Gantenerumab: a novel human anti-Abeta antibody demonstrates sustained cerebral amyloid-beta binding and elicits cell-mediated removal of human amyloid-beta.
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Bohrmann B, Baumann K, Benz J, Gerber F, Huber W, Knoflach F, Messer J, Oroszlan K, Rauchenberger R, Richter WF, Rothe C, Urban M, Bardroff M, Winter M, Nordstedt C, Loetscher H
Gantenerumab: a novel human anti-Abeta antibody demonstrates sustained cerebral amyloid-beta binding and elicits cell-mediated removal of human amyloid-beta.
J Alzheimers Dis. 2012;28(1):49-69. doi: 10.3233/JAD-2011-110977.
- PubMed ID
- 21955818 [ View in PubMed]
- Abstract
The amyloid-beta lowering capacity of anti-Abeta antibodies has been demonstrated in transgenic models of Alzheimer's disease (AD) and in AD patients. While the mechanism of immunotherapeutic amyloid-beta removal is controversial, antibody-mediated sequestration of peripheral Abeta versus microglial phagocytic activity and disassembly of cerebral amyloid (or a combination thereof) has been proposed. For successful Abeta immunotherapy, we hypothesized that high affinity antibody binding to amyloid-beta 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-Abeta antibody, gantenerumab, optimized in vitro for binding with sub-nanomolar affinity to a conformational epitope expressed on amyloid-beta fibrils using HuCAL((R)) phage display technologies. In peptide maps, both N-terminal and central portions of Abeta were recognized by gantenerumab. Remarkably, a novel orientation of N-terminal Abeta bound to the complementarity determining regions was identified by x-ray analysis of a gantenerumab Fab-Abeta(1-11) complex. In functional assays gantenerumab induced cellular phagocytosis of human amyloid-beta deposits in AD brain slices when co-cultured with primary human macrophages and neutralized oligomeric Abeta42-mediated inhibitory effects on long-term potentiation in rat brain. In APP751(swedish)xPS2(N141I) transgenic mice, gantenerumab showed sustained binding to cerebral amyloid-beta and, upon chronic treatment, significantly reduced small amyloid-beta plaques by recruiting microglia and prevented new plaque formation. Unlike other Abeta antibodies, gantenerumab did not alter plasma Abeta suggesting undisturbed systemic clearance of soluble Abeta. These studies demonstrated that gantenerumab preferentially interacts with aggregated Abeta in the brain and lowers amyloid-beta by eliciting effector cell-mediated clearance.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Gantenerumab Amyloid beta A4 protein Protein Humans YesAntagonistBinderAntibodyDetails