A Comparison of the Pharmacological Properties of Carbohydrate Remodeled Recombinant and Placental-Derived β-Glucocerebrosidase: Implications for Clinical Efficacy in Treatment of Gaucher Disease

Abstract

The objective of these studies was to characterize the macrophage mannose receptor binding and pharmacological properties of carbohydrate remodeled human placental-derived and recombinant β-glucocerebrosidase (pGCR and rGCR, respectively). These are similar but not identical molecules that were developed as enzyme replacement therapies for Gaucher disease. Both undergo oligosaccharide remodeling during purification to expose terminal mannose sugar residues. Competitive binding data indicated carbohydrate remodeling improved targeting to mannose receptors over native enzyme by two orders of magnitude. Mannose receptor dissociation constants (Kd) for pGCR and rGCR were each 13 nmol/L. At 37°C, 95% of the total macrophage binding was mannose receptor specific. In vivo, pGCR and rGCR were cleared from circulation by a saturable pathway. The serum half-life (t1/2) was 3 minutes when less than saturable amounts were injected intravenously (IV) into mice. Twenty minutes postdose, β-glucocerebrosidase activity increased over endogenous levels in all tissues examined. Fifty percent of the injected activity was recovered. Ninety-five percent of recovered activity was in the liver. Parenchymal cells (PC), Kupffer cells (KC), and liver endothelium cells (LEC) were responsible for 75%, 22%, and 3%, respectively, of the hepatocellular uptake of rGCR and for 76%, 11%, and 12%, respectively, of the hepatocellular uptake of pGCR. Both molecules had poor stability in LEC and relatively long terminal half-lives in PC (t1/2 = 2 days) and KC (t1/2 = 3 days).

Comparative Therapeutic Effects of Velaglucerase Alfa and Imiglucerase in a Gaucher Disease Mouse Model

“…Small clinical trials showed improvement in the clinical and biochemical features of the disease [5] . Later, recombinant α-mannosyl-terminated human GCase (imiglucerase, Imig) was developed and was shown to have biologic and therapeutic equivalency to alglucerase [6] , [9] . This therapy has become the standard of care for significantly involved patients with Gaucher disease type 1 [8] .…”

“…In addition, Vela has the wild type sequence with an arginine at position 495. Previously, the exchange of the histidine and arginine at position 495 was shown to have no effect on any in vitro physicokinetic properties [9] , [28] , or on the crystal structure [17] , [29] .…”

A Glycotherapeutic Approach to Functionalize Biomaterials‐Based Systems

“…Receptors for mannose are abundant in Kupffer cells, alveolar macrophages, peritoneal macrophages, splenic macrophages and brain macrophages (microglia, astrocytes, and dendritic cells derived from monocyte). [ 37a,49 ] The mannose‐transmembrane receptor present in dendritic cells and macrophages is a 17d kDa C‐type lectin protein. [ 37b,50 ] These mannose‐based receptors fulfill a vital role in modulating the immune response of the host via a strong involvement in phagocytosis, antigen presentation and processing, intracellular signaling and cell migration.…”

“…[ 37a,49 ] The mannose‐transmembrane receptor present in dendritic cells and macrophages is a 17d kDa C‐type lectin protein. [ 37b,50 ] These mannose‐based receptors fulfill a vital role in modulating the immune response of the host via a strong involvement in phagocytosis, antigen presentation and processing, intracellular signaling and cell migration. [ 37c,38a,51 ] More specifically, a high density of the mannose transmembrane receptors can be observed on the surface of dendritic cells.…”

“…[ 37b,50 ] These mannose‐based receptors fulfill a vital role in modulating the immune response of the host via a strong involvement in phagocytosis, antigen presentation and processing, intracellular signaling and cell migration. [ 37c,38a,51 ] More specifically, a high density of the mannose transmembrane receptors can be observed on the surface of dendritic cells. [ 38b,52 ] Liver Kupffer cells also express galactosyl and fucose receptors, which can uptake particles with galactose moieties and fucosylated carriers, respectively.…”