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Therapeutic Efficacy of a Doxorubicin Immunoconjugate in a Preclinical Model of Spontaneous Metastatic Human Melanoma¹

Fred Hutchinson Cancer Research Center, Seattle, Washington 98104 [G. P. S., P. J. M.], University of Washington School of Medicine, Seattle, Washington 98119 [P. J. M.], and Department of Immunology, The Scripps Research Institute, La Jolla, California 92037 [R. A. R., B. M. M.]

Doxorubicin (DOX) was conjugated to a monoclonal antibody (mAb 425) directed against the human epidermal growth factor receptor. The immunoreactivity of these conjugates, with an average of six to eight molecules of DOX per antibody, was largely conserved, and their in vitro cytotoxicity against metastatic human melanoma cells (M24 met) was improved over that of free DOX. An evaluation of the therapeutic efficacy of mAb 425-DOX indicated that this immunoconjugate suppressed the growth of primary and secondary M24 met tumors in mice with severe combined immunodeficiency and prolonged the life span of these animals, whereas an equivalent dose of free DOX was ineffective. Conjugation of DOX to an irrelevant mAb also increased its antitumor effect over that of equivalent amounts of free drug but to a lesser extent than that achieved by the mAb 425-DOX conjugate. These results demonstrate targeted delivery and striking antitumor activity of DOX immunoconjugates in a preclinical model of spontaneous, metastatic human melanoma that was insensitive to free DOX.

¹ This work was supported in part by NIH Grant CA 42508 (R. A. R. and B. M. M.).

² To whom requests for reprints should be addressed, at Fred Hutchinson Cancer Research Center, M 718, 1124 Columbia Street, Seattle, WA 98104.

Received 10/25/94. Accepted 3/31/95.

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