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Application of Target-specific Drug Immunoconjugates to Experimental Bone Marrow Replacement Therapy in Mice¹

Department of Immunology, University of Alberta, Edmonton, Alberta, Canada T6G 2H7 [L. D., D. G., R. V., E. D.], and Departments of Immunology [S. X.] and Urology [L. Y.], Beijing Medical University, Beijing, 100083, China

Immunoconjugates whose cytotoxic component consists of a phytopeptide are often used as purging agents in bone marrow replacement therapy. Less popular are drug immunoconjugates containing a small molecular weight cytotoxic drug attached to the target-specific conjugand via an appropriate spacer molecule. High target specificity, resistance of the drug to intralysosomal proteases and, once cleaved from the spacer, ready exit of the drug from the lysosome are among the advantages drug immunoconjugates hold over phytotoxin immunoconjugates. The cytotoxic drug daunomycin attached via an acid-sensitive spacer to monoclonal antibody of appropriate specificity was shown to purge murine bone marrow of contaminating tumor cells without affecting its hematopoietic potential. Lethally irradiated mice reconstituted with syngeneic bone marrow from which contaminating lymphoma cells had been removed survived indefinitely. Furthermore, lymphoma-bearing mice, provided they were sufficiently irradiated to eliminate tumor cells in situ, were successfully reconstituted with fully allogeneic bone marrow from which potentially graft-versus-host-reactive T-cells had been purged.

¹ This work was supported by Grant MT-9944 from the Medical Research Council of Canada and funds from Biomira, Inc., Edmonton, Alberta, Canada, and the University Hospitals Foundation, Edmonton, Alberta, Canada.

² To whom requests for reprints should be addressed, at Department of Immunology, Medical Sciences Building, University of Alberta, Edmonton, Alberta, Canada T6G 2H7.

Received 8/ 5/88. Revised 6/28/89. Revised 10/30/89. Accepted 11/ 8/89.