Elan Corp PLC (ELN)

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Unique brain PK properties of 3D6 and bapineuzumab depend on cerebral amyloid load in PDAPP transgenic mice
P4-406
Background: Passive immunization with anti-Aß antibodies leads to the reduction of AD-like neuropathology in transgenic mice. Previously we showed that anti Aß antibodies enter the brain and bind to amyloid plaques.

Methods: Now using 125I-labeled 3D6, the mouse form of the phase 3 clinical candidate bapineuzumab, we further characterized the specificity and the pharmacokinetics of this antibody in the brain and serum.

Results: The results of our studies demonstrate that 125I-labeled anti-Aß antibodies (3D6 and bapineuzumab) delivered intravenously accumulated over time in the brain. This accumulation was particularly evident in regions rich in amyloid plaques and was correlated with the overall level of plaque burden. The binding of 3D6 to brain amyloid plaques did not saturate at the doses tested since cold 3D6 dosed as high as 30 mg/kg did not compete with the binding of the 125I-labeled 3D6. Following one intravenous injection, serum levels of 125I-labeled 3D6 decreased exponentially over time while levels in the hippocampus increased to reach the maximal concentrations by day 14 (brain Tmax) and remained stable up to 27 days. Based on mean PK profile, the brain half-life (T1/2) of 3D6 was estimated to be 54 days whereas the serum T1/2 was 6 days.

Conclusions: In summary, we demonstrated that both 3D6 and bapineuzumab cross the blood brain barrier, that the CNS clearance is markedly slower than the serum clearance, and that this slower CNS clearance correlates with binding to amyloid in a transgenic model of Alzheimer’s disease.
Frederique Bard, Janssen Alzheimer Immunotherapy Research and Development
Gene Kinney, Janssen Alzheimer Immunotherapy R&D
Michael Fox, Elan Pharmaceuticals
Stuart Friedrich, Wyeth Biotech
Ted Yednock, Janssen Alzheimer Immunotherapy R&D

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