Therapeutic delivery of proteins to macrophages: implications for treatment of Gaucherʹs disease

Background The primary defect in Gaucherʹs disease, a lysosomal disorder affecting macrophages, is in the activity of glucocerebrosidase. Treatment with exogenous enzyme (modified to increase its affinity for macrophage glycoprotein receptors) aims to restore this activity. However, the fate of the exogenous enzyme in vivo is unknown. We used radiolabelled enzyme to assess macrophage receptor activity for mannosylated ligands in vivo. Methods We examined the uptake and tissue distribution of radiolabelled enzyme molecules by γ scintigraphy after bolus injection of iodine-123-labelled recombinant or placental enzyme (imiglucerase and alglucerase, respectively) in eight patients with type 1 Gaucherʹs disease, and in one healthy individual. The metabolism of the tracer enzyme was followed by scintigraphy and by analysis of blood, urine, and faeces. Results The tracer enzyme was rapidly cleared from blood (half-life 4·7 min [SD 1·0]). Concomitantly, there was avid uptake by the liver (about 30% of the injected dose), the spleen (about 15%), and the bone marrow. 40–55% of the tracer was cleared rapidly from the viscera (half-life 1–2 h) and 45–60% was cleared slowly (half-life 34–42 h). The half-life in the bone marrow was 14·1 h. Infusion of alglucerase at dose of 5 U/kg bodyweight normalised acid β-glucosidase activity of splenic Gaucherʹs cells in vivo. When the enzyme was administered at a seven-fold higher dose (35 U/kg over 1 h), the receptor-mediated uptake in vivo was saturated, as shown by the increase in blood-clearance half-life of tracer enzyme from 4·5 min to 12 min. Interpretation Avid and saturable uptake of modified glucocerebrosidase was found, which indicates high-affinity targeting to the macrophage system in vivo. The rate of enzyme turnover suggests a rational basis for use of this therapy in treatment of Gaucherʹs disease.