RADIODIAGNOSIS OF SCCL WITH ANTIBODIES TO NEUROPHYSINS

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The purpose of this project is to determine the contribution that antibodies to human neurophysins can make to radiodiagnosis of small-cell carcinoma of the lung (SCCL). Human neurophysins (HNPs) are produced by most SCCL tumors, and this persistent property leads to the generation of surface makers (neurophysin- related antigens, NPRA) that are recognized by antibodies to HNPs. Pilot studies conducted with 131 I-labelled forms of these antibodies indicate they can be employed to effectively radioimage SCCL in all patients with HNP-producing tumors. Specific Aims are directed towards: (i) performing a comprehensive evaluation of 131 I-labelled polyclonal anti-HNPs as radiodiagnostic agents for SCCL with respect to their provision of a sensitive, specific, and informative method of tumor imaging that complements standard methods of diagnosis; (ii) appraising available monoclonal anti-HNPs (and their Fab, Fab' and F(ab')2 fragments) for possible clinical application based on their capacity to bind to SCCL cells in vitro, their ability to provide clear radioimages of tumor xenografts in athymic mice, their specificity for tumor cells, and their biodistribution of clearance; (iii) conducting patient studies with a radiolabelled preparation and monoclonal anti-HNP chosen from animal studies for its potential clinical utility; and (iv) applying our knowledge of HNP biosynthesis and tumor vascular resistance to develop improved methods for radioimaging SCCL tumors with anti-HNPs. Concurrent clinical investigations with polyclonal antibodies and animal studies on monoclonal antibody evaluation will precede the experimental use of monoclonal antibodies in patients and those studies on pharmacological manipulation designed to improve delivery of radionuclide to tumors. Quantitative information on tumor binding of radionuclides, tissue dosimetry, and the tumor specificity of our antibodies will be obtained by gamma-camera bidirectional scintigraphy, radiometric analysis and immunocytochemistry. Antibody binding in vitro will be assessed by cytofluorometry and radiometric analysis. A chronically catheterized conscious rat preparation will be employed for biodistribution and clearance studies. The proposed research is expected to lead not only to the adoption of anti-HNPs as valuable diagnostic agents, but also to their eventual use in the therapeutic management of SCCL.