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 Å2 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.
Highlights
Solanezumab (Eli Lilly) and crenezumab (Genentech) are the leading clinical antibodies targeting Amyloid-b (Ab) to be tested in multiple Phase III clinical trials for the prevention of Alzheimer’s disease in at-risk individuals
Solanezumab (Eli Lilly) and crenezumab (Genentech) are humanised monoclonal antibodies targeting the mid-region of the neurotoxic Ab peptide[3,4], an early biomarker of Alzheimer’s disease pathology and the major component of plaques found in AD-affected brain
We have previously reported the picomolar affinity of solanezumab for soluble monomeric Ab and wanted to understand the structure of Ab recognised by solanezumab and how it engages that structure[13]
Summary
Solanezumab (Eli Lilly) and crenezumab (Genentech) are the leading clinical antibodies targeting Amyloid-b (Ab) to be tested in multiple Phase III clinical trials for the prevention of Alzheimer’s disease in at-risk individuals. Ab capture by these clinical antibodies is explained here with the first reported mid-region Ab-anti-Ab complex crystal structure. Results of large scale phase three clinical trials of solanezumab, and another clinical anti-Ab antibody called bapineuzumab (Pfizer, Johnson & Johnson) in patients with mild to moderate Alzheimer’s disease were reported in 2014 Both studies concluded that treatment did not improve clinical outcomes in AD patients. To that end we crystallised a recombinant solanezumab Fab fragment complexed to the mid-region of the Ab peptide and determined its structure to a resolution of 2.4 A
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