Recombinant Ricin A Chain Conjugated to Monoclonal Antibodies: Improved Tumor Cell Inhibition in the Presence of Lysosomotropic Compounds

S. Ramakrishnan, L. L. Houston

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

Recombinant ricin A chain was chemically linked to monoclonal antibodies directed toward human breast cancer cells, a human T-cell differentiation antigen, and mouse transferrin receptor. Three types of immu-notoxins were prepared; in two of them the antibody was linked to recombinant ricin A chain by a disulfide bond and in the third, a nonreducible thioether bond was used. Immunotoxins containing a non-reducible linkage may have some advantage over conjugates containing a reducible linkage because of improved stability in vivo. Conjugation of recombinant ricin A chain through either the endogenous thiol group or through a derivatized amino group produced immunotoxins with comparable cytotoxicity. The thioether coqjugate was 1000-fold less cytotoxic to target tumor cells than the respective disulfide-linked immunotoxin. However, addition of monensin, a monocarboxylic ionophore, greatly enhanced the cytotoxicity of the thioether-linked immunotoxin. Monensin increased the immunotoxin activity better than other lysosomotropic reagents that were tested. The increase in activity of recombinant ricin A chain-containing immunotoxins mediated by monensin argues against a role for contaminating ricin B chain in potentiation.

Original languageEnglish (US)
Pages (from-to)613-617
Number of pages5
JournalCancer Research
Volume49
Issue number3
StatePublished - Feb 1 1989

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