P1‐359: Widespread Brain Distribution and Robust Bace1 Inhibition Following Intracerebroventricular Infusion of Anti‐bace1 in Non‐human Primates
Year: 2014
Type: article
Abstract: Therapeutic antibodies hold promise for treating neurodegenerative diseases, including Alzheimer's disease. However, their utility is limited by poor penetration across the blood-brain barrier (BBB). Steady-state brain/plasma concentration ratio for antibodies delivered systemically is ∼1:1000. Intracerebroventricular (ICV) delivery provides potentially valuable administration route for bypassing the BBB, although, whether ICV delivery enables antibodies to penetrate the CSF-brain barrier to ultimately reach the brain parenchyma is poorly understood. To gain further insight on antibody distribution and efficacy following ICV delivery, we evaluated the pharmacokinetics and pharmacodynamics (amyloid beta concentrations) of anti-BACE1 antibody (Atwal et al., 2011), delivered systemically versus ICV. Human anti-BACE1 antibody (5.6 mg/day), control antibody (5.2 mg/day), or vehicle was delivered for 6 weeks unilaterally into the lateral ventricle of adult cynomolgus non-human primates, using Medtronic's SynchroMed II pump and a preclinical ICV catheter. Antibody stability in the infusion system was pre-established. A separate group of animals received 4 weekly IV injections of 50 mg/kg anti-BACE1. Samples were collected from serum/plasma and CSF throughout the study for analysis by ELISA. At study end, brain samples were harvested for analysis by immunohistochemistry and ELISA. Both ICV- and IV-delivered antibodies achieved high (μM) serum concentrations and reduced plasma Aβ by ∼50%. In the CSF, high (μM) antibody concentrations were detected only in ICV-infused animals. Accordingly, CSF Aβ levels revealed a robust and sustained reduction (80%) with ICV-infused anti-BACE1 antibody, but were unaltered with IV-delivered antibody. In brain parenchyma, we observed 20-40 nM of ICV-delivered antibody with near-uniform distribution across different regions, even in the contralateral hemisphere. Consistent with its pharmacokinetics, ICV-infused anti-BACE1 led to ∼50% Aβ reduction in brain parenchyma. In contrast, IV-delivered anti-BACE1 resulted in ∼0.6 nM average antibody concentration in brain, and had no effects on brain Aβ levels. Immunohistochemical staining for human IgG in the brain corroborated the ELISA findings. Further, a lack of staining for cynomolgus monkey IgG suggested that the BBB remained intact during ICV administration. Our data demonstrate widespread distribution of anti-BACE1 antibody, and robust Aβ reductions in both CSF and brain compartments, using device-mediated ICV delivery in a non-human primate model.
Source: Alzheimer s & Dementia
Authors: Daniela Bumbaca, Daniela Bumbaca, Kristin Wildsmith, Reina Fuji, Kimberly Scearce‐Levie, Janice Maloney, William Meilandt, Hilda Solanoy, Yanmei Lu, Kate Peng, Blair Wilson, Pamela Chan, Andrew Kosky, Marisa Goo, Ann Daugherty, Jessica Couch, Thomas Keene, Karen Hayes, Lisa Jungbauer Nikolas, Deanna Lane, Robert Switzer, Eric Adams, Ryan Watts, Saileta Prabhu, Lisa Shafer, Deepak Thakker, Jasvinder Atwal
Institutions: Genentech, Medtronic (United States)
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2082664066