The Effect of Chemical Deglycosylation of Ricin A-Chain on the Therapeutic Potential of Ricin A-Chain Immunotoxins
Novel antitumour agents have been synthesised in several laboratories by linking the A-chain of the plant toxin, ricin, to monoclonal antibodies directed against tumour-associated antigens. These immunotoxins bind to antigens on the tumour cell surface via the antibody moiety and the A-chain enters the cell, killing it by inactivating its ribosomes. Although such immunotoxins often show good specificity and high potency in vitro they have generally produced less impressive antitumour effects in vivo (Reviewed in Thorpe, 1985; Vitetta and Uhr, 1985; Blakey et al 1987a). The poor therapeutic activity of ricin A-chain immunotoxins in vivo can be partly explained by their rapid clearance from the bloodstream. This rapid clearance of ricin A-chain immunotoxins is mainly due to recognition of mannose and fucose residues on the A-chain component by receptors present on liver parenchymal and non-parenchymal cells (Kupffer and sinusoidal endothelial cells). The evidence for this comes from several reports that ricin A-chain (Skilleter and Foxwell, 1986; Blakey and Thorpe, 1986) and ricin A-chain immunotoxins (Blakey et al 1987b; Bourrie et al 1986; Worrell et al 1986; Blakey et al 1987c) are taken up by liver cells in vitro and in vivo through a route that can be antagonised by mannose and fucose — terminating glycoproteins and saccharides.
KeywordsRapid Clearance Sinusoidal Endothelial Cell Sodium Cyanoborohydride Fucose Residue Sodium Metaperiodate
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