The specific cytotoxicity of immunoconjugates containing blocked ricin is dependent on the residual binding capacity of blocked ricin: evidence that the membrane binding and A-chain translocation activities of ricin cannot be separated.
Recently we have developed blocked ricin, a derivative of native ricin in which the galactose-binding sites of the B-chain are blocked by covalent modification with affinity ligands. This modification impedes the binding function of the B-chain, while sparing its ability to facilitate the entry of the toxic subunit of ricin, the A-chain, into the cytoplasm. Immunotoxins prepared with blocked ricin approach the cytotoxic potency of native ricin with antibody-dependent specificity. Here we report that the high cytotoxic potency of these immunoconjugates, which is attributed to the preserved translocation function of the ricin B-chain, is dependent on the minimal residual lectin activity of blocked ricin. Our findings support the notion that two functions of ricin, membrane binding and translocation, cannot be separated.
Goldmacher
V S
VS
ImmunoGen, Inc., Cambridge, MA 02139.
Lambert
J M
JM
Blättler
W A
WA
D000936:Antigen-Antibody Complex / Q000378:metabolism / Q000633:toxicity*; D001665:Binding Sites; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D005690:Galactose / Q000378:metabolism; D006801:Humans; D007785:Lactose / Q000494:pharmacology; D037102:Lectins / Q000378:metabolism; D008221:Lymphoid Tissue; D012276:Ricin / Q000276:immunology / Q000378:metabolism / Q000633:toxicity*; D017026:Swainsonine / Q000494:pharmacology
D000936:Antigen-Antibody Complex; D037102:Lectins; D012276:Ricin; D007785:Lactose; D017026:Swainsonine; D005690:Galactose