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BackgroundParkinson's disease is a progressive neurodegenerative disorder with no currently approved disease-modifying therapies. Alpha-synuclein targeting monoclonal antibodies provide a potential therapeutic strategy.ObjectivesTo evaluate published studies of the efficacy and/or safety of monoclonal antibodies that target alpha-synuclein in human subjects.MethodsA systematic review of peer-reviewed journal articles was conducted. PubMed, Embase and Scopus were searched up to March 2, 2025. Results were synthesised narratively. Risk of bias was assessed, and sensitivity analysis excluding studies with high risk was performed.ResultsAfter screening 1509 papers, 10 publications incorporating a total of 13 studies were included. These assessed Prasinezumab, Cinpanemab, Exidavnemab and Lu-AF82422 with heterogeneity amongst studies. Tolerability was generally favourable across all studies. Cinpanemab showed almost no efficacy, whilst Prasinezumab demonstrated mixed motor symptom improvements. Safety profiles for all monoclonal antibodies reflected mostly consistent rates of adverse events. Six studies were removed in the sensitivity analysis due to high risks of bias, which reduced Prasinezumab's apparent efficacy findings.ConclusionsThe efficacy of monoclonal antibodies in Parkinson's disease remains uncertain with most positive results coming from the studies with high risks of bias. Prasinezumab demonstrated an efficacy profile with the potential of significance, warranting further research. This lack of efficacy reported with Cinpanemab is consistent with the manufacturer's decision to discontinue it. Safety data on Exidavnemab and Lu-AF82422 in healthy volunteers support further investigation in Parkinson's disease patients. Future trials may benefit from the inclusion of subjects at earlier disease stages, diagnosed before clinical features have emerged. Trial Registration: ClinicalTrials.gov identifier: NCT03100149.
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