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Br J Pharmacol. 2017 Nov;174(22):4173-4185. doi: 10.1111/bph.14021. Epub 2017 Oct 6.

Widespread brain distribution and activity following i.c.v. infusion of anti-β-secretase (BACE1) in nonhuman primates.

Author information

1
Department of Development Sciences, Genentech, Inc., South San Francisco, CA, USA.
2
Department of Neuroscience, Genentech, Inc., South San Francisco, CA, USA.
3
Department of Biochemical and Cellular Pharmacology, Genentech, Inc., South San Francisco, CA, USA.
4
Department of Pharmaceutical Technical Development, Genentech, Inc., South San Francisco, CA, USA.
5
Medtronic, Inc., Minneapolis, MN, USA.
6
NeuroScience Associates, Knoxville, TN, USA.
7
Northern Biomedical Research, Norton Shores, MI, USA.

Abstract

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 β-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 (~70%) of CSF amyloid-β (Aβ) peptides. Antibody distribution was near uniform across the brain parenchyma, ranging from 20 to 40 nM, resulting in a ~50% reduction of Aβ in the cortical parenchyma. In contrast, animals administered anti-BACE1 i.v. showed no significant change in CSF or cortical Aβ levels and had a low (~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 Aβ concentrations, due to enhanced brain exposure to antibody.

PMID:
28859225
PMCID:
PMC5659992
DOI:
10.1111/bph.14021
[Indexed for MEDLINE]
Free PMC Article

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