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

Cetus Corporation, Emeryville, California 94608

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 immunotoxins 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 nonreducible 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 conjugate 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.

¹ Present address: Department of Medicine, Division of Hematology/Oncology, Duke University Medical Center, Durham, NC 27710.

² Present address: NeoRx Corporation, 410 Harrison St., Seattle, WA 98119.

³ To whom correspondence should be addressed at Cetus Corporation, 1400 Fifty-third Street, Emeryville, CA 94608.

Received 8/16/88. Revised 10/17/88. Accepted 10/21/88.