The long term goals described in this physician-scientist grant proposal are to learn the hybridoma technology and apply it to the radiologic and scintigraphic diagnosis of disease. The application of monoclonal antibodies currently being used in Nuclear Medicine is limited by immunogenicity, relatively low affinity, and inherent limitations in pharmacokinetics. In the past, analysis of factors that affect antibody targeting has been hampered ny inability to control for the effect of numerous confounding variables. By utilizing the extremely modifiable model target which we have created, behavior of families of modified antibodies can be compared in a rigorous manner. In this way, we intend to systematically analyze the effect of affinity, avidity, half-life, class and subclass, antigen density and circulating antigen in order to understand the contribution of these factors to antibody targeting and imaging. Initially, families of closely related mouse monoclonals different classes and with different affinities and avidities will be used to determine whether higher binding will significantly increase their effectiveness in targeting and imaging of haptenated beads. Subsequently, mutant antibodies generated by somatic cell genetics and recombinant DNA technology will be evaluated. Once the optimal characteristics of antibodies for targeting have been defined, SCID mice populated with human lymphoid cells will be investigated for use in generating human monoclonal antibodies with these attributes. In this way, we hope to produce optimized monoclonal antibodies for ultimate use in Nuclear Medicine diagnosis and therapy.
