Rational selection of the monoclonal α-synuclein antibody amlenetug (Lu AF82422) for the treatment of α-synucleinopathies
Pekka Kallunki, Florence Sotty, Katarina Willén, Michał Lubas, Laurent David, Malene Ambjørn, Ann‐Louise Bergström, Louise Buur, Ibrahim Malik, Steffen Nyegaard, Thomas Eriksen, Berit Olsen Krogh, Jeffrey B. Stavenhagen, Kathrine J. Andersen, Lars Østergaard 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 Nielsen Søderberg, Sandra Vergo, Allan Jensen, Jan Egebjerg, Pernille Gry Wulff-Larsen, Mikkel Harndahl, Dina Silke Malling Damlund, Kaare Bjerregaard-Andersen, Karina Fog
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.