Cellular Uptake of Glucocerebrosidase in Gaucher Patients Receiving Enzyme Replacement Treatment

Abstract

This was the first in vivo study to quantify the accumulated enzymatic activity in patients receiving ERT for GD1. It showed that intra-leukocyte activity at baseline and at 15 min post-perfusion could be used as a possible marker for therapeutic individualization in patients receiving ERT for GD1.

Relationship Between Glucocerebrosidase Activity and Clinical Response to Enzyme Replacement Therapy in Patients With Gaucher Disease Type I

“…A number of causes have been postulated for this low penetration of the exogenous enzyme into monocyte–macrophage of GD1 patients. These include different macrophage immunophenotypes , the high variability of the M6P receptor , the saturation of the mannose receptor at high doses or that the enzyme is eliminated by peptidases or outside of the vascular endothelium at a faster rate than the rate of uptake by the monocyte .…”

“…High between‐subjects variability in the maximum activity achieved after the infusion into the leucocytes, which is later distributed throughout the organism (Act 75 ) could be due to the patients have different values of endogenous enzyme and because of the variability in the degree of exogenous enzyme uptake . Therefore, the amount of enzyme that comes from the ERT (Act 75‐0 ) in patients with OR is virtually the same amount as healthy individuals have of endogenous enzyme.…”

“…Consequently, as monocyte/macrophage system, a type of polymorphonuclear leucocyte (monocytes in circulation and macrophages in tissues), is the target cells in GD1, hence the quantification of intraleucocyte enzyme activity in patients treated with ERT could be used as a tool to monitor ERT. Moreover, intraleucocyte enzymatic activity seems to show a linear correlation with the low or intermediate doses studied . However, studies of high doses have suggested a no linear relationship with enzyme activity (nonlinear pharmacokinetic behaviour) .…”

“…Published studies on the pharmacokinetics of ERT have suggested that, after intravenous administration, the activity of circulating enzyme decreases rapidly in plasma because the principal distribution model of the ERT is through uptake by mannose‐6‐phosphate (M6P) into peripheral monocytes and their distribution in tissues as macrophages. A direct extravasation to tissues through the vascular endothelium with subsequent uptake by macrophages is theoretically less important or null due to its high molecular weight (70 KDa), which causes the tissue distribution of most proteins to be limited to the vascular or interstitial spaces .…”

Quantitative assessment of the exposure–efficacy relationship of glucocerebrosidase using Markovian elements in Gaucher patients treated with enzyme replacement therapy

“…The therapeutic enzyme is designed to be internalized by monocyte/macrophage through receptor‐mediated endocytosis via mannose receptors 37 . Therefore, the leukocyte enzymatic activity is considered the PK endpoint to predict the individual enzymatic activity 19 . Furthermore, GCase activity was measured in peripheral leukocytes because blood monocytes are a type of leukocyte and previous studies have shown GCase activity in monocytes represents 96% of total leukocyte approximately 38 …”