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.
Authors
- Katarina Willén
- Lars Olsen (ORCID: https://orcid.org/0000-0002-7607-7130)
- Sandra Vergo
- Dina Silke Malling Damlund
- Kathrine J. Andersen
- Allan Jensen (ORCID: https://orcid.org/0000-0001-8124-4880)
- Pekka Kallunki (ORCID: https://orcid.org/0000-0003-1341-7238)
- Josefine Nielsen Søderberg
- Søren Christensen (ORCID: https://orcid.org/0000-0003-2500-0085)
- Malene Ambjørn (ORCID: https://orcid.org/0000-0003-4149-8231)
- Kaare Bjerregaard-Andersen (ORCID: https://orcid.org/0000-0003-3609-3408)
- Florence Sotty (ORCID: https://orcid.org/0000-0001-8701-3397)
- Jan Egebjerg
- Berit Olsen Krogh
- Karina Fog (ORCID: https://orcid.org/0000-0003-0106-704X)
- Paul W.H.I. Parren (ORCID: https://orcid.org/0000-0002-4365-3859)
- Thomas Eriksen (ORCID: https://orcid.org/0000-0001-5774-1166)
- Ibrahim Malik (ORCID: https://orcid.org/0000-0003-2048-2097)
- Jeffrey B. Stavenhagen
- Mikkel Harndahl
- Ersoy Cholak (ORCID: https://orcid.org/0000-0003-1172-5683)
- Laurent David (ORCID: https://orcid.org/0000-0002-3354-400X)
- Tom Vink (ORCID: https://orcid.org/0000-0001-6205-1733)
- Edward N. van den Brink (ORCID: https://orcid.org/0000-0002-3391-7056)
- Rik Rademaker
- Ann‐Louise Bergström (ORCID: https://orcid.org/0009-0005-4302-2845)
- Louise Buur (ORCID: https://orcid.org/0009-0006-2878-3838)
- David Satijn
- Lars Østergaard Pedersen
- Steffen Nyegaard
- Pernille Gry Wulff-Larsen
- Michal Lubas
Institutions
- Lundbeck (Denmark) (DK)
- Genmab (Netherlands) (NL)
Publication Details
- Journal
- npj Parkinson s Disease
- Published
- 2025-05-22
- DOI
- https://doi.org/10.1038/s41531-024-00849-1
- Citations
- 3
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 4.17
Funders
- H. Lundbeck A/S