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- W2536824832 abstract "Previously, we have identified structural determinants on disease modified protein tau that have essential regulatory function for formation of neurofibrillary pathology in Alzheimer's disease (AD). The identified tau determinants, which are recognized by monoclonal antibody DC8E8, served as a lead for the design of an active vaccine AADvac1 that entered the Phase II clinical trial on human AD patients. In the present study we address the questions about the sequence and structure requirements of DC8E8-based immunotherapy. The kinetics of DC8E8 interaction with tau were studied by surface plasmon resonance (SPR), conformation of tau epitope and DC8E8 combining site was revealed by X-ray crystallography, and observed tau binding mode was verified by alanine mutagenesis of DC8E8 paratope residues. Monoclonal antibody DC8E8 is unique among the anti-tau antibodies as it interacts with three, respectively four homologous epitopes on a single tau molecule. SPR affinity studies uncovered finely tuned specificity of DC8E8 to individual components of its quadruple epitope on the tau molecule. Further, we solved several X-ray structures of the DC8E8 Fab fragment and its complex with a panel of tau peptides up to 1.69 Å resolution. Antibody recognition is mediated by a unique paratope binding pocket embracing the conserved sequence motif HXPGGG on the tau molecule, which adopts a tight type I beta-turn. The binding mode of DC8E8 effectively blocks the beta-structure forming hexapeptides adjacent to the epitope, which explains the potent DC8E8 inhibitory effect on tau aggregation. Finally, alanine scanning mutagenesis experimentally confirmed the importance of specific DC8E8 paratope residues that are indispensable for binding therapeutic tau epitopes. Present results of structural and functional analysis shed light on the mechanism of action of active and passive immunotherapy based on the monoclonal antibody DC8E8 and its therapeutic tau epitope encompassed in the tau vaccine AADvac1. These findings further substantiate the potency of active and passive vaccine to protect the brain from tau neurodegeneration." @default.
- W2536824832 created "2016-10-28" @default.
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- W2536824832 date "2016-07-01" @default.
- W2536824832 modified "2023-09-27" @default.
- W2536824832 title "O4-04-06: The First Tau Vaccine for Therapy of Alzheimer's Disease and FTLD: From Tau Structure to Human Clinical Trials" @default.
- W2536824832 doi "https://doi.org/10.1016/j.jalz.2016.06.629" @default.
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