| 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-A1-11 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 APP751swedishxPS2N141I 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. |
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