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

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