scholarly journals Kinetics of Blood–Brain Barrier Transport of Monoclonal Antibodies Targeting the Insulin Receptor and the Transferrin Receptor

2021 ◽  
Vol 15 (1) ◽  
pp. 3
Author(s):  
William M. Pardridge
Keyword(s):  
Fusion Protein ◽  
Mathematical Models ◽  
Insulin Receptor ◽  
Blood Brain Barrier ◽  
Transferrin Receptor ◽  
Brain Barrier ◽  
Luminal Membrane ◽  
Blood Brain ◽  
Kinetics Of ◽  
The Brain

Biologic drugs are large molecule pharmaceuticals that do not cross the blood–brain barrier (BBB), which is formed by the brain capillary endothelium. Biologics can be re-engineered for BBB transport as IgG fusion proteins, where the IgG domain is a monoclonal antibody (MAb) that targets an endogenous BBB transporter, such as the insulin receptor (IR) or transferrin receptor (TfR). The IR and TfR at the BBB transport the receptor-specific MAb in parallel with the transport of the endogenous ligand, insulin or transferrin. The kinetics of BBB transport of insulin or transferrin, or an IRMAb or TfRMAb, can be quantified with separate mathematical models. Mathematical models to estimate the half-time of receptor endocytosis, MAb or ligand exocytosis into brain extracellular space, or receptor recycling back to the endothelial luminal membrane were fit to the brain uptake of a TfRMAb or a IRMAb fusion protein in the Rhesus monkey. Model fits to the data also allow for estimates of the rates of association of the MAb in plasma with the IR or TfR that is embedded within the endothelial luminal membrane in vivo. The parameters generated from the model fits can be used to estimate the brain concentration profile of the MAb over time, and this brain exposure is shown to be a function of the rate of clearance of the antibody fusion protein from the plasma compartment.

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

2021 ◽  
Vol 14 (6) ◽  
pp. 535
Author(s):  
William M. Pardridge ◽  
Tom Chou
Keyword(s):  
Monoclonal Antibodies ◽  
Mathematical Models ◽  
Insulin Receptor ◽  
Blood Brain Barrier ◽  
Transferrin Receptor ◽  
Plasma Concentrations ◽  
Mass Action ◽  
Brain Barrier ◽  
Capillary Endothelium ◽  
Blood Brain

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.

scholarly journals Distribution and Kinetics of 3-O-Methyl-6-[18F]fluoro-L-DOPA in the Rhesus Monkey Brain

1991 ◽  
Vol 11 (5) ◽  
pp. 726-734 ◽  
Author(s):  
Doris J. Doudet ◽  
Catherine A. McLellan ◽  
Richard Carson ◽  
H. Richard Adams ◽  
Hitoshi Miyake ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Rhesus Monkeys ◽  
Brain Barrier ◽  
Nigrostriatal System ◽  
Dopamine System ◽  
Blood Brain ◽  
Homogenous Distribution ◽  
Plasma Metabolite ◽  
Kinetics Of ◽  
The Brain

Most attempts to model accurately [18F]-DOPA imaging of the dopamine system are based on the assumptions that its main peripheral metabolite, 3-O-methyl-6-[18F]fluoro-L-DOPA ([18F]3-OM-DOPA), crosses the blood-brain barrier but is present as a homogenous distribution throughout the brain, in part because it is not converted into [18F]DOPA in significant quantities. These assumptions were based mainly on data in rodents. Little information is available in the primate. To verify the accuracy of the above assumptions, we administered 18F-labeled 3-OM-DOPA to normal rhesus monkeys and animals with lesions of the DA nigrostriatal system. No selective 18F regional accumulation in brain was apparent in normal or lesioned animals. The plasma metabolite analysis revealed that only the negatively charged metabolites (e.g., sulfated conjugates) that do not cross the blood-brain barrier were found in significant quantities in the plasma. A one-compartment, three-parameter model was adequate to describe the kinetics of [18F]3-OM-DOPA. In conclusion, assumptions concerning [18F]3-OM-DOPA's behavior in brain appear acceptable for [18F]DOPA modeling purposes.

scholarly journals Impact of blood-brain barrier permeabilization induced by ultrasound associated to microbubbles on the brain delivery and kinetics of cetuximab: An immunoPET study using 89Zr-cetuximab

2020 ◽  
Vol 328 ◽  
pp. 304-312 ◽  
Author(s):  
Vu Long Tran ◽  
Anthony Novell ◽  
Nicolas Tournier ◽  
Matthieu Gerstenmayer ◽  
Arnaud Schweitzer-Chaput ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Delivery ◽  
Blood Brain ◽  
Kinetics Of ◽  
The Brain

The Distribution and Kinetics of [18F]6-Fluoro-3-O-Methyl-l-Dopa in the Human Brain

1994 ◽  
Vol 14 (4) ◽  
pp. 664-670 ◽  
Author(s):  
Lindi Wahl ◽  
Raman Chirakal ◽  
Gunter Firnau ◽  
E. Stephen Garnett ◽  
Claude Nahmias
Keyword(s):  
Blood Brain Barrier ◽  
Time Course ◽  
Nonhuman Primates ◽  
Dopamine Metabolism ◽  
Brain Barrier ◽  
Blood Brain ◽  
Measured Time ◽  
Bidirectional Transport ◽  
Kinetics Of ◽  
The Brain

