Engineering a dimeric single-domain antibody for improved detection and neutralization of amyloid-β oligomers
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Soluble Aβ oligomers are regarded as major neurotoxic agents in Alzheimer’s disease. Several monoclonal antibodies have been developed to target Aβ oligomers, but most of them show limited specificity binding also to monomers and fibrils. To generate an antibody with high specificity for the oligomers, we aimed to increase the efficiency and sensitivity of a human VH–derived Aβ-oligomer-specific single domain antibody, called DesAb-O. We engineered a dimeric DesAb-O variant, DiDesAb-O, which showed significantly higher binding affinity for Aβ oligomers as compared to the monomeric sdAb. DiDesAb-O selectively detected Aβ42 oligomers not only in vitro and in cultured cells using synthetic preparations, but also in the cerebrospinal fluid from Alzheimer’s patients. Moreover, it inhibited the binding of these toxic species to cellular membranes and neutralized their neurotoxicity both in cells and in patient-derived cerebrospinal fluid at lower concentrations compared to DesAb-O. These results indicate that rational dimerization of single-domain antibodies can substantially enhance target engagement and functional efficacy, providing a promising strategy for the development of improved diagnostic and therapeutic molecules for Alzheimer’s disease.
Similar content being viewed by others
Data-driven modeling of amyloid-β targeted antibodies for Alzheimer’s disease
Similar content being viewed by others
Data-driven modeling of amyloid-β targeted antibodies for Alzheimer’s disease
Date Issued
2026-07-03
Date Acceptance
2026-02-11
Citation
Communications Biology, 2026, 9
ISSN
2399-3642
Publisher
Nature Portfolio
Journal / Book Title
Communications Biology
Volume
9
Copyright Statement
© The Author(s) 2026. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Publication Status
Published
Article Number
ARTN 896
Date Publish Online
2026-03-27