The goal of this research is to construct improved antibody-radioisotope conjugates for diagnosis and therapy of human cancer. Currently, the chemical properties for some chelates that provide stable complexes with radiometals also produce unacceptable patterns of biodistribution in the normal tissues of injected animals. We have demonstrated, however, that chemical linkers placed between the chelated radionuclide and the antibody can alter the biodistribution patterns and greatly improve the ratio of dose delivered to the tumor compared to normal tissue. These studies show that the chemical nature of this spacer/linker can modulate the biodistribution of the antibody-linker-chelateradioisotope conjugate. These results in turn offer the opportunity to select an improved linker that permits the application of a wide spectrum of chelate-specific radionuclides to tumor imaging/therapy that have similar characteristics: (i) stable chelation to prevent metal radionuclide toxicity; (ii) rapid tumor localization; (iii) improved biodistribution that lessens targeting of radiosensitive normal tissue; (iv) improved clearance from the blood; and (v) undiminished antibody specificity. We now propose to test whether a linker-spacer, which has been shown by our preliminary studies to have such properties when linking a specific chelate and antibody, retains those properties with other forms of chelated radioisotopes and with monoclonal/polyclonal antibody systems. Since we have well characterized systems of antibodies both in experimental, tumor bearing animals and in human patients, we can evaluate new conjugates in a rapid, cost-effective manner. Many of the syntheses to be performed have either been completed or have been partially completed, permitting rapid development of the several chemical products required. The chemical stability of the linker-conjugate will be determined by HPLC and TLC analyses of plasma and urine samples collected from the injected animals. The metabolic process of linkers will be determined in vitro by incubating radioimmunoconjugates with serum samples and with muscle, liver and tumor tissue homogenates and in vivo with liver and tumor tissue homogenates. The tumor imaging will be investigated using nude mice implanted with human tumor xenografts.
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