This Program Project Grant has as its sole purpose, the preparation and use of monoclonal antibodies (MoAbs), conjugated or not, to treat breast cancer. The ultimate goal is the performance of clinical trials (as those proposed) to test for toxicity and prove effectiveness of such preparations. Participants in this program have already produced breast- directed MoAbs and with them, in conjugated and un-conjugated form, they have arrested growth of and destroyed human breast tumors. They possess knowledge of the preparation of breast- directed MoAbs, on their conjugation to toxins, radioisotopes and chemotherapy drugs, and in their clinical testing, but are aware of possible problems arising in their use in breast cancer treatment as a result of tumor cell heterogeneity, low antigenic expression in the tumors, host reactivity to different MoAbs and their conjugates, and uncertainties arising from doses, schedules and quantitation of therapeutic response in clinical trials. The specific objectives of the 3 individual Research Projects of this Program Project Grant are: 1. Performance of clinical trials, to determine toxicity, and maximal biological and tolerable doses. 2. Characterize, in model systems, breast-directed murine MoAbs we possess and create new ones as required, which are strictly designed for therapeutic purposes. Selection of most appropriate MoAbs will be performed by immunohistopathology, and ideally, those with antigens with lesser heterogeneous expression and which are inducible will be preferred. 3. Devising methods to interfere with target breast tumor heterogeneity and increase antigenic expression with hormones and other factors. 4. Development of methods to measure accurately tumoricidal ability of MoAbs and their conjugates and for the assessment of remaining tumor load. 5. Creating of chimeric MoAbs by transposition of murine variable regions to a human Ig frame.
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