Epitopes described in "Gantenerumab: a novel human anti-Aβ antibody demonstrates sustained cerebral amyloid-β binding and elicits cell-mediated removal of human amyloid-β."

Article Authors:Bernd Bohrmann; Karlheinz Baumann; Jörg Benz; Francoise Gerber; Walter Huber; Frédéric Knoflach; Jürg Messer; Krisztina Oroszlan; Robert Rauchenberger; Wolfgang F Richter; Christine Rothe; Margit Urban; Michael Bardroff; Michael Winter; Christer Nordstedt; Hansruedi Loetscher
Article Title:Gantenerumab: a novel human anti-Aβ antibody demonstrates sustained cerebral amyloid-β binding and elicits cell-mediated removal of human amyloid-β.
Reference Detail
Reference ID:1022723
Abstract:The amyloid- lowering capacity of anti-A antibodies has been demonstrated in transgenic models of Alzheimer's disease (AD) and in AD patients. While the mechanism of immunotherapeutic amyloid- removal is controversial, antibody-mediated sequestration of peripheral A versus microglial phagocytic activity and disassembly of cerebral amyloid (or a combination thereof) has been proposed. For successful A immunotherapy, we hypothesized that high affinity antibody binding to amyloid- plaques and recruitment of brain effector cells is required for most efficient amyloid clearance. Here we report the generation of a novel fully human anti-A antibody, gantenerumab, optimized in vitro for binding with sub-nanomolar affinity to a conformational epitope expressed on amyloid- fibrils using HuCAL(®) phage display technologies. In peptide maps, both N-terminal and central portions of A were recognized by gantenerumab. Remarkably, a novel orientation of N-terminal A bound to the complementarity determining regions was identified by x-ray analysis of a gantenerumab Fab-A(1-11) complex. In functional assays gantenerumab induced cellular phagocytosis of human amyloid- deposits in AD brain slices when co-cultured with primary human macrophages and neutralized oligomeric A42-mediated inhibitory effects on long-term potentiation in rat brain. In APP751(swedish)xPS2(N141I) transgenic mice, gantenerumab showed sustained binding to cerebral amyloid- and, upon chronic treatment, significantly reduced small amyloid- plaques by recruiting microglia and prevented new plaque formation. Unlike other A antibodies, gantenerumab did not alter plasma A suggesting undisturbed systemic clearance of soluble A. These studies demonstrated that gantenerumab preferentially interacts with aggregated A in the brain and lowers amyloid- by eliciting effector cell-mediated clearance.
Affiliations:F. Hoffmann-La Roche Ltd., pRED, Basel, Switzerland. bernd.bohrmann@roche.com
Reference Type:Literature
PubMed ID:21955818
Journal:J Alzheimers Dis
Journal Volume:28
Article Pages:49-69
Journal ISSN:1387-2877
Article Chemical List:Amyloid beta-Peptides;Antibodies, Monoclonal;Antibodies, Monoclonal, Humanized;gantenerumab
Article MeSH List:Amino Acid Sequence; Amyloid beta-Peptides(antagonists & inhibitors; metabolism); Animals; Antibodies, Monoclonal(metabolism; pharmacology); Antibodies, Monoclonal, Humanized(metabolism); CHO Cells; Cerebral Cortex(cytology; drug effects; metabolism); Cricetinae; Cricetulus; Crystallography, X-Ray; Excitatory Postsynaptic Potentials(drug effects); Female; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular Sequence Data; Phagocytosis(drug effects); Protein Binding; Protein Structure, Tertiary; Rats; Rats, Sprague-Dawley
Curation Last Updated:2015-09-04 20:01:14