biostudies-literatureUnknown11(1)Kallunki PH. Lundbeck A/SGenmabAmlenetug (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 NPJ Parkinson's disease132https://www.ebi.ac.uk/biostudies/studies/S-EPMC12098740biostudies-literatureRational selection of the monoclonal α-synuclein antibody amlenetug (Lu AF82422) for the treatment of α-synucleinopathies.PMC12098740Fog KChristensen SBjerregaard-Andersen KEgebjerg JSotty FJensen AParren PWHINyegaard SAmbjorn MDamlund DSMOlsen LRDavid LSoderberg JNBergstrom ALRademaker RSatijn DKallunki PWillen KKrogh BOEriksen TTMalik IPedersen LOHarndahl MNLubas Mvan den Brink ENAndersen KJCholak EWulff-Larsen PGVergo SVink TBuur LStavenhagen JBfalseRational 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 2025-01-01T00:00:00Z2025 May2026-06-02T00:30:11.824Z2026-05-24T03:07:06.046ZS-EPMC120987404040475510.1038/s41531-024-00849-1