Widespread brain distribution and activity following anti-BACE1 intracerebroventricular infusion in nonhuman primates.

BACKGROUND AND PURPOSE The potential for therapeutic antibody treatment of neurological diseases is limited by poor penetration across the blood-brain barrier. I.c.v. delivery is a promising route to the brain; however, it is unclear how efficiently antibodies delivered i.c.v. penetrate the cerebrospinal spinal fluid (CSF)-brain barrier and distribute throughout the brain parenchyma. EXPERIMENTAL APPROACH We evaluated the pharmacokinetics and pharmacodynamics of an inhibitory monoclonal antibody against beta-secretase 1 (anti-BACE1) following continuous infusion into the left lateral ventricle of healthy adult cynomolgus monkeys. KEY RESULTS Animals infused with anti-BACE1 i.c.v. showed a robust and sustained reduction (similar to 70%) of CSF amyloid-beta (A beta) peptides. Antibody distribution was near uniform across the brain parenchyma, ranging from 20 to 40 nM, resulting in a similar to 50% reduction of A beta in the cortical parenchyma. In contrast, animals administered anti-BACE1 i.v. showed no significant change in CSF or cortical A beta levels and had a low (similar to 0.6 nM) antibody concentration in the brain. CONCLUSION AND IMPLICATIONS I.c.v. administration of anti-BACE1 resulted in enhanced BACE1 target engagement and inhibition, with a corresponding dramatic reduction in CNS A beta concentrations, due to enhanced brain exposure to antibody.