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Publication Abstract from PubMed

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

Molecular basis for mid-region amyloid-beta capture by leading Alzheimer's disease immunotherapies.,Crespi GA, Hermans SJ, Parker MW, Miles LA Sci Rep. 2015 Apr 16;5:9649. doi: 10.1038/srep09649. PMID:25880481^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.