Kinetic fingerprints differentiate the mechanisms of action of anti-Aβ antibodies

Nat Struct Mol Biol. 2020 Dec;27(12):1125-1133. doi: 10.1038/s41594-020-0505-6. Epub 2020 Sep 28.

Abstract

The amyloid cascade hypothesis, according to which the self-assembly of amyloid-β peptide (Aβ) is a causative process in Alzheimer's disease, has driven many therapeutic efforts for the past 20 years. Failures of clinical trials investigating Aβ-targeted therapies have been interpreted as evidence against this hypothesis, irrespective of the characteristics and mechanisms of action of the therapeutic agents, which are highly challenging to assess. Here, we combine kinetic analyses with quantitative binding measurements to address the mechanism of action of four clinical stage anti-Aβ antibodies, aducanumab, gantenerumab, bapineuzumab and solanezumab. We quantify the influence of these antibodies on the aggregation kinetics and on the production of oligomeric aggregates and link these effects to the affinity and stoichiometry of each antibody for monomeric and fibrillar forms of Aβ. Our results reveal that, uniquely among these four antibodies, aducanumab dramatically reduces the flux of Aβ oligomers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy
  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Amyloid beta-Peptides / chemistry
  • Antibodies, Monoclonal, Humanized / chemistry
  • Antibodies, Monoclonal, Humanized / pharmacology*
  • Humans
  • Kinetics
  • Models, Biological
  • Models, Molecular
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • Peptide Fragments / antagonists & inhibitors*
  • Peptide Fragments / chemistry
  • Peptide Mapping / methods
  • Protein Aggregates / drug effects
  • Protein Conformation
  • Structure-Activity Relationship

Substances

  • Amyloid beta-Peptides
  • Antibodies, Monoclonal, Humanized
  • Neuroprotective Agents
  • Peptide Fragments
  • Protein Aggregates
  • amyloid beta-protein (1-42)
  • aducanumab
  • gantenerumab
  • solanezumab
  • bapineuzumab

Associated data

  • Dryad/10.5061/dryad.79cnp5hsn