Relationship between therapeutic activity and preferential targeting of toxic soluble aggregates by amyloid-beta-directed antibodies

BackgroundAmyloid-beta (A{beta})-directed antibodies tested clinically for therapeutic activity against Alzheimers disease (AD) have shown varying degrees of efficacy. Although all of these antibodies target the A{beta} peptide, their binding profile to different molecular species of A{beta} differs and may underlie the observed variability in clinical outcomes. ObjectiveExplore the relationship between targeting of soluble toxic A{beta} species and therapeutic efficacy. MethodsSurface plasmon resonance (SPR) was used to conduct a side-by-side comparison of the binding of various A{beta}-directed antibodies to monomers and soluble A{beta} oligomers from AD brains. Immunohistochemistry was performed to assess reactivity with plaque. Preclinical activity was assessed in human amyloid precursor protein (APP) transgenic mouse models of AD. ResultsNon-selective, pan-A{beta} reactive antibodies such as crenezumab and gantenerumab, which have failed to produce a clinical benefit, bound all forms of A{beta} tested. In a competition assay, these antibodies lost the ability to bind toxic AD brain oligomers when exposed to monomers. Aggregate-selective antibodies such as aducanumab, lecanemab and donanemab, showed reduced monomer binding and a greater ability to withstand monomer competition which correlated with their reported inhibition of cognitive decline. Of the antibodies in earlier stages of clinical testing, ACU193 and PMN310 displayed the greatest ability to retain binding to toxic AD brain oligomers while PRX h2731 was highly susceptible to monomer competition. Plaque binding was observed with all aggregate-reactive antibodies with the exception of PMN310, which was strictly selective for soluble oligomers. Targeting of oligomers by PMN310 protected cognition and was not associated with microhemorrhages in mouse models of AD. ConclusionsOverall, these results suggest that selectivity for soluble toxic A{beta} oligomers may be a driver of clinical efficacy, with a potentially reduced risk of ARIA if engagement with plaque is minimized.