合理选择单克隆α-突触核蛋白抗体amlenetug (Lu AF82422)治疗α-突触核蛋白病

IF 6.7 1区 医学 Q1 NEUROSCIENCES
Pekka Kallunki, Florence Sotty, Katarina Willén, Michal Lubas, Laurent David, Malene Ambjørn, Ann-Louise Bergström, Louise Buur, Ibrahim Malik, Steffen Nyegaard, Thomas Thiilmark Eriksen, Berit O. Krogh, Jeffrey B. Stavenhagen, Kathrine J. Andersen, Lars Ø. Pedersen, Ersoy Cholak, Edward N. van den Brink, Rik Rademaker, Tom Vink, David Satijn, Paul W.H.I. Parren, Søren Christensen, Line R. Olsen, Josefine N. Søderberg, Sandra Vergo, Allan Jensen, Jan Egebjerg, Pernille Gry Wulff-Larsen, Mikkel N. Harndahl, Dina S. M. Damlund, Kaare Bjerregaard-Andersen, Karina Fog
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引用次数: 0

摘要

Amlenetug (Lu AF82422)是一种靶向α-突触核蛋白的人单克隆抗体,目前正处于临床开发阶段,用于治疗多系统萎缩。我们描述了一系列的研究,表征其功能特性,并支持其作为一个可行的临床候选人的选择。Amlenetug抑制不同α-突触核蛋白纤维组合和从MSA脑匀浆中分离的聚集体在小鼠原代神经元中诱导的种子。在体内,amlenetug与α-synuclein组装体在小鼠脑内共注射和外周给药均抑制α-synuclein的产生。Amlenetug抑制α-synuclein种子的摄取以及c端截断α-synuclein种子的积累,并与人类α-synuclein的单体、聚集和截断形式结合。amlenetug的表位定位为112-117个氨基酸,并通过晶体结构分析对其进行了鉴定。根据我们的数据,我们假设靶向α-突触核蛋白可能会通过抑制进一步的病理发展来减缓疾病的进一步进展,但对已建立的病理和症状没有影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Rational selection of the monoclonal α-synuclein antibody amlenetug (Lu AF82422) for the treatment of α-synucleinopathies

Rational selection of the monoclonal α-synuclein antibody amlenetug (Lu AF82422) for the treatment of α-synucleinopathies

Amlenetug (Lu AF82422) is a human monoclonal antibody targeting α-synuclein in clinical development for multiple system atrophy. We describe a series of studies that characterize its functional properties and supported its selection as a viable clinical candidate. Amlenetug inhibits seeding induced in mouse primary neurons by various α-synuclein fibrillar assemblies and by aggregates isolated from MSA brain homogenate. In vivo, both co-injection of amlenetug with α-synuclein assemblies in mouse brain and peripheral administration inhibit α-synuclein seeding. Amlenetug inhibits uptake of α-synuclein seeds as well as accumulation of C-terminal truncated α-synuclein seeds and demonstrates binding to monomeric, aggregated, and truncated forms of human α-synuclein. The epitope of amlenetug was mapped to amino acids 112-117 and further characterized by crystallographic structure analysis. Based on our data, we hypothesize that targeting α-synuclein will potentially slow further disease progression by inhibiting further pathology development but be without impact on established pathology and symptoms.

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来源期刊
NPJ Parkinson's Disease
NPJ Parkinson's Disease Medicine-Neurology (clinical)
CiteScore
9.80
自引率
5.70%
发文量
156
审稿时长
11 weeks
期刊介绍: npj Parkinson's Disease is a comprehensive open access journal that covers a wide range of research areas related to Parkinson's disease. It publishes original studies in basic science, translational research, and clinical investigations. The journal is dedicated to advancing our understanding of Parkinson's disease by exploring various aspects such as anatomy, etiology, genetics, cellular and molecular physiology, neurophysiology, epidemiology, and therapeutic development. By providing free and immediate access to the scientific and Parkinson's disease community, npj Parkinson's Disease promotes collaboration and knowledge sharing among researchers and healthcare professionals.
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