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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月22日

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  • 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

摘要

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.