Molecular basis for mid-region amyloid-β capture by leading Alzheimer's disease immunotherapies

Sci Rep. 2015 Apr 16:5:9649. doi: 10.1038/srep09649.


Solanezumab (Eli Lilly) and crenezumab (Genentech) are the leading clinical antibodies targeting Amyloid-β (Aβ) to be tested in multiple Phase III clinical trials for the prevention of Alzheimer's disease in at-risk individuals. Aβ capture by these clinical antibodies is explained here with the first reported mid-region Aβ-anti-Aβ complex crystal structure. Solanezumab accommodates a large Aβ epitope (960 Å(2) buried interface over residues 16 to 26) that forms extensive contacts and hydrogen bonds to the antibody, largely via main-chain Aβ atoms and a deeply buried Phe19-Phe20 dipeptide core. The conformation of Aβ captured is an intermediate between observed sheet and helical forms with intramolecular hydrogen bonds stabilising residues 20-26 in a helical conformation. Remarkably, Aβ-binding residues are almost perfectly conserved in crenezumab. The structure explains the observed shared cross reactivity of solanezumab and crenezumab with proteins abundant in plasma that exhibit this Phe-Phe dipeptide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / therapy*
  • Amyloid beta-Peptides / chemistry
  • Amyloid beta-Peptides / immunology*
  • Amyloid beta-Peptides / metabolism
  • Antibodies, Monoclonal / chemistry
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / therapeutic use*
  • Antibodies, Monoclonal, Humanized / chemistry
  • Antibodies, Monoclonal, Humanized / immunology
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Binding Sites
  • Crystallography, X-Ray
  • Dipeptides / blood
  • Dipeptides / immunology
  • Humans
  • Hydrogen Bonding
  • Immunotherapy
  • Molecular Dynamics Simulation
  • Protein Structure, Tertiary


  • Amyloid beta-Peptides
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Dipeptides
  • solanezumab
  • crenezumab

Associated data

  • PDB/4XXD