The monoclonal antibody program is designed to develop new treatment approaches for lung cancer by using monoclonal antibodies conjugates which recognize differentiation antigens and monoclonal antibodies which interefere with the autocrine growth pathways of lung cancer. The antibodies will be delivered by the intravenous and perfusion routes. Epithelial antigens which are commonly expressed on non-small cell lung cancers include: 1) human milk fat globule (HMFG) antigens, 2) Lewis blood group antigens, 3) other complex carbohydrate antigens including lacto- N-fucopentoase III (LNFPIII). Our first approach will be to evaluate the KC4 anti-HMFG antibody as well as the NKH-1 antibody which binds to a commonly expressed differentiation antigen on small cell lung cancer. We will evaluate these antibodies both unlabeled and radiolabeled. The radioisotopes will include 125-I, 131-I, 90-Yt, 212-lead, and 212-bismuth. We will assess antitumor effects in vitro with growth curves and with soft agarose cloning assays. In vivo, we will utilize athymic nude mice with subcutaneously implanted tumors and nude rats with intrabronchially implanted tumors. The latter will enable us to evaluate lung perfusions to reduced or eliminate systemic effects and increase the dose to tumor. The perfusion system should provide an excellent model for study of alpha and beta emitting radioimmunoconjugates. In these studies we will determine the optimal antibody dose and the radiation dosimetry to tumor and various organs with the different isotopes in differing concentrations and specific activities. Once the optimal dose of antibody and isotope are established we will be able to evaluate the in vivo therapeutic and toxic effects in the tumor bearing dogs provided by the CSU component of this project. Small cell lung cancers are known to produce and secrete a number of growth factors including gastrin releasing peptide (bombesin), insulin like growth factor and transferrin. The growth factors for non-small cell lung cancers are less well defined but epidermal growth factor appears to stimulate the growth of many of these carcinomas. Monoclonal antibodies to these growth factors or their receptors may interfere with their autocrine growth and inhibit proliferation. BBC353, a monoclonal antibody which binds GRP with high affinity, inhibits the growth of small cell lung cancer lines in vitro and in some instances in vivo. Antibodies which react with growth factors or their receptors may also affect some normal cells and may produce toxicity in vivo. In these experiments, we will evaluate the optimal in vivo conditions for therapy including dose, route and schedule. Our model systems will allow delivery of high doses of antibody and radiolabeled antibodies without systemic toxicities.
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