Widespread brain distribution and activity following i.c.v. infusion of anti-β-secretase (BACE1) in nonhuman primates
| Autor: | Karen Hayes, Reina N. Fuji, Lisa L. Shafer, Saileta Prabhu, William J. Meilandt, Keith R. Hildebrand, Ryan J. Watts, Thomas Keene, Jessica Couch, Blair Wilson, Jasvinder K. Atwal, Janice A. Maloney, Ann L. Daugherty, Kapil Gadkar, Kimberly Scearce-Levie, Kristin R. Wildsmith, Yanmei Lu, Andrew Kosky, Marisa Goo, Robert C. Switzer, Kun Peng, Eric Adams, Deepak R. Thakker, Pamela Chan, Deanna S. Lane, Lisa Jungbauer Nikolas, Hilda Solanoy, Daniela Bumbaca Yadav |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Pharmacology biology Continuous infusion medicine.drug_class business.industry Inhibitory postsynaptic potential Monoclonal antibody 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Pharmacokinetics mental disorders Parenchyma Immunology biology.protein medicine Antibody business Amyloid precursor protein secretase I²C 030217 neurology & neurosurgery |
| Zdroj: | British Journal of Pharmacology. 174:4173-4185 |
| ISSN: | 0007-1188 |
| DOI: | 10.1111/bph.14021 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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