With the development of the monoclonal technology, serotherapy of cancer can finally be evaluated critically in the clinic. The major problems encountered to date include the therapeutic potency of monoclonal antibodies and the phenotypic heterogeneity of tumor cell targets. To increase the potency of monoclonal antibodies, conjugates have been prepared with drugs, radionuclides or plant toxins. One potential advantage of toxin conjugates is their great specificity, killing only those cells which bind and take up the immunotoxin. One potential limitation is the presence of cells within a tumor which fail to bind the immunoconjugate or fail to take up and translocate the toxin. During the last 4 years we have studied methods for overcoming the phenotypic heterogeneity among tumor cells to achieve complete and selective elimination of B lymphoma, T lymphoma and breast cancer cells from human bone marrow. In the course of these studies, a synergistic interaction has been observed between immunotoxins which bind to two distinct cell surface proteins expressed by >90% of breast and ovarian carcinomas. In continued studies, we propose to define mechanisms which contribute to this synergistic antitumor activity. We will test the hypothesis that synergistic interactions of immunotoxins depend upon different patterns of expression, trafficking or cooperativity of different target antigens and that these characteristics, in turn, depend upon the structure of the antigens and their interaction with membranes before and after immunotoxin binding. Factors will be studied which regulate expression of antigens know to make effective targets for immunotoxins. New antigenic targets will be sought based upon the outcome of these studies. Two of the most promising areas for clinical application of these observations will be explored. Immunotoxins which exert synergistic antitumor activity will be used to eliminate breast cancer cells from human bone marrow, facilitating autologous bone marrow transplantation in this disease. Preclinical studies will be undertaken in a nude mouse heterograft model for epithelial ovarian cancer to determine whether synergy can be demonstrated in vivo as well as in cell culture.
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