against ABBV-8E12. Based on the acceptable safety and tolerability profile of single doses of ABBV-8E12, AbbVie is currently enrolling patients into two phase 2 clinical trials to assess efficacy and safety of multiple doses of ABBV-8E12 in patients with early Alzheimer's disease or PSP.

摘要

tau 神经纤维缠结存在于患有阿尔茨海默病和其他 tau 病的患者的大脑中。tau 病理学从一个脑区向另一个脑区的进行性扩散,被认为是由于神经元之间错误折叠的 tau 的细胞外突触间传递引起的。临床前研究表明,针对 tau 的抗体可以阻止错误折叠的 tau 在细胞间的这种转移。因此,针对 tau 的抗体有可能阻止或减缓在人类 tau 病中观察到的 tau 病理学的进展。为了验证这一假说,开发了一种人源化抗 tau 抗体(ABBV-8E12),并完成了该抗体的 1 期临床试验。这项双盲、安慰剂对照的 1 期研究在 30 名进行性核上性麻痹(PSP)患者中测试了 ABBV-8E12 的单剂量,剂量范围从 2.5 至 50mg/kg。研究发现 ABBV-8E12 具有可接受的安全性,在安慰剂和给药组之间,不良事件的数量或严重程度没有临床关注的趋势。药代动力学模型显示,该抗体具有与其他人源化抗体一致的血浆半衰期和脑脊液:血浆比,并且没有针对 ABBV-8E12 的免疫原性迹象。基于 ABBV-8E12 单剂量的可接受安全性和耐受性特征,艾伯维公司目前正在招募患者参加两项 2 期临床试验,以评估 ABBV-8E12 多剂量在早期阿尔茨海默病或 PSP 患者中的疗效和安全性。

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