P4‐006: The role of brain macrophages on the clearance of amyloid plaques following the treatment of Tc2576 with BIIB037

Effective passive immunotherapy of anti-beta amyloid antibodies with effector function might require antibody Fc domain-mediated brain macrophage activation with subsequent phagocytosis of Abeta. Herein we report that BIIB037, a murine chimeric antibody with Fc effector function, appears to require brain macrophage activation for amyloid plaque clearance. BIIB037, a murine chimeric IgG2a that recognizes a conformational epitope to human, fibrillar Abeta was administered intraperitoneally to Tg2576 mice and compared to PBS-treated controls. The area and morphology of vascular amyloid and parenchymal plaques and changes in brain macrophage area and distribution were assessed with immunohistochemistry. Defining Abeta in vessels and parenchymal plaques used the mouse anti-human Abeta monoclonal antibody 6E10. Brain macrophages were defined by a rabbit anti-macrophage polyclonal antibody to ionized calcium-binding adaptor molecule-1 (IBA-1). Samples were examined visually and quantified using Visiopharm software. Treatment with BIIB037 resulted in amyloid reduction. Amyloid plaques in treated animals were less abundant and smaller than in controls. In addition, the plaques were generally discrete,consisting of a circular dense core. Many of the plaques in untreated animals were “multicored” and surrounded by more diffuse amyloid material. In both treated and controls,brain macrophages adjacent to parenchymal plaques were more densely distributed and larger than those scattered randomly throughout the neuropil, suggesting Ab caused a state of macrophage activation regardless of treatment. However, brain macrophages in treated animals often encircled the plaques and were less dendritic. In neither treated nor controls was the number or size of macrophages increased around leptomeningeal vessels. Treatment with BIIB037 results in amyloid load reduction and the plaques present have a different morphology than controls: they are smaller and rounder, often consisting of dense cores of Abeta. These cores are often ringed by brain macrophages, a feature rarely noted in the brains from treated animals. This pattern suggests amyloid load reduction is associated with phagocytosis in BIIB037 treated animals. Finally, the paucity of activated macrophages around vessels suggest that BIIB037 does not affect vascular amyloid in leptomeningeal vessels.