RT Journal Article
SR Electronic
T1 Kinetic fingerprint of antibody therapies predicts outcomes of Alzheimer clinical trials
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 815308
DO 10.1101/815308
A1 Sara Linse
A1 Tom Scheidt
A1 Katja Bernfur
A1 Michele Vendruscolo
A1 Christopher M. Dobson
A1 Samuel I. A. Cohen
A1 Eimantas Sileikis
A1 Martin Lundquist
A1 Fang Qian
A1 Tiernan O’Malley
A1 Thierry Bussiere
A1 Paul H. Weinreb
A1 Catherine K. Xu
A1 Georg Meisl
A1 Sean Devenish
A1 Tuomas P. J. Knowles
A1 Oskar Hansson
YR 2019
UL http://biorxiv.org/content/early/2019/10/22/815308.abstract
AB Alzheimer’s 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 (1,2), 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 (3–7). 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 (3) 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.