The primary objective of this competing renewal application is to initiate a clinical trial to determine if the second antibody (SA) method for removing extraneous amounts of radiolabeled antibody from the blood will improve tumor/nontumor ratios in patients. I-MN-14 anti-CEA IgG, a second generation, high-affinity murine MAb, will be used in combination with baboon anti-mouse IgG as the SA. The clinical objective is to determine the optimal dose for SA injection to preserve tumor uptake of the radiolabeled antibody while reducing circulating levels of the radioantibody that contributes to the total red marrow dose. This Phase I trial will be conducted using relatively low doses of the radiolabeled antibody and SA in order to provide initial evidence of safety for infusion of the SA. A second major objective of this application is the further development of alternative procedures for improving tumor/nontumor ratios. Since preclinical studies with the SA will be completed, we propose to initiate preclinical studies with the avidin-biotin targeting approach that has been shown by others to improve tumor/blood ratios. In this portion of the proposal, we will use the same GW-39 nude mouse model to develop procedures that optimize the avidin-biotin approach. By using the same model as we have used for the SA, we will be able to determine if the avidin-biotin approach will afford significant advantages over the SA procedure. We have elected to focus on the 3-step avidin-biotin conjugates, will be prepared. Coupling biotin to dextran will increase the total number of biotins that developed for coupling large number of drugs to MAbs will be used. In-and eventually Y-labeled biotinylated ITC-DTPA will be used for the final step. Biodistribution studies will be determine the optimal conditions for each agent, and then radioimmunotherapy studies will be initiated. Ultimately, this procedure will be compared not only to the SA method, but to directly labeled IgG and fragments, to determine if this approach warrants clinical consideration. Although I and Y are highlighted in this application, the long-term goal of this program is the evaluation of alternative procedures for RAIT that will include several candidate radionuclides in order to assist in the selection of agents and procedures for clinical trials.
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