Role of the B-Chain in the Cytotoxic Action of Antibody-Ricin and Antibody-Abrin Conjugates

Attempts have been made in several laboratories to construct cell type-specific cytotoxic agents by linking antibody molecules to the highly potent toxins, abrin and ricin (for a review of the mode of action of abrin and ricin, see chapter by S. Olsnes, this volume). Two main strategies have been adopted. The first is to link the holotoxin directly to the antibody. Conjugates of this type always appear to exert a powerful cytotoxic effect upon cells with the appropriate antigens but suffer from a lack of complete specificity because they can also bind to non-target cells by the galactose-binding sites on the toxin B-chain (reviewed by Thorpe et al., 1982a). The other approach is to link the antibody by a disulfide bond to the isolated toxin A-chain. Conjugates of this second type, although free from the problem of non-specific binding, show great variability in cytotoxic potency, some being as effective as the native toxin and others being weakly or non-cytotoxic (reviewed by Olsnes and Pihl, 1982a; Martinez et al., 1982; Thorpe et al., 1982a). The consistent and generally superior cytotoxic performance of the intact toxin conjugates appears to be attributable to an ability of the B-chain to facilitate delivery of the A-chain moiety to the cytosol.