Fertan E, Lam JY, Albertini G, Dewilde M, Wu Y, Akingbade OE, Boeken D, English EA, DeStrooper B, Klenerman D. Single-molecule characterisation of soluble beta-amyloid aggregate binding by Aducanumab, Lecanemab, Gantenerumab, and Donanemab. 2024 Oct 12 10.1101/2024.10.11.617910 (version 1) bioRxiv.
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Eisai
Eisai
Eisai
Eisai
This paper by Fertan et al. aligns with our understanding of the binding profile of lecanemab, an IgG1 antibody directed against aggregated soluble and insoluble forms of Aβ (U.S. Prescribing Information). In previous studies, lecanemab showed preferential binding to Aβ protofibrils, with 1,000-fold greater affinity than for Aβ monomer. Lecanemab also binds to fibrils, which comprise amyloid plaques, but with a 10-fold greater affinity for protofibrils relative to fibrils (Soderberg et al., 2023).
Fertan et al. describe the binding profile using a SiMoA assay, mimicking aggregates. Lecanemab showed strongest binding to soluble Aβ42 aggregates. The paper also demonstrates the binding of lecanemab to soluble co-aggregates containing both Aβ42 and pGlu3-Aβ, consistent with lecanemab binding to soluble aggregate species regardless of the state of pyro-glutamylation. Binding of lecanemab to pGlu3-Aβ alone bound to silica nanoparticles is a new finding, which may provide further insight into the conformational changes in Aβ that facilitate lecanemab binding, but it is unclear how closely these represent physiological species present in AD brain.
The binding profile of lecanemab provides the mechanistic rationale for ongoing treatment with lecanemab to clear protofibrils that continue to be produced even after amyloid plaques are cleared.
References:
Söderberg L, Johannesson M, Nygren P, Laudon H, Eriksson F, Osswald G, Möller C, Lannfelt L. Lecanemab, Aducanumab, and Gantenerumab - Binding Profiles to Different Forms of Amyloid-Beta Might Explain Efficacy and Side Effects in Clinical Trials for Alzheimer's Disease. Neurotherapeutics. 2022 Oct 17; PubMed.
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