Widespread brain distribution and activity following i.c.v. infusion of anti‐β‐secretase (BACE1) in nonhuman primates
Open accessAbstract
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.
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mAbs exhibit limited distribution to the brain, with mAb concentrations determined to be 0.1-0.2% and 0.02% of the steady-state circulating mAb concentration in rodents and cynomolgus monkey, respectively.
“mAbs exhibit limited distribution to the brain, and mAb concentrations was determined to be 0.1–0.2 % and 0.02 % of the steady‐state circulating mAb concentration in rodents and cynomolgus monkey, respectively.92, 93”
From Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development (2018) · cites this paper as [93]
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- Authors
- Yadav, D. B., Maloney, J. A., Wildsmith, K. R., Fuji, R. N., Meilandt, W. J., Solanoy, H., Lu, Y., Peng, K., Wilson, B., Chan, P., Gadkar, K., Kosky, A., Goo, M., Daugherty, A., Couch, J. A., Keene, T., Hayes, K., Nikolas, L. J., Lane, D., Switzer, R., Adams, E., Watts, R. J., Scearce‐Levie, K., Prabhu, S., Shafer, L., Thakker, D. R., Hildebrand, K., & Atwal, J. K.
- Affiliations
- Genentech (US)
- Medtronic (United States) (US)
- Medtronic, Inc. Minneapolis MN USA
- NeuroScience Associates Knoxville TN USA
- Northern Biomedical Research Norton Shores MI USA
- Department of Neuroscience Genentech, Inc. South San Francisco CA USA
- Corresponding author
- Hildebrand, Keith
- Atwal, Jasvinder K
- ORCID
- Venue
- British Journal of Pharmacology
- Publisher
- Wiley
- Published
- 2017-10-06
- Volume
- 174
- Issue
- 22
- Pages
- 4173-4185
- ISSN
- 0007-1188 (ISSN-L)
- 1476-5381
- PMC
- PMC5659992
- OpenAlex
- W2753001377
- Cited by
- 49
- References
- 43
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 5 · 2023: 4 · 2022: 13 · 2021: 8 · 2020: 3 · 2019: 4 · 2018: 4
- FWCI
- 2.22
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- British Journal of Pharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Genentech Foundation
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
- Keywords
- intracerebroventricular infusion, blood-brain barrier penetration, cerebrospinal fluid amyloid-beta, pharmacokinetics, pharmacodynamics, target engagement, Macaca fascicularis, Alzheimer's disease
- MeSH terms
- Animals, Antibodies, Monoclonal, Brain, Female, Macaca fascicularis, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Amyloid Precursor Protein Secretases, Infusions, Intraventricular
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