Crystal structure reveals conservation of amyloid-β conformation recognized by 3D6 following humanization to bapineuzumab

• DOI: 10.1186/alzrt261
• Publication Date: 2014-06-02T12:34:44Z
• Authors: Hadar Feinberg; José W Saldanha; Linnea Diep; Amita Goel; Angela Widom; Geertruida M Veldman; William I Weis; Dale Schenk; Guriqbal S Basi
• Keywords: Conformational epitope; Humanized antibody; Epitope mapping

Immunotherapy targeting amyloid-β peptide is under active clinical investigation for treatment of Alzheimer's disease (AD). Among the hypotheses being investigated impact on outcome are preferred epitope or conformation to target treatment, and mechanism action underlying immunotherapy. Bapineuzumab (humanized 3D6), a neo-epitope specific antibody recognizing amyloid-β1-5 with strong preference an exposed Asp residue at N-terminus peptide, has undergone advanced testing AD.To gain further insight into conformation, we interrogated structural details amino-terminal epitopes in using x-ray crystallography 3D6Fab:amyloid-β complexes. Humanization 3D6 was carried out standard procedures integrating recombinant methods, sequence informatics, homology modeling predictions identify important mouse framework residues retention finished humanized product.Here report crystal structure Fab fragment complex amyloid-β1-7 solved 2.0 Å resolution. The bound as 310 helix. buried deepest binding pocket, Cβ atom 6 visible entrance pocket near surface antibody. We evaluate model based used guide humanization bapineuzumab, actual Fab. Fab:amyloid-β validates design antibody, confirms recognized by previously mapped ELISA.The antigen novel distinct from other antibodies N-terminal epitopes. Our result provides first demonstrating conservation contact residues, recognized, between parent murine its version.