Relationship between therapeutic activity and preferential targeting of toxic soluble aggregates by amyloid-beta-directed antibodies
Amyloid-beta (Abeta)-directed antibodies tested clinically for therapeutic activity against Alzheimer disease (AD) have shown varying degrees of efficacy. Although all of these antibodies target the Abeta peptide, their binding profile to different molecular species of Abeta (monomers, oligomers, fibrils) differs and may underly the observed variability in clinical outcomes. Surface plasmon resonance (SPR) was used to conduct a side-by-side comparison of the binding of various Abeta-directed antibodies to monomers and soluble low and high molecular weight Abeta oligomers from AD brains. Immunohistochemistry was performed to assess reactivity with Abeta fibrils in plaque. Non-selective, pan-Abeta reactive antibodies such as crenezumab and gantenerumab, which have failed to produce a clinical benefit, bound all forms of Abeta tested. In a competition assay aimed at replicating the in vivo abundance of monomers in the blood and the central nervous system (CNS), these antibodies lost the a