Abstract
BACKGROUND: Monoclonal antibodies (mAbs) have shown disappointing results in targeting α-synuclein (α-Syn) aggregates in PD, leading us to question whether this therapeutic approach is fundamentally flawed or unrealized potential awaiting better application. This review aims to assess the current evidence, identify key challenges hindering this therapeutic approach, and highlight priorities for future research.
METHODS: A narrative review of the literature was conducted focusing on available evidence with respect to safety, efficacy, pharmacokinetics, CNS exposure, peripheral and central target engagement, emerging biomarkers and PET scan imaging tracers, and lessons from immunotherapy development in Alzheimer's disease.
FINDINGS: Five RCTs, three phase-I and two phase-II trials, testing three different forms of mAb (n = 786) were identified. All studies showed that mAbs were generally safe. They demonstrated low but measurable CSF mAb concentration (CSF:Serum = 0.2-0.5%) with limited evidence regarding central target engagement. Phase-II trials failed to meet their primary efficacy endpoints and showed no significant slowing of disease progression (Cinpanemab 250 mg P-value = 0.7, 1250 mg P-value = 0.78, 3500 mg P-value = 0.7; Prasinezumab 1500 mg P-value = 0.24, 4500 mg P-value = 0.72). These disappointing results are attributed to several factors, including late timing of intervention, poor BBB permeability, heterogeneity in α-Syn pathology, not using sensitive tools to detect central target engagement and Delayed PET scan tracers' development.
CONCLUSION: Although there is strong preclinical evidence supporting the efficacy of mAb in PD, several limitations prevent this from translating into tangible clinical benefit. These limitations do not necessarily indicate a fundamental flaw in the therapeutic concept, but they do highlight the urgent need for future research to prioritize addressing these limitations.