title: Gantenerumab: a novel human anti-Aβ antibody demonstrates sustained cerebral amyloid-β binding and elicits cell-mediated removal of human amyloid-β.
abstract: The amyloid-β lowering capacity of anti-Aβ antibodies has been demonstrated in transgenic models of Alzheimer's disease (AD) and in AD patients. While the mechanism of immunotherapeutic amyloid-β removal is controversial, antibody-mediated sequestration of peripheral Aβ versus microglial phagocytic activity and disassembly of cerebral amyloid (or a combination thereof) has been proposed. For successful Aβ immunotherapy, we hypothesized that high affinity antibody binding to amyloid-β 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-Aβ antibody, gantenerumab, optimized in vitro for binding with sub-nanomolar affinity to a conformational epitope expressed on amyloid-β fibrils using HuCAL(®) phage display technologies. In peptide maps, both N-terminal and central portions of Aβ were recognized by gantenerumab. Remarkably, a novel orientation of N-terminal Aβ bound to the complementarity determining regions was identified by x-ray analysis of a gantenerumab Fab-Aβ(1-11) complex. In functional assays gantenerumab induced cellular phagocytosis of human amyloid-β deposits in AD brain slices when co-cultured with primary human macrophages and neutralized oligomeric Aβ42-mediated inhibitory effects on long-term potentiation in rat brain. In APP751(swedish)xPS2(N141I) transgenic mice, gantenerumab showed sustained binding to cerebral amyloid-β and, upon chronic treatment, significantly reduced small amyloid-β plaques by recruiting microglia and prevented new plaque formation. Unlike other Aβ antibodies, gantenerumab did not alter plasma Aβ suggesting undisturbed systemic clearance of soluble Aβ. These studies demonstrated that gantenerumab preferentially interacts with aggregated Aβ in the brain and lowers amyloid-β by eliciting effector cell-mediated clearance.
authors.affiliation: F. Hoffmann-La Roche Ltd., pRED, Basel, Switzerland. bernd.bohrmann@roche.com
authors.forename: Bernd
authors.initials: B
authors.lastname: Bohrmann
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Baumann
authors.forename: Jörg
authors.initials: J
authors.lastname: Benz
authors.forename: Francoise
authors.initials: F
authors.lastname: Gerber
authors.forename: Walter
authors.initials: W
authors.lastname: Huber
authors.forename: Frédéric
authors.initials: F
authors.lastname: Knoflach
authors.forename: Jürg
authors.initials: J
authors.lastname: Messer
authors.forename: Krisztina
authors.initials: K
authors.lastname: Oroszlan
authors.forename: Robert
authors.initials: R
authors.lastname: Rauchenberger
authors.forename: Wolfgang F
authors.initials: WF
authors.lastname: Richter
authors.forename: Christine
authors.initials: C
authors.lastname: Rothe
authors.forename: Margit
authors.initials: M
authors.lastname: Urban
authors.forename: Michael
authors.initials: M
authors.lastname: Bardroff
authors.forename: Michael
authors.initials: M
authors.lastname: Winter
authors.forename: Christer
authors.initials: C
authors.lastname: Nordstedt
authors.forename: Hansruedi
authors.initials: H
authors.lastname: Loetscher
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism* / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000378:metabolism*; D016466:CHO Cells; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010587:Phagocytosis / Q000187:drug effects; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C571128:gantenerumab