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Specific Activation of the Prodrug Mitomycin Phosphate by a Bispecific Anti-CD30/Anti-Alkaline Phosphatase Monoclonal Antibody¹

Laboratory of Tumor Biology, Medizinische Klinik I University of Cologne, D-5000 Köln 41, Federal Republic of Germany [U. S., F. H., C. P., A. E., V. D., M. P.], and Oncogen, Seattle, Washington 98121 [P. S.]

The bispecific monoclonal antibody (Bi-MAb) HRS-3/AP-1 was developed by somatic hybridization of the 2 mouse hybridoma cell lines HRS-3 and AP-1, which produce monoclonal antibodies with reactivity against the Hodgkin's- and Reed-Sternberg cell-associated CD30 antigen and alkaline phosphatase, respectively. After an active incubation with alkaline phosphatase, purified whole immunoglobulin molecules and F(ab')₂ fragments of the Bi-MAb were equally effective in converting a relatively noncytotoxic prodrug, mitomycin phosphate (MOP), into mitomycin alcohol, which was 100 times more toxic to the Hodgkin's- and Reed-Sternberg cell line L540 (CD30⁺) than MOP. The cytotoxic activity of MOP was unaffected when the cells were pretreated with either the Bi-MAb or the enzyme alone. The Bi-MAb HRS-3/AP-1 did not bind to HPB-ALL cells (CD30^-) and was not able to activate MOP on these cells. In cocultivation experiments with HPB-ALL and L540 cells, the activation of MOP by the Bi-MAb HRS-3/AP-1 and alkaline phosphatase led to considerable cytotoxicity against the antigen-negative by-stander cells. Thus, this immunotherapeutic approach might be effective in tumors in which not all the tumor cells express the respective tumor antigen.

¹ This study was supported by a grant from the Deutsche Forschungsgemeinschaft.

² To whom requests for reprints should be addressed, at Medizinische Klinik I University of Cologne, Josef-Stelzmann-Strasse 9, D-5000 Köln 41, Federal Republic of Germany.

Received 4/17/90. Accepted 7/17/90.

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