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.

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.…”

CSF Dynamics: Implications for Hydrocephalus and Glymphatic Clearance

“…This assumption fails to capture extracranial influences on CSF flow, as is thought to occur with pathophysiology. Recent computational models have moved beyond this assumption by incorporating "rest-of-body" compartments, including lymphatic vessels, cardiac ventricles, and peripheral vasculature (Van De Vyver AJ, Walz AC, Heins MS, et al, 2022). This new approach allows for the study of CSF dynamics in the context of different bodily functions, such as sympathetic and parasympathetic autoregulation, central body fluid ingestion and excretion, and peripheral cardiovascular phenomena, such as cardiac arrest or hemorrhages (Lakin WD, Stevens SA, Tranmer BI & Penar PL., 2003).…”