The overall objective of this program is to demonstrate a role for radiolabeled, engineered antibodies in the treatment of human colonic cancer and other solid tumors which produce carcinoembryonic antigen (CEA). An initial clinical goal is to evaluate existing preparations such as Y-90 labeled, mouse-human chimeric anti-CEA antibodies in phase I trials to determine the maximum tolerated dose. Later, we will use phase II trials for this preparation as a benchmark for comparison to other, improved preparations, including engineered antibody fragments and more stable radiometal chelates which offer more favorable tumor to normal tissue uptake ratios which can improve the therapeutic index. These studies include a comprehensive approach towards (a) antibody engineering, antibody production and testing, (b) RIT evaluation in animal models, including imaging, therapy, dosimetry, immunopathology, and radiobiology, (c) synthesis and testing of a variety of metal ion complexes, their conjugation chemistry to antibodies with several chemical linkers, and (d) movement of improved preparations through the IND process for human studies. Engineered antibody fragments will include a stabilized chimeric F(ab')2 fragment, a chimeric CH2 deleted fragment, and chimeric single chain antibodies. Two anti-CEA antibodies will be employed, each with high CEA specificity, but differing in their epitope recognition and antigen affinity. This approach will allow us to manipulate normal tissue uptake, especially in the liver, and to switch preparations in patients who undergo an immune response to administered chimeric antibodies. Novel metal ion complexes include (a) macrocyles with improved stability for binding Y-90, cu-67, and other therapeutically useful radiometals, (b) carboboranes such as the Venus Flytrap Cluster which has improved liver clearance compared to In- 111/DTPA systems, and is suitable for other transition metal radionuclides such as Rh-105, and (c) metal oxide clusters which are suitable for radiometals such as Re-186. Appropriate radiometal/chelate/antibody preparations will be submitted for INDs for use in phase I/phase II trials with the overall goal of demonstrating tumor reduction, especially in smaller lesions. This program is unique in allowing us to monitor and control all of the parameters involved in RIT from the generation of antibodies and radiometal conjugates to their evaluation in human studies.
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