A post hoc subgroup analysis has suggested potential therapeutic benefits of prasinezumab, a humanized monoclonal anti-α-synuclein antibody, in patients with rapidly progressing Parkinson's disease (PD), despite initial trials showing limited impact on primary outcomes. Caution is needed due to the retrospective nature of subgroup analyses, and potential confounding factors that may have influenced the observed treatment effects in specific patient subsets. Critical considerations are provided here for designing and implementing preclinical studies and clinical trials involving monoclonal antibodies, suggesting that future research should prioritize refining preclinical models and optimizing biomarker-based patient selection to reduce risks of false trial outcomes, eventually advancing antibody-based therapies in PD effectively and safely.