On 28 September, Dr Sara Linse, Prof Oskar Hansson and colleagues published an article in Nature Structural & Molecular Biology, analyzing the mechanism of action of four anti-amyloid antibodies that have been evaluated in clinical trials: aducanumab, gantenerumab, bapineuzumab and solanezumab. Based on the results of their laboratory analyses, each of these antibodies interferes with different aspects of the amyloid process.
Amyloid plaque formation is a neuropathological feature of Alzheimer’s disease (AD), caused by the accumulation and aggregation of amyloid beta proteins in the brain. As part of this process, amyloid-beta proteins build up in a highly toxic oligomeric form, damaging brain cells and instigating other forms of neuropathology. The last two decades have seen the development of several anti-amyloid antibodies for clinical trials, designed to target amyloid aggregates for removal by the immune system. Of the four antibodies listed above, aducanumab has advanced the furthest in development, and is currently under evaluation at the US Food and Drug Administration – while clinical trials for bapineuzumab have been discontinued.
To understand the differing clinical findings for these four antibodies, and to fully decipher their mechanisms of action, Dr Linse and colleagues performed kinetic analyses and quantitative binding measurements, assessing how each antibody interferes with the different stages of the amyloid accumulation process. Their results confirm that each antibody binds a different part of the amyloid protein, and has a differential affinity for monomeric and fibrillar (plaque) forms of amyloid-beta. Due to these differing affinities, the antibodies each interfere with different stages of the amyloid aggregation process, with varying efficacy. Among the four antibodies, aducanumab was identified as a highly effective inhibitor of the key molecular process that leads to amyloid oligomer formation.
