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

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.

Exploring How Antibody Format Drives Clearance from the Brain

“…6 While the routes of administration in this report and our current study differ, it has been proposed that the transfer of antibodies from CSF to the interstitial fluid (ISF) of the brain, following ICV delivery, predominantly occurs after antibody transit back to serum. 42 Subsequently, they traversed the BBB to access the ISF.…”

“…They observed a bell-shaped relationship between antibody size and brain exposure following IV delivery, with a 50 kDa Fab exhibiting the highest whole brain exposure among the analyzed antibodies . While the routes of administration in this report and our current study differ, it has been proposed that the transfer of antibodies from CSF to the interstitial fluid (ISF) of the brain, following ICV delivery, predominantly occurs after antibody transit back to serum . Subsequently, they traversed the BBB to access the ISF.…”

Receptor-mediated drug delivery of bispecific therapeutic antibodies through the blood-brain barrier

“…Early work showed that the insertion of a dialysis fiber into brain causes local brain injury leading to BBB disruption to both small molecules ( Morgan et al, 1996 ; Groothuis et al, 1998 ) and to large molecules such as albumin ( Westergren et al, 1995 ), and to the formation of a glial scar around the fiber ( Hascup et al, 2009 ). Recently, brain microdialysis has been applied to the brain delivery of monoclonal antibodies, where special fibers are used that have a MWCO of 1,000,000 Da ( Chang et al, 2018 ; Sopko et al, 2020 ; LePrieult et al, 2021 ; Van De Vyver et al, 2022 ). The assumption with this methodology is that the antibody distribution into the dialysate is a measure of antibody transport into the brain ISF.…”

Enhancing Antibody Exposure in the Central Nervous System: Mechanisms of Uptake, Clearance, and Strategies for Improved Brain Delivery

“…In a recent study conducted by Van De Vyver et al, pharmacokinetics in the brains of healthy rats were modeled to analyze the effects of non-targeting mAbs administered via intravenous (IV) or intracerebroventricular (ICV) route [33]. Pathway analysis from their study suggested that antibody exposure in the interstitial fluid (ISF) of the brain is predominantly mediated by mAbs traversing the BBB rather than entering the ISF directly from the CSF, regardless of route of administration [33]. While some researchers have speculated that transcytosis of IgG antibodies may be facilitated by receptors on brain endothelial cells, such as the neonatal Fc receptor (FcRn), several studies have refuted this hypothesis [15,16,34].…”