Ex vivo comparison of ACU193 and lecanemab reveals binding differences in mouse brain.

INTRODUCTION: Immunotherapy targeting amyloid beta (Aβ) is limited by amyloid-related imaging abnormalities (ARIA), hypothesized to result from the direct binding of anti-Aβ monoclonal antibodies (mAbs) to vascular cerebral amyloid angiopathy (CAA), eliciting an immune response. METHODS: Immunofluorescent staining was used to characterize ex vivo plaque and vascular binding of recombinant FDA-approved lecanemab and clinical candidate sabirnetug (ACU193) in 30 min and 24 h fixed APP:hE4 mouse brain tissue. RESULTS: Fixation time was a key factor influencing Aβ antigen labeling with prolonged fixation differentially affecting pan-Aβ and mAb immunoreactivity. Compared with ACU193, lecanemab showed greater cortical plaque and cerebellar vascular labeling and encompassed a larger fraction of total pan-Aβ and β-pleated-sheet-rich signal, reflecting both mAb target abundance and selectivity. DISCUSSION: These findings emphasize that experimental protocols and antibody properties jointly shape the observed mAb binding patterns and highlight differences that may contribute to antibody-specific ARIA risk observed clinically.