In:
Scientific Reports, Springer Science and Business Media LLC, Vol. 5, No. 1 ( 2015-04-16)
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
2045-2322
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2015
detail.hit.zdb_id:
2615211-3
