Kallunki Pekka, Sotty Florence, Willén Katarina, Lubas Michal, David Laurent, Ambjørn Malene, Bergström Ann-Louise, Buur Louise, Malik Ibrahim, Nyegaard Steffen, Eriksen Thomas Thiilmark, Krogh Berit O, Stavenhagen Jeffrey B, Andersen Kathrine J, Pedersen Lars Ø, Cholak Ersoy, van den Brink Edward N, Rademaker Rik, Vink Tom, Satijn David, Parren Paul W H I, Christensen Søren, Olsen Line R, Søderberg Josefine N, Vergo Sandra, Jensen Allan, Egebjerg Jan, Wulff-Larsen Pernille Gry, Harndahl Mikkel N, Damlund Dina S M, Bjerregaard-Andersen Kaare, Fog Karina
H. Lundbeck A/S, Research, Ottiliavej 9, 2500, Valby, Denmark.
Genmab, Uppsalalaan 15, 3584 CT, Utrecht, The Netherlands.
NPJ Parkinsons Dis. 2025 May 22;11(1):132. doi: 10.1038/s41531-024-00849-1.
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.
Amlenetug（Lu AF82422）是一种针对α-突触核蛋白的人源单克隆抗体，正处于针对多系统萎缩的临床开发阶段。我们描述了一系列表征其功能特性的研究，并支持其被选为可行的临床候选药物。Amlenetug可抑制多种α-突触核蛋白纤维状聚集体以及从多系统萎缩脑匀浆中分离出的聚集体在小鼠原代神经元中诱导的种子形成。在体内，将Amlenetug与α-突触核蛋白聚集体共同注射到小鼠脑内以及外周给药均可抑制α-突触核蛋白的种子形成。Amlenetug可抑制α-突触核蛋白种子的摄取以及C末端截短的α-突触核蛋白种子的积累，并证明其与人α-突触核蛋白的单体、聚集体和截短形式结合。Amlenetug的表位被定位到氨基酸112 - 117，并通过晶体结构分析进一步表征。基于我们的数据，我们推测靶向α-突触核蛋白可能通过抑制进一步的病理发展来潜在地减缓疾病的进一步进展，但对已有的病理和症状没有影响。
