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

• Published in: British journal of pharmacology Vol. 174; no. 22; pp. 4173 - 4185
• Main Authors: Yadav, Daniela Bumbaca, Maloney, Janice A, Wildsmith, Kristin R, Fuji, Reina N, Meilandt, William J, Solanoy, Hilda, Lu, Yanmei, Peng, Kun, Wilson, Blair, Chan, Pamela, Gadkar, Kapil, Kosky, Andrew, Goo, Marisa, Daugherty, Ann, Couch, Jessica A, Keene, Thomas, Hayes, Karen, Nikolas, Lisa Jungbauer, Lane, Deanna, Switzer, Robert, Adams, Eric, Watts, Ryan J, Scearce‐Levie, Kimberly, Prabhu, Saileta, Shafer, Lisa, Thakker, Deepak R, Hildebrand, Keith, Atwal, Jasvinder K
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01.11.2017
• Subjects: Amyloid beta-Peptides - blood; Amyloid beta-Peptides - cerebrospinal fluid; Amyloid beta-Peptides - metabolism; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - immunology; Animals; Antibodies, Monoclonal - blood; Antibodies, Monoclonal - cerebrospinal fluid; Antibodies, Monoclonal - pharmacokinetics; Antibodies, Monoclonal - pharmacology; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - immunology; Brain - metabolism; Female; Infusions, Intraventricular; Macaca fascicularis; Research Paper; Research Papers
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.14021

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.