Gantenerumab: A Novel Human Anti-Aβ Antibody Demonstrates Sustained Cerebral Amyloid-β Binding and Elicits Cell-Mediated Removal of Human Amyloid-β

The amyloid-beta lowering capacity of anti-A beta 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 A beta versus microglial phagocytic activity and disassembly of cerebral amyloid (or a combination thereof) has been proposed. For successful A beta 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-A beta 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 A beta were recognized by gantenerumab. Remarkably, a novel orientation of N-terminal A beta bound to the complementarity determining regions was identified by x-ray analysis of a gantenerumab Fab-A beta(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 A beta(42)-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 A beta antibodies, gantenerumab did not alter plasma A beta suggesting undisturbed systemic clearance of soluble A beta. These studies demonstrated that gantenerumab preferentially interacts with aggregated A beta in the brain and lowers amyloid-beta by eliciting effector cell-mediated clearance.