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Background

Current evidence suggests that progressive neurodegeneration in Alzheimer's disease (AD) may be catalyzed by the prion-like propagation of soluble toxic amyloid-beta oligomers (AβO) rather than plaque burden. Binding of Aβ monomers and/or fibrils by therapeutic antibodies has been associated with suboptimal efficacy and adverse events (eg ARIA-E) in clinical trials. These observations suggest that antibodies capable of specifically or selectively neutralizing toxic AβO are needed to achieve improved efficacy and safety.

Methods

Computational algorithms were developed to identify epitope sequences and conformations likely to be exposed in toxic AβO but not on monomers or fibrils. The binding profile of monoclonal antibodies raised against predicted epitopes was assessed by surface plasmon resonance (SPR) analysis and immunohistochemistry (IHC). Inhibition of oligomer propagation was …