Kinetic fingerprint of antibody therapies predicts outcomes of Alzheimer clinical trials

Alzheimer9s disease affects nearly 50 million people worldwide with an overall cost of over 1% of the global economy. The amyloid cascade hypothesis, according to which the misfolding and aggregation of the amyloid-β peptide (Aβ) triggers a series of pathological processes that eventually result in massive brain tissue loss, has driven many therapeutic efforts for the past 20 years. Repeated failures, however, have highlighted the challenges of characterizing the molecular mechanisms of therapeutic candidates targeting Aβ, and connecting them to the outcomes of clinical trials. Here, we determine the mechanism of action of four clinical stage antibodies (aducanumab, gantenerumab, bapineuzumab and solanezumab). We quantify the dramatic differences that these antibodies have on the aggregation kinetics and on the production of oligomeric aggregates, and link these effects to the affinity and stoichiometry of each antibody for the monomeric and fibrillar forms of Aβ. We show that the binding parameters of each antibody correlate with the corresponding level of amyloid clearance in clinical trials and that the reduction in oligomer flux correlates with the cognitive improvement. We reveal that, uniquely amongst these four antibodies, aducanumab dramatically reduces the flux of oligomeric forms of Aβ. These results demonstrate the power of quantitative molecular analysis in predicting the outcomes of clinical trials.