THERAPEUTIC EFFICACY OF A DOXORUBICIN IMMUNOCONJUGATE IN A PRECLINICAL MODEL OF SPONTANEOUS METASTATIC HUMAN-MELANOMA

Doxorubicin (DOX) was conjugated to a monoclonal antibody (mAb 425) di rected against the human epidermal growth factor receptor, The immunor eactivity of these conjugates, with an average of six to eight molecul es of DOX per antibody, was largely conserved, and their in vitro cyto toxicity against metastatic human melanoma cells (M24 met) was improve d 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 i mmunodeficiency 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 equ ivalent amounts of free drug but to a lesser extent than that achieved by the mAb 425-DOX conjugate, These results demonstrate targeted deli very and striking antitumor activity of DOX immunoconjugates in a prec linical model of spontaneous, metastatic human melanoma that was insen sitive to free DOX.