Heavy-Chain Complementarity-Determining Regions Determine Conformation Selectivity of Anti-Aβ Antibodies

<i>Background/Aims:</i> Amyloid-β (Aβ) protofibrils are neurotoxic soluble intermediates in the Aβ aggregation process eventually forming senile plaques in Alzheimer’s disease. This Aβ species is a potential biomarker for Alzheimer’s disease and also a promising target for immunotherapy. In this study, we investigated the characteristics of conformation-dependent Aβ antibodies specific for Aβ protofibrils. <i>Methods:</i> Mice were immunized with Aβ protofibrils to generate hybridomas producing Aβ-specific monoclonal antibodies. Binding of antibodies to different Aβ conformations was investigated with inhibition ELISA. The antibodies’ complementarity-determining region (CDR) sequences were determined and compared. <i>Results:</i> A majority of the antibodies were of the IgM class, all selectively binding to aggregated Aβ. Two IgG antibodies were generated: one with selective affinity for Aβ protofibrils and the other bound Aβ in all conformations. A high degree of similarity between the heavy-chain CDRs of the conformation-dependent antibodies was found, and all high-affinity Aβ antibodies displayed a high degree of sequence similarity in the light-chain CDRs. <i>Conclusion:</i> Sequence similarity in the heavy-chain CDRs is associated with conformation selectivity of the antibodies, while sequence similarity in the light-chain CDRs correlates with the affinity for Aβ.