The overall objective of this program is to demonstrate that radiolabelled monoclonal antibodies, recombinant antibodies, and synthetic antibodies can be used for tumor imaging and therapy. Antibodies to carcinoembryonic antigen will be used throughout this Program because of their specificity for colon cancer. The main advantages of using recombinant and synthetic antibodies are the murine monoclonal antibodies can be engineered into mouse-human chimeric antibodies to eliminate an immune response in humans and the antigen combining sites can be redesigned for higher affinity constants and more desirable epitope specificities, and the reagents are indefinitely stable unlike monoclonal antibodies grown in hybridoma cell lines. The recombinant antibodies will be expressed in murine transfectomas. The recombinant antibodies will be extensively tested in mice and nude mice bearing tumor xenografts before being used in humans. An orderly series of experiments in animals is planned to determine the parameters and efficacy of using radiolabeled antibodies in humans. These experiments involve input from a group of experts in Nuclear Medicine, Radiation Oncology, Radiobiology, Radiation Physics, Surgery, Immunohistology, Immunochemistry, Chelation Chemistry, and Radiopharmacology. The effect of copper-67 and yttrium-90 labeled antibodies on tumors and normal tissue will be carefully studied before recommending their use in humans. Radioimaging studies in humans include tumor and normal tissue biodistribution, lymph node uptake, different routes of injection, liver uptake, immune response to repeated injections of antibody, and the possibility of an anti-idiotype response. The Large Scale Tissue Culture Laboratory will produce recombinant and synthetic antibodies from transfectomas in the amounts needed for these experiments. The synthetic antibodies will be designed from oligonucleotide cassettes corresponding to subregions of heavy and light chains, and utilizing our molecular modeling facility. CEA and epitope subregions will be expressed in order to study the nature of the antigen-combining site and to model the antigen-antibody interaction. These projects should lead to the rational design and use of natural, recombinant, and synthetic antibodies for tumor imaging and therapy in humans, and will lead to a better understanding of the in vivo distribution of antibodies to CEA.
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