Fertan, Emre;
Lam, Jeff YL;
Albertini, Giulia;
Dewilde, Maarten;
Wu, Yunzhao;
Akingbade, Oluwatomi ES;
Böken, Dorothea;
... Klenerman, David; + view all
(2025)
Lecanemab preferentially binds to smaller aggregates present at early Alzheimer's disease.
Alzheimer's & Dementia
, 21
(4)
, Article e70086. 10.1002/alz.70086.
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Abstract
INTRODUCTION: The monoclonal antibodies Aducanumab, Lecanemab, Gantenerumab, and Donanemab were developed for the treatment of Alzheimer's disease (AD). METHODS: We used single-molecule detection and super-resolution imaging to characterize the binding of these antibodies to diffusible amyloid beta (Aβ) aggregates generated in-vitro and harvested from human brains. RESULTS: Lecanemab showed the best performance in terms of binding to the small-diffusible Aβ aggregates, affinity, aggregate coating, and the ability to bind to post-translationally modified species, providing an explanation for its therapeutic success. We observed a Braak stage-dependent increase in small-diffusible aggregate quantity and size, which was detectable with Aducanumab and Gantenerumab, but not Lecanemab, showing that the diffusible Aβ aggregates change with disease progression and the smaller aggregates to which Lecanemab preferably binds exist at higher quantities during earlier stages. DISCUSSION: These findings provide an explanation for the success of Lecanemab in clinical trials and suggests that Lecanemab will be more effective when used in early-stage AD. HIGHLIGHTS: Anti amyloid beta therapeutics are compared by their diffusible aggregate binding characteristics. In-vitro and brain-derived aggregates are tested using single-molecule detection. Lecanemab shows therapeutic success by binding to aggregates formed in early disease. Lecanemab binds to these aggregates with high affinity and coats them better.
| Type: | Article |
|---|---|
| Title: | Lecanemab preferentially binds to smaller aggregates present at early Alzheimer's disease |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/alz.70086 |
| Publisher version: | https://doi.org/10.1002/alz.70086 |
| Language: | English |
| Additional information: | © 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
| Keywords: | Alzheimer's disease, amyloid beta, diffusible aggregate, monoclonal antibody, single‐molecule detection, super‐resolution microscopy, therapeutic success, Alzheimer Disease, Humans, Amyloid beta-Peptides, Antibodies, Monoclonal, Humanized, Brain, Antibodies, Monoclonal |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10207804 |
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