(M-134) A Minimal Physiology-based Pharmacokinetics Model of Blood-Brain Barrier Transport for Monoclonal Antibodies Targeting the Transferrin Receptor

Haiqing Wang, Ph. D. – Sr. Director, DMPK, Alnylam Pharmaceuticals

Objective: The limited efficiency of systemic drug delivery to central nervous system (CNS) has led to the use of invasive intrathecal dosing in clinical studies. Recent advances have identified the transferrin receptor (TfR) as a potential target for antibody-mediated blood-brain barrier (BBB) transport, offering a promising avenue for delivering large-molecule therapeutics to CNS. Despite some clinical successes of TfR-conjugated drugs, achieving the desired drug profile for efficient TfR-mediated delivery to specific brain compartments remains challenging. Our objective was to develop a quantitative model integrating antibody binding affinity and corresponding drug exposure in plasma and CNS compartments to understand how various factors of anti-TfR antibodies affect the efficiency of CNS drug delivery and whether high-affinity TfR-antibody accumulation in BBB endothelial cells affects delivery efficiency.

Methods: We developed a physiology-based pharmacokinetics (PBPK) model to explore how brain and cerebrospinal fluid (CSF) exposures are affected by varying antibody binding affinities at different dosing levels and routes of administration. Our model is calibrated against published preclinical pharmacokinetics (PK) data and simplifies the mathematical description of TfR-mediated trans- and intracellular disposition of anti-TfR antibodies via BBB. Subsequently, we conducted a sensitivity analysis to examine the effects of multiple factors, including dosing levels, binding affinities, etc.

Results: Our model replicates PK profiles of both non-specific and TfR antibodies in plasma, CSF, and brain ISF. Notably, over an extended duration, CSF and brain ISF exhibit parallel trends, suggesting that CSF PK measurements may serve as predictive tools for brain ISF PK for both non-specific and TfR antibodies in long term. The model quantified the contributions to brain drug uptake by BBB-crossing and CSF-crossing pathways, depending on the route of administration. Specifically, brain ISF predominantly acquires drugs via the BBB during both intravenous and intracerebroventricular administration, with minimal contribution from CSF to brain ISF uptake. Moreover, reducing systemic clearance significantly enhances plasma PK, resulting in prolonged exposure in CSF and brain ISF. Additionally, diminishing lymphatic clearance modestly increases brain ISF exposure. As binding affinity increases, the area under the curve (AUC) for brain ISF, CSF, and the brain ISF-to-plasma AUC ratio initially rises, then declines, exhibiting a bell-shaped curve in relation to the logarithm of binding affinity.

Conclusions: Our model provides insights into the biodistribution and the influence of binding affinity in the CNS, informing the development of monoclonal antibodies for CNS diseases.

Citations: no