ANTIBODY-CHELATE CONJUGATES

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The specific aims of this project is to interact with Projects 1 and 2 to develop improved bifunctional chelating agent technology for clinical use, and to characterize immunoconjugates not only by standard methods, but also by determining the exact sites of attachment of bifunctional chelating agents to monoclonal antibodies. Our plans for the next grant period are: 1. To develop large-scale clinical pre-labeling with the new bifunctional chelating agents DOTA-peptide and -isothiocyanate, so that therapeutic amounts of 90Y can be administered to patients with minimal amounts of antibody. To study a set of rationally chosen peptide linkers to optimize the biological properties of these molecules. The pre- labeling approach promises to greatly improve the biological properties of yttrium immunoconjugates, and others as well. 2. To explore the advantages of TETA-peptide reagents for 67Cu radioimmunotherapy. It is expected that the peptide linker can lead to lower levels of radioactivity in the liver than ar currently obtained with the 2-iminothiolane linker. 3. Using the methods developed during the current period, to map the peptide sites on the antibodies conjugated with reagents employed during the next grant period. This degree of characterization will allow us to correlate biodistribution patterns and modified sites. 4. To begin biological testing of engineered proteins that we have produced. This will lead to targeting molecules with selected properties, which may be tailored to the physiology of each target. Many metal ions form chelate complexes. Stable attachment of metal ions to antibodies by means of "bifunctional" chelating agents can add the nuclear, physical, and chemical properties of the metallic elements to these target-selective proteins. As the clinical use of radiolabeled monoclonal antibodies proceeds, a few antibodies have been found to be useful in vivo for both diagnosis and therapy of human patients. A prime example is the antibody Lym-1. this mouse lgG2a(k) antibody, produced against Burkitt's lymphoma, binds to a membrane-bound glycoprotein which is strongly expressed on many human lymphoma and lymphocytic leukemia cells. We have successfully imaged patients with these diseases using this antibody labeled with 131I, 67Cu, 111In. We have also delivered effective radioimmunotherapy on this antibody to lymphoma patients using 131I and 67Cu.