Tumor-associated CD75s gangliosides and CD75s-bearing glycoproteins with Neu5Acalpha2-6Galbeta1-4GlcNAc-residues are receptors for the anticancer drug rViscumin.
The anticancer drug rViscumin, currently under clinical development, has been shown in previous studies to be a sialic acid specific ribosome inactivating protein (RIP). Comparative binding assays with the CD75s-specific monoclonal antibodies HB6 and J3-89 revealed rViscumin to be a CD75s-specific RIP due to identical binding characteristics toward CD75s gangliosides. The receptor gangliosides are IV6nLc4Cer, VI6nLc6Cer, and the newly characterized ganglioside VIII6nLc8Cer, all three carrying the Neu5Acalpha2-6Galbeta1-4GlcNAc motif. To elucidate the clinical potential of the rViscumin targets, CD75s gangliosides were determined in several randomly collected gastrointestinal tumors. The majority of the tumors showed an enhanced expression of CD75s gangliosides compared with the unaffected tissues. The rViscumin binding specificity was further investigated with reference glycoproteins carrying sialylated and desialylated type II N-glycans. Comparative Western blots of rViscumin and ricin, an rViscumin homologous but galactoside-specific RIP, revealed specific recognition of type II N-glycans with CD75s determinants by rViscumin, whereas ricin failed to react with terminally sialylated oligosaccharides such as CD75s motifs and others. This strict binding specificity of rViscumin and the increased expression of CD75s gangliosides in various tumors suggest this anticancer drug as a promising candidate for an individualised adjuvant therapy of human tumors.
Müthing
Johannes
J
Institute for Medical Physics and Biophysics, University of Münster, Münster 48149, Germany. jm@uni-muenster.de
Meisen
Iris
I
Kniep
Bernhard
B
Haier
Jörg
J
Senninger
Norbert
N
Neumann
Ulrich
U
Langer
Martin
M
Witthohn
Klaus
K
Milosević
Jadranka
J
Peter-Katalinić
Jasna
J
D000911:Antibodies, Monoclonal / Q000378:metabolism; D015703:Antigens, CD / Q000737:chemistry / Q000145:classification / Q000276:immunology / Q000378:metabolism*; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000145:classification / Q000276:immunology / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000378:metabolism; D002855:Chromatography, Thin Layer / Q000379:methods; D004591:Electrophoresis, Polyacrylamide Gel / Q000379:methods; D005677:G(M1) Ganglioside / Q000302:isolation & purification / Q000378:metabolism; D005732:Gangliosides / Q000302:isolation & purification / Q000378:metabolism*; D005770:Gastrointestinal Neoplasms / Q000737:chemistry; D006023:Glycoproteins / Q000097:blood / Q000737:chemistry; D006098:Granulocytes / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D015233:Models, Statistical; D028321:Plant Preparations / Q000276:immunology; D010940:Plant Proteins / Q000276:immunology; D011955:Receptors, Drug / Q000378:metabolism*; D054790:Ribosome Inactivating Proteins, Type 2; D012276:Ricin / Q000737:chemistry; D012799:Sialyltransferases; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D014118:Toxins, Biological / Q000276:immunology; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015295:Antigens, Tumor-Associated, Carbohydrate; D000970:Antineoplastic Agents; D005677:G(M1) Ganglioside; D005732:Gangliosides; D006023:Glycoproteins; D028321:Plant Preparations; D010940:Plant Proteins; D011955:Receptors, Drug; D054790:Ribosome Inactivating Proteins, Type 2; D012276:Ricin; D012799:Sialyltransferases; D014118:Toxins, Biological; C488862:mistletoe lectin I; C021298:ganglioside, GD1a; C033851:ganglioside, GD1b; C016481:trisialoganglioside GT1; C093493:ST6GAL1 protein, human; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase