The broad long-term goal of this project is to harness the physical and chemical properties of metallic elements to the diagnosis and treatment of cancer. Bifunctional chelating agents are powerful molecules tightly attaching metal ions to biological molecules. Thus the enhanced combined properties of the conjugates can probe specifically, report function, and treat living tumors.
Specific aims are to produce new anti-hapten monoclonal antibodies (MoAbs) with high affinity and specificity for the metal chelates of In, Ga, Y, and Tc; to study the biological behavior of new bifunctional monoclonal antibodies having one tumor specific binding site and the other chelate (hapten or biotin) specific; to use these new agents in a novel pretargeted immunoscintigraphy technique in which antibody and radiolabel are given separately, to lower liver and blood background and improve tumor to background ratios; to determine the optimum interval between bifunctional MoAb and radiolabeled hapten or biotin-chelate, determine the effect of """"""""chase"""""""" agents and make early images at 1 to 3 hours using Tc-99m and Ga-68 with the ultimate aim of making SPECT and PET tumor images in cancer patients;: to study new macrocyclic chelators for increased in vivo and in vivo stability and kinetic inertness to ligand exchange with In-111, Tc-99m, Ga-68, and Y-90 MoAbs; to use various metabolizable chelate-antibody linkers to increase clearance of background activity via the kidney; to carry out tumoricidal experiments using pretargeting of tumors and Y-90 chelates; to carry out clinical scintillation imaging using both PET and SPECT in human cancer patients with the most promising agents. The Methodology involves hybridoma technology using specially designed antigens, screening mice with radiolabeled antigen, tumor mouse distribution of new bifunctional antibodies with dual specificity for tumor and chelate, use of an avidin- biotin system in a pretargeted immunoscintigraphy method with 1-2 hr images using Tc-99m and Ga-68 and therapy with Y-90. These studies should provide methods for reducing background and improving the effectiveness of monoclonal antibodies in tumor imaging and therapy. These methods will provide the clinician with an """"""""instant kit"""""""" that can be labeled with readily available radionuclides economically, for easy application in todays nuclear medicine department.
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