Mathematical Models of Blood-Brain Barrier Transport of Monoclonal Antibodies Targeting the Transferrin Receptor and the Insulin Receptor.

William M Pardridge,Tom Chou

doi:10.3390/ph14060535

Abstract

We develop and analyze mathematical models for receptor-mediated transcytosis of monoclonal antibodies (MAb) targeting the transferrin receptor (TfR) or the insulin receptor (IR), which are expressed at the blood-brain barrier (BBB). The mass-action kinetic model for both the TfR and IR antibodies were solved numerically to generate predictions for the concentrations of all species in all compartments considered. Using these models, we estimated the rates of MAb endocytosis into brain capillary endothelium, which forms the BBB in vivo, the rates of MAb exocytosis from the intra-endothelial compartment into brain extracellular space, and the rates of receptor recycling from the endothelial space back to the luminal endothelial plasma membrane. Our analysis highlights the optimal rates of MAb association with the targeted receptor. An important role of the endogenous ligand, transferrin (Tf) or insulin, in receptor-mediated-transport (RMT) of the associated MAb was found and was attributed to the five order magnitude difference between plasma concentrations of Tf (25,000 nM) and insulin (0.3 nM). Our modeling shows that the very high plasma concentration of Tf leads to only 5% of the endothelial TfR expressed on the luminal endothelial membrane.

Highlights

Biologics are large molecule pharmaceuticals that do not cross the blood-brain barrier (BBB)
Model simulations with no TfRMAb administration, i.e., A0 = 0, allowed for modeling of Tf transport through the BBB, and these results showed that at steady state, the concentration of the Tf-transferrin receptor (TfR) complex at the luminal endothelial membrane [variable D(t), Figure 1], the concentration of the Tf-TfR complex within the intra-endothelial compartment [variable
Measurement of the kinetics of TfRMAb binding to the Tf-TfR complex is important because Tf binding to the TfR

Summary

Introduction

Biologics are large molecule pharmaceuticals that do not cross the blood-brain barrier (BBB). Therapeutic recombinant proteins, enzymes, decoy receptors, or monoclonal antibodies can be re-engineered as BBB-transportable IgG fusion proteins using molecular. The latter are monoclonal antibodies (MAb) that target endogenous receptor-mediated transport (RMT) systems on the BBB, such as the transferrin receptor (TfR) or insulin receptor (IR). Trojan horse antibodies have entered clinical trials targeting either the human IR [2] or the human TfR1 [3], [NCT04251026, NCT04639050]. A high affinity IRMAb against the human insulin receptor (HIR) was genetically fused to the lysosomal enzyme, iduronidase (IDUA), and this HIRMAb-IDUA fusion protein, designated valanafusp alpha, was tested in a year-long clinical trial in pediatric patients with mucopolysaccaridosis Type I (MPSI), called Hurler syndrome [2].

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