Objective: Lu AF82422 is a human IgG1 monoclonal antibody that binds all known forms of alpha-synuclein (aSyn), including monomeric, aggregated and truncated. Data are presented on the selection, characterisation and efficacy of Lu AF82422 in inhibiting aSyn seeding-mediated pathology.

Background: aSyn, the major constituent of intracellular fibrillar aggregates, plays a key role in the pathogenesis of Parkinson’s disease (PD) and other synucleinopathies, such as multiple system atrophy (MSA) and dementia with Lewy bodies (DLB). Several aSyn antibodies have been developed by various companies and are currently at different stages of clinical development. Growing evidence points to different forms of aSyn assemblies being implicated in PD, DLB and MSA.

Method: Recombinant aSyn fibrils and extracts of PD and MSA brains were used to characterise the ability of Lu AF82422 to bind pathological forms of aSyn and to inhibit seeding in vitro and in vivo. SPR, ELISA, immunoprecipitation (IP) and immunohistochemistry (IHC) were used to characterise Lu AF82422 target binding. In vitro efficacy was assessed in cellular models of seeded aggregation from recombinant fibrils and MSA brain extracts. In vivo efficacy was shown in seeding models in mice after intrastriatal injection of fibrils.

Results: Lu AF82422 binds to monomeric and aggregated aSyn, including aggregates in PD, DLB and MSA brains. The binding of Lu AF82422 to pathological aSyn in Lewy bodies and glial cytoplasmic inclusions was demonstrated in post-mortem brains of PD, DLB and MSA patients, respectively, by IHC, ELISA and IP. Inhibition of aSyn-mediated seeding of pathology in primary neurons was shown with both recombinant full length and truncated fibrils as well as extracts from post-mortem brains of MSA patients. In wild-type mice, Lu AF82422 displayed significant concentration-dependent reduction of aSyn seeded aggregation in the brain following co-injection of recombinant fibrils in the presence of the antibody.

Conclusion: Lu AF82422 binds to aSyn aggregates isolated from disease-brain material with high affinity and dose-dependently inhibits seeding of aSyn aggregates in vitro and in vivo. Based on the strong preclinical findings, Lu AF82422 has been progressed into clinical development as a potential disease-modifying treatment for synucleinopathies.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-anti-alpha-synuclein-antibody-lu-af82422-binds-to-pathological-alpha-synuclein-species-from-human-brains-and-inhibits-seeded-alpha-synuclein-aggregation/