The objective of this project is to optimize imaging of cancer using radiolabeled monoclonal antibody (MAB) and to understand the factors that affect tumor and normal tissue uptake of label and MAB so that effective therapy with labeled MAB can be planned. Initial studies utilized murine anti-CEA MAB for imaging colon cancer. Patients planned for diagnostic or therapeutic operative procedures have been studied with (111) In MAB preoperatively, and imaging results have been compared with operative findings and tissue analyses. A clinical role for (111) In anti-CEA MAB imaging has been documented in presurgical cancer staging of patients with known or suspected hepatic metastases. Factors related to tumor imaging include tumor size, tumor location, tumor CEA content and tumor CEA immunohistology. A problem of post-scan artifactual elevation of plasma CEA related to HAMA production has been identified. In the current application, these studies will be augmented by further studies of MAB metabolism and human immune response to MAB. In addition, patients with adenocarcinomas of the stomach, pancreas, breast and lung will be studied. Based upon results of in vitro and animal studies in our laboratory, reduction in liver uptake will be accomplished by use of human chimeric MAB, manipulation of MAB affinity and evaluation of specific antibody pretreatment (SAP). A second panel of MABs specific for TAG-72 will be studied in similar fashion and evaluated mixed with anti-CEA MAB (""""""""cocktail""""""""). By fusion of anti-CEA hybridomas with anti-TAG-72, quadromas will be produced. The resultant bispecific hybrid MABs will be tested in nude mice and evaluated in patients for tumor uptake and imaging. It is hypothesized that bispecific antibodies will have a major benefit in dealing with tumor and cellular heterogeneity. These studies are important for critical evaluation and scientific development of labeled MAB for cancer imaging and therapy. Innovative aspects of the proposal include: preoperative imaging, tissue analyses, presurgical cancer staging, manipulations for reduction of liver uptake (SAP, affinity), human chimeric antibodies and bispecific hybrid antibodies.
