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

  • NPJ Parkinsons Dis. 2025 May 22;11(1):132. doi: 10.1038/s41531-024-00849-1.
Pekka Kallunki  1 ,  Florence Sotty  2 ,  Katarina Willén  2 ,  Michal Lubas  2 ,  Laurent David  2 ,  Malene Ambjørn  2 ,  Ann-Louise Bergström  2 ,  Louise Buur  2 ,  Ibrahim Malik  2 ,  Steffen Nyegaard  2 ,  Thomas Thiilmark Eriksen  2 ,  Berit O Krogh  2 ,  Jeffrey B Stavenhagen  2 ,  Kathrine J Andersen  2 ,  Lars Ø Pedersen  2 ,  Ersoy Cholak  2 ,  Edward N van den Brink  3 ,  Rik Rademaker  3 ,  Tom Vink  3 ,  David Satijn  3 ,  Paul W H I Parren  3 ,  Søren Christensen  2 ,  Line R Olsen  2 ,  Josefine N Søderberg  2 ,  Sandra Vergo  2 ,  Allan Jensen  2 ,  Jan Egebjerg  2 ,  Pernille Gry Wulff-Larsen  2 ,  Mikkel N Harndahl  2 ,  Dina S M Damlund  2 ,  Kaare Bjerregaard-Andersen  2 ,  Karina Fog  2
Affiliations
  • 1. H. Lundbeck A/S, Research, Ottiliavej 9, 2500, Valby, Denmark. [email protected].
  • 2. H. Lundbeck A/S, Research, Ottiliavej 9, 2500, Valby, Denmark.
  • 3. Genmab, Uppsalalaan 15, 3584 CT, Utrecht, The Netherlands.
PMID: 40404755 DOI: 10.1038/s41531-024-00849-1
Abstract

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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