The analysis of positron tomographic studies of 3,4-dihydroxyphenylethylamine (dopamine) metabolism in which [18F]6-fluoro-l-3,4-dihydroxyphenylalanine (F-dopa) is used as a tracer is confounded by the presence of [18F]6-fluoro-3- O-methyl-l-3,4-dihydroxyphenylalanine (OMFD). This labeled molecule, formed by the action of peripheral cathechol- O-methyltransferase on F-dopa, crosses the blood–brain barrier and contributes to the radioactivity measured by the tomograph. Corrections for this radioactivity in the brain have been proposed. They rely upon the assumption that regional variations in the handling of this molecule by the brain are negligible. Although this assumption is pivotal for the proper quantification of dopamine metabolism using F-dopa, the distribution and kinetics of OMFD have never been studied in humans. We present results in humans that show that there is little selective regional 18F accumulation in the brain, that the distribution volume of OMFD is close to unity, and that a single, reversible compartment is adequate to model the measured time course of radioactivity after an OMFD injection. Analysis of plasma samples for labeled metabolites showed that more than 95% of the radioactivity was associated with OMFD at all times. Our results for OMFD kinetics are in accord with published results obtained in nonhuman primates and for the bidirectional transport of large neutral amino acids across the blood-brain barrier measured using a synthetic amino acid. However, our results also indicate that there are small but significant differences in OMFD kinetics in different parts of the brain that may prevent inferences about the handling of OMFD in one part of the brain from being extended to other parts of the brain.

scholarly journals The insulin receptor is expressed and functional in cultured blood-brain barrier endothelial cells but does not mediate insulin entry from blood to brain

2018 ◽  
Vol 315 (4) ◽  
pp. E531-E542 ◽  
Author(s):  
Maria Hersom ◽  
Hans C. Helms ◽  
Christoffer Schmalz ◽  
Thomas Å. Pedersen ◽  
Stephen T. Buckley ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Insulin Receptor ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Endothelial Cells ◽  
Insulin Transport ◽  
Blood Brain ◽  
The Brain ◽  
Receptor Inhibitor

Insulin and its receptor are known to be present and functional in the brain. Insulin cerebrospinal fluid concentrations have been shown to correlate with plasma levels of insulin in a nonlinear fashion, indicative of a saturable transport pathway from the blood to the brain interstitial fluid. The aim of the present study was to investigate whether insulin was transported across brain endothelial cells in vitro via an insulin receptor-dependent pathway. The study showed that the insulin receptor was expressed at both the mRNA and protein levels in bovine brain endothelial cells. Luminally applied radiolabeled insulin showed insulin receptor-mediated binding to the endothelial cells. This caused a dose-dependent increase in Akt-phosphorylation, which was inhibited by coapplication of an insulin receptor inhibitor, s961, demonstrating activation of insulin receptor signaling pathways. Transport of insulin across the blood-brain barrier in vitro was low and comparable to that of a similarly sized paracellular marker. Furthermore, insulin transport was not inhibited by coapplication of an excess of unlabeled insulin or an insulin receptor inhibitor. The insulin transport and uptake studies were repeated in mouse brain endothelial cells demonstrating similar results. Although it cannot be ruled out that culture-induced changes in the cell model could have impaired a potential insulin transport mechanism, these in vitro data indicate that peripheral insulin must reach the brain parenchyma through alternative pathways rather than crossing the blood-brain barrier via receptor mediated transcytosis.

scholarly journals THE ONTOGENY OF P-GLYCOPROTEIN IN THE DEVELOPING HUMAN BLOOD BRAIN BARRIER: IMPLICATION FOR OPIOID TOXICITY IN NEONATES

2015 ◽  
Vol 101 (1) ◽  
pp. e1.1-e1
Author(s):  
Gideon Koren ◽  
Jessica Lam ◽  
Lauren Kelly ◽  
Stephanie Baella ◽  
David Chitayat ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Systemic Circulation ◽  
Brain Barrier ◽  
Glycoprotein P ◽  
Postnatal Maturation ◽  
Luminal Membrane ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Life Threatening ◽  
The Brain

Neonates have been shown to have a heightened sensitivity to the central depressive effects of opioids compared to older infants and adults. The limited development of P-glycoprotein (P-gp), located on the luminal membrane of the brain endothelial cells, may limit the ability of the neonate to efflux morphine from the brain back to the systemic circulation. Presently, little is known about blood brain barrier P-gp expression during human development. The objective of the study was to determine the ontogeny of P-gp in the human BBB. Postmortem cortex samples from gestational age (GA) 20–26 weeks, GA 36–40 weeks, postnatal age (PNA) 0–3 months, PNA 3–6 months, and adults were immunostained for P-gp. Analysis was carried out by spinning disc confocal microscopy. The intensity of P-gp staining in adults was significantly higher compared to at GA 20–26 weeks (p=0.0002), GA 36–40 weeks (p=0.0002), and PNA 0–3 months (p=0.0044). P-gp intensity at GA 20–26 weeks (p=0.0011), GA 36–40 weeks (p=0.0013), and PNA 0–3 months (p=0.0173) was significantly lower compared to at PNA 3–6 months. P-gp expression in the BBB is limited at birth, increases with postnatal maturation, and reaches adult levels at approximately 3–6 months of age. Given the immaturity of BBB P-gp after birth, morphine may concentrate in the brain. This provides mechanistic support to life threatening opioid toxicity seen with maternal codeine use during breastfeeding.

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