The goal of this project is to develop a therapeutic approach for breast cancer using biologically active radioimmunoconjugates combined with other strategies. While our current focus is on the human chimeric form of L-6 (Ch L-6), a biologically active antibody reacting relatively specifically with adenocarcinoma, other MoAbs with interesting properties are under investigation. These include a biologically active MoAb that internalizes in adenocarcinoma cells, permitting new opportunities to enhance therapeutic effect. In our preliminary studies with L-6/l-131 Ch L-6, we have obtained measurable tumor regression in three of four patients with metastatic breast cancer. These early results suggest that this approach holds significant therapeutic potential. Redness and swelling over superficial lesions, a drop in serum complement, and an increase in the cytotoxic activity of these patient's peripheral blood mononuclear cells, suggest a biologic response to these antibodies which may relate to the degree of l-131 chimeric L-6 deposited in the tumor tissue. We are interested in a variety of enhancement strategies to further increase the therapeutic index: better radionuclides and radiochemistry for increasing tumor uptake and radiation dose rate; increasing radiolabeled MoAb to the tumor by preceding BRM, such as biologically active MoAb, interleukin, interferon, or radiation. Immunoplasmapheresis of the circulating radiolabeled MoAb after peak tumor uptake, provides a mechanism for decreasing radiation dose to the bone marrow. Pharmacokinetics and radiation dosimetry derived from quantitative imaging will provide the method for judging the effect of these approaches on the therapeutic index. Strengths of this project include an investigative team that has a record of accomplishment with the Lym-1 antibody in patients with lymphoma, has identified the problems to resolve in applying this approach to solid tumors, and has demonstrated some success in the brief period of this project. This project benefits from the comparative studies in Project 1 with B cell malignancies, and from the radiochemical developments of Project 3. The results of this investigation will provide information that is generally applicable to treatment with other radiolabeled antibodies, as well as other antibody targeted cancer therapeutic agents.
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