The structural foundations of anti-amyloid-β immunotherapies: Unravelling antibody-antigen interactions in Alzheimer's disease treatment

Abstract

Background

Anti-amyloid-β (Aβ) immunotherapies are emerging as treatments for Alzheimer's disease (AD).

Objective

This review examines the structure-activity relationships of anti-Aβ therapeutics tested in phase 3 trials.

Methods

We analyzed crystallographic data and molecular models to elucidate the Aβ binding mechanisms of donanemab, lecanemab, aducanumab, bapineuzumab, gantenerumab, solanezumab, and crenezumab.

Results

Lecanemab recognizes minimally degraded Aβ missing 1–2 residues, avoiding common Aβ in circulation and further degraded material sequestered in plaques. Bapineuzumab buries the N-terminus of Aβ requiring Asp1 and is reactive with benign, common Aβ. Donanemab buries the truncated N-Glu3 terminus with strong contacts engaging the cyclized pyro-Glu3 modification. Gantenerumab shows lecanemab-like properties but also binds common Aβ. Aducanumab likely needs mAb-mAb cooperation to scavenge a spectrum of Aβ oligomers explaining higher doses. Solanezumab and crenezumab target a pre-amyloid epitope resulting in off-target engagement, including monomers and likely excluding Aβ-ApoE complexes.

Conclusions

Preventing primary Aβ nucleation failed due to limitations imposed by the blood-brain barrier, intracellular aggregation routes, and the natural abundance of Aβ. Anti-Aβ monoclonal antibody therapies in clinical use capture Aβ at various stages of decay where post translational modifications have been used effectively as proxies for time spent in vivo. By targeting a relatively labile epitope of aging Aβ, lecanemab selects more biologically active species of Aβ avoiding both benign monomers and old fortified species. This focal point may account for the significant cognitive effects of lecanemab. The structure of aducanumab suggests a broadly neutralizing role has evolved for natural immunity to AD.