title: Molecular basis for mid-region amyloid-β capture by leading Alzheimer's disease immunotherapies.
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.
authors.affiliation: ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia.
authors.forename: Gabriela A N
authors.initials: GA
authors.lastname: Crespi
authors.affiliation: ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia.
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Hermans
authors.affiliation: 1] ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia [2] Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Parker
authors.affiliation: 1] ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia [2] Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Luke A
authors.initials: LA
authors.lastname: Miles
mesh_terms: D000544:Alzheimer Disease / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000097:blood / Q000276:immunology; D006801:Humans; D006860:Hydrogen Bonding; D007167:Immunotherapy; D056004:Molecular Dynamics Simulation; D017434:Protein Structure, Tertiary
chemical_list: D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D004151:Dipeptides; C550616:solanezumab; C573372:crenezumab