Lecanemab Demonstrates Superior Binding to Soluble Amyloid-beta Aggregates Compared to Other Antibodies
核心洞察
Lecanemab exhibits the highest affinity for soluble amyloid-beta (搜索) aggregates, particularly protofibrils, compared to aducanumab, gantenerumab, and donanemab in in vitro studies.
Donanemab's efficacy appears to rely solely on plaque clearance, as it showed no binding to soluble amyloid-beta (搜索) aggregates in the experiments.
Lecanemab and aducanumab both bind to pyroglutamine forms of amyloid-beta (搜索), expanding the understanding of their mechanisms of action.
Cambridge, UK—A recent study comparing four anti-amyloid antibodies—lecanemab, aducanumab, gantenerumab, and donanemab—reveals that lecanemab demonstrates superior binding to soluble amyloid-beta (搜索) (Aβ) aggregates in vitro. The research, led by David Klenerman at the University of Cambridge and Bart De Strooper at the UK Dementia Research Institute (搜索), University College London, offers insights into the varying clinical outcomes of these antibodies in Alzheimer's disease (搜索) treatment.
The study, posted as a preprint on bioRxiv, characterized each antibody's ability to bind soluble Aβ aggregates. Lecanemab showed the strongest binding affinity, while donanemab did not bind any soluble aggregates, suggesting its efficacy is primarily through plaque clearance. Interestingly, both lecanemab and aducanumab bound pyroglutamine forms of Aβ.
Antibody Binding Affinities
The researchers used single-molecule arrays and super-resolution microscopy to visualize antibody binding. For synthetic Aβ42 monomers, lecanemab had the highest sensitivity, detecting as little as 2 pM. In contrast, the limit of detection (LoD) for gantenerumab was 70 pM, for aducanumab 200 pM, and donanemab showed no binding. For pyroGlu-Aβ monomers, LoDs were 4 pM, 5 pM, and 56 pM for lecanemab, donanemab, and aducanumab, respectively, while gantenerumab did not bind.
When Aβ42 or pyroGlu-Aβ were aggregated into protofibrils (100-125 nm), lecanemab again showed the highest affinity, detecting 2 pM. Aducanumab's affinity was at 63 pM, while gantenerumab and donanemab did not bind these species. The fact that donanemab did not bind clumped pyroGlu-Aβ suggests its binding region might be buried in the aggregate and inaccessible.
Binding to Natural Aβ Aggregates
To test natural material, the authors isolated soluble Aβ aggregates from postmortem samples of Braak stage 0, III, or V brains. None of the antibodies bound well to stage 0 extracts. At stage 3, lecanemab bound much more strongly than did aducanumab or gantenerumab. At stage V, aducanumab bound the most strongly, suggesting a preference for larger aggregates. Donanemab did not bind soluble aggregates from brain at any stage.
Clinical Implications
The data may help explain lecanemab’s therapeutic success. The researchers noted that additional studies of plaque binding will be needed to elucidate donanemab's mechanism of action. These findings highlight the importance of understanding the specific binding profiles of anti-amyloid antibodies to optimize therapeutic strategies for Alzheimer's disease (搜索), which affects millions worldwide. Alzheimer's Disease International estimates that over 55 million people live with dementia worldwide, with numbers projected to rise to 78 million by 2030.