Study of the plasma clearance of antibody--ricin-A-chain immunotoxins. Evidence for specific recognition sites on the A chain that mediate rapid clearance of the immunotoxin.
In recent years, antibody--ricin-A-chain immunotoxins have been investigated as anti-neoplastic agents. To achieve in vivo therapy it is necessary that the immunotoxin remains in circulation at a sufficiently high level for a sufficiently long time to allow binding to tumor cells to occur. Therefore, examination of the pharmacology of immunotoxins may elucidate the reasons for the poor in vivo tumoricidal effect of immunotoxin described before. In this study the plasma clearance of antibody--ricin-A-chain immunotoxins, after intravenous injection in animals of different species, has been examined. Sensitive and reproducible techniques were developed to monitor the level of immunotoxin and its constituents in the blood. It is shown that immunotoxins are rapidly eliminated from the bloodstream. Neither the properties of the antibody moiety nor the nature of the linkage binding ricin A-chain to antibody account for the disappearance of immunotoxin from the plasma. On the other hand, we found that the rapid clearance of immunotoxin is due to the mannose residues on the ricin A-chain moiety which are specifically recognized by liver cells. When immunotoxin is administrated together with yeast mannan, which enhances the level of active immunotoxin in circulation by inhibition of liver uptake, the anti-cancer efficacy of immunotoxin in vivo is drastically improved.
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D004220:Disulfides / Q000378:metabolism; D007074:Immunoglobulin G / Q000378:metabolism; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008168:Lung / Q000378:metabolism; D008253:Macaca mulatta; D008264:Macrophages / Q000378:metabolism; D008351:Mannans; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D011485:Protein Binding; D011817:Rabbits; D051381:Rats; D012276:Ricin / Q000097:blood*; D013045:Species Specificity; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D004220:Disulfides; D007074:Immunoglobulin G; D008351:Mannans; D012276:Ricin