Epitope prediction for oligomer‐selective antibodies in tau and Aβ

Abstract Background Previous studies of Alzheimer’s disease (AD) pathology point to cytotoxic tau as a cause of neuronal cell death, which is induced or exacerbated by soluble misfolded Aβ oligomers. Soluble misfolded species of both tau and Aβ are both observed to propagate cell‐to‐cell. A method for identifying antibodies to tau and Aβ that are conformationally‐selective to propagative misfolded oligomeric forms, and which also have low affinity to isolated monomers or, particularly for Aβ, low affinity to fibrils, is thus a highly desired goal that holds significant promise for AD therapy. Method We have developed a novel computational platform to identify epitopes that may be selectively exposed on oligomers. Epitope prediction ideally uses an experimentally determined fibril structure as input, but the method alters this structure using molecular dynamics, to more accurately model the regions that may be exposed on soluble oligomers. Both primary sequence and structural conformation are taken into account: The epitope should be conformationally‐distinct from those conformations presented in the functional healthy protein. Epitope scaffolding is then employed to optimize the presentation of the epitope in animal immunizations, so that the resulting antibodies are predicted to be selective to misfolded oligomeric forms. Result Oligomer‐specific epitope predictions for tau and for Aβ have been used to raise preclinical antibodies that have selectivity for pathogenic tau and Aβ species. In vitro SPR measurements confirmed selective binding to synthetic oligomers and soluble pre‐formed fibrils (PFFs), vs. native healthy protein. As well, the antibodies showed little immunoreactivity toplaque or vascularAβ deposits via immunohistochemistry, while SEC fractionation of AD brain homogenate shows selective binding to toxic dimers, tetramers and dodecamers, in contrast to aducanumab and bapineuzumab. Tau antibodies recognized tau from AD brain extract, and inhibited seeding activity in a FRET assay. Aβ antibodies alleviated the cognitive deficits caused by oligomers in mouse NOR studies. Conclusion Lead antibodies to tau and Aβ developed using rationally designed conformational epitopes are likely to achieve greater therapeutic potency by selectively targeting soluble toxic oligomers, and reducing the risk of target distraction and ARIA.

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