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Investigating brain uptake of a non-targeting monoclonal antibody after intravenous and intracerebroventricular administration.

Authors :
Van De Vyver AJ
Walz AC
Heins MS
Abdolzade-Bavil A
Kraft TE
Waldhauer I
Otteneder MB
Source :
Frontiers in pharmacology [Front Pharmacol] 2022 Aug 29; Vol. 13, pp. 958543. Date of Electronic Publication: 2022 Aug 29 (Print Publication: 2022).
Publication Year :
2022

Abstract

Monoclonal antibodies play an important role in the treatment of various diseases. However, the development of these drugs against neurological disorders where the drug target is located in the brain is challenging and requires a good understanding of the local drug concentration in the brain. In this original research, we investigated the systemic and local pharmacokinetics in the brain of healthy rats after either intravenous (IV) or intracerebroventricular (ICV) administration of EGFRvIII-T-Cell bispecific (TCB), a bispecific monoclonal antibody. We established an experimental protocol that allows serial sampling in serum, cerebrospinal fluid (CSF) and interstitial fluid (ISF) of the prefrontal cortex in freely moving rats. For detection of drug concentration in ISF, a push-pull microdialysis technique with large pore membranes was applied. Brain uptake into CSF and ISF was characterized and quantified with a reduced brain physiologically-based pharmacokinetic model. The model allowed us to interpret the pharmacokinetic processes of brain uptake after different routes of administration. The proposed model capturing the pharmacokinetics in serum, CSF and ISF of the prefrontal cortex suggests a barrier function between the CSF and ISF that impedes free antibody transfer. This finding suggests that ICV administration may not be better suited to reach higher local drug exposure as compared to IV administration. The model enabled us to quantify the relative contribution of the blood-brain barrier (BBB) and Blood-CSF-Barrier to the uptake into the interstitial fluid of the brain. In addition, we compared the brain uptake of three monoclonal antibodies after IV dosing. In summary, the presented approach can be applied to profile compounds based on their relative uptake in the brain and provides quantitative insights into which pathways are contributing to the net exposure in the brain.<br />Competing Interests: AV, IW, MO, and A-CW were employed by F. Hoffmann-La Roche Ltd. TK and AA-B were employed by Roche Diagnostics GmbH at the time of submission of this manuscript. A-CW, IW, MO, TK, and AA-B are stockholders of F. Hoffmann-La Roche Ltd. MH was employed by and is stockholder of Charles River Laboratories at the time of submission of this manuscript.<br /> (Copyright © 2022 Van De Vyver, Walz, Heins, Abdolzade-Bavil, Kraft, Waldhauer and Otteneder.)

Details

Language :
English
ISSN :
1663-9812
Volume :
13
Database :
MEDLINE
Journal :
Frontiers in pharmacology
Publication Type :
Academic Journal
Accession number :
36105215
Full Text :
https://doi.org/10.3389/fphar.2022.958543