Ricin linked to monophosphopentamannose binds to fibroblast lysosomal hydrolase receptors, resulting in a cell-type-specific toxin.

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Abstract
The receptor specificity of the plant seed toxin ricin, which ordinarily binds to galactose-containing receptors, was altered by coupling monophosphopentamannose residues to ricin by reductive amination and by reversibly binding lactose to the modified ricin. The added monophosphopentamannose residues provide ricin with the recognition factor common to fibroblast lysosomal hydrolases and enable the modified ricin (Man6P-ricin) to bind to the fibroblast Man6P receptor and inhibit protein synthesis in the cells via this receptor. The addition of lactose to Man6P-ricin saturates the galactose site on Man6P-ricin and prevents the binding of Man6P-ricin to cells via galactose-containing ricin receptors. The Man6P receptor-mediated toxicity of Man6P-ricin, identified in human fibroblasts by competition by Man6P and blockade by alkaline phosphatase treatment, was not detected in HeLa cells or human amnion cells. In the presence of lactose, the fibroblasts were 8 and 13 times more sensitive than amnion and HeLa cells, respectively. Highly toxic cell-type-specific reagents can be made by the proper alteration of toxin receptor specificities. An attempt to construct a highly toxic altered toxin by adding Man6P residues to diphtheria toxin fragment A was unsuccessful. A possible explanation is that in Man6P-ricin the ricin B chain performs some entry function, even though the initial binding step occurs at the Man6P receptor. The present work is a further attempt to construct a cell-type-specific cytotoxic reagent with potential antineoplastic activity utilizing the concepts previously developed for artificial hybrid proteins.