Anti-Aβ antibody m266 penetrates the blood-brain barrier but does not reduce the deposition of plaque in a mouse model of Alzheimer's disease

Accumulating evidence suggests that diffusible oligomers of Aβ (ADDLs) may be responsible for the dementia associated with Alzheimer's disease (AD). ADDLs bind to hippocampal and cortical neurons, impair neuronal function and induce deficits in cognition. One therapeutic approach for the treatment of AD is the development of antibodies that reduce Aβ in brain and thereby modulate ADDL levels. The monoclonal antibody m266 is known to bind monomers and dimers of Aβ in the periphery. Since some antibody may penetrate the blood-brain-barrier and modulate central Aβ levels, we evaluated m266 levels in the CSF and brain of hAPP over-expressing mice, its association with existing plaques and ability to attenuate the deposition of ADDLs into plaques. To assess antibody levels in brain, 12-month-old transgenic mice were administered 125I-labeled m266 (8mpk), the CSF and brain collected and processed for analysis. In addition, m266 was evaluated in a transgenic model of ADDL deposition. Recent studies have shown that ADDLs, when infused into the transgenic mouse brain, incorporate into growing plaques and seed new plaques. To investigate the ability of m266 to abate ADDL formation and deposition in brain, biotin-labeled ADDLs were infused into the hippocampus of mice to label existing plaques. The animals were then treated weekly, for 4 weeks with m266 or vehicle (8mpk; IV injection) and the deposition of endogenous ADDLs into plaques assessed with immunofluorescence. Two hours after IV infusion of 125I-labeled m266, ∼0.1% of the antibody was detected in the CSF and ∼0.18% in brain. Although m266 was present in the transgenic mouse brain, immunohistochemical studies revealed that the antibody was not associated with plaques; evidence that m266 was not directly acting to remove existing Aβ deposits. Evaluation of m266 in a model that determines the rate that ADDLs are added to existing plaques further demonstrated that the antibody did not attenuate the deposition of new material in the transgenic brain. These data suggest that m266 was not capable of abating the formation and deposition of ADDLs in the cortex and hippocampus of transgenic mice. Data from human clinical trials will assess the impact of m266 on cognition in patients with AD.