Sustained levels of antibodies against Aβ in amyloid-rich regions of the CNS following intravenous dosing in human APP transgenic mice

Passive immunization with anti-A beta antibodies leads to the reduction of AD-like neuropathology in transgenic mice. Previously we showed that anti-A[3 antibodies enter the brain and bind to amyloid plaques. Now using I-125-labeled 3D6, the mouse parent antibody of the clinical candidate bapineuzumab, we further characterized the pharmacokinetic profile of this antibody in the brain and serum. Our studies demonstrated that following a single intravenous injection, the labeled antibody accumulates and persists in plaque rich regions of the brain in transgenic PDAPP mice. Accumulation was specific to amyloid since it did not occur in non-transgenic animals lacking human APP, could not be measured in transgenic animals prior to plaque deposition, and correlated with the level of plaque burden in aging transgenic mice. After a single intravenous injection, CNS levels of I-125-labeled 3D6 continued to increase for 14 days even as serum levels of the antibody declined. The calculated half-life of antibody in the circulation was 6 days, while antibody levels in the CNS remained stable for nearly a month. When given at supra-therapeutic levels, unlabeled antibody did not compete with tracer levels of labeled antibody for accumulation in the CNS, indicating that the binding capacity of plaques was very high. Our results demonstrate that even when administered in the periphery at very low (tracer) doses, 3D6 and bapineuzumab cross the blood brain barrier to accumulate in plaque rich regions of the brain. CNS clearance is markedly slower than in the serum and correlates with binding to deposited amyloid in a transgenic model of Alzheimer's disease. (c) 2012 Elsevier Inc. All rights reserved.