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

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

SUBMITTER: Crespi GA 

PROVIDER: S-EPMC4549621 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature