Bibliographic
This study tests the hypothesis that antibody specificity for deposited beta amyloid plaque is critical for plaque removal since soluble Abeta peptide would block recognition of deposited forms. In order to test this hypothesis, the authors developed and engineered high affinity murine monoclonal antibodies that selectively target deposited plaque in an AD brain. Mouse Mabs were generated that were specific for Abetap3-x with either minimal (mE8-IgG1) or maximal (mE8-IgG2a) effector function. These antibodies robustly labeled deposited plaque in both AD and PDAPP brain sections and led to a significant reduction of deposited Abeta in an ex vivo phagocytosis assay. Therapeutic plaque-lowering studies performed with the anti-Abp3-42 antibodies in extremely aged PDAPP mice (23 to 26 months of age) demonstrated that mE8 on either maximal or minimal effector function significantly lowered deposited Abeta, whereas mice treated with the N-terminal antibody 3D6 (mIgG2b), which binds both soluble and insoluble Abeta, lacked efficacy. The underlying mechanism of action responsible for these contrasting results was identified as a differential target engagement for the antibodies; the Abp3-42 antibodies crossed the blood-brain barrier and bound to the deposited Abeta, whereas the 3D6 antibody lacked plaque binding, a finding thought to be due to its saturation with soluble Abeta in the brain. Importantly, micro hemorrhage analyses demonstrated that the Abp3-42 antibodies did not increase this adverse event, whereas mice treated with 3D6 had extensive micro bleeds. These studies have profound implications for the development of therapeutic Abeta antibodies for Alzheimer’s disease.