Novel strategies to increase the therapeutic ratio in clinical radioimmunotherapy (RIT) trials. A humanized construct of the CC49 (HuCC49) high affinity anti-TAG-72 MAb is now available, as well aw with the CH2 region deleted (HuCC49deltaCH2). The CH2 domain deleted MAb may have more rapid tumor penetration, a decreased circulation time and retain tumor localization/persistence characteristics. Based on the promising clinical results obtained in ovarian cancer patients at UAB with 177Lu-CC49, it would be valuable to determine in preclinical studies whether 131|- or 177LU-HuCC49deltaCh2 administered in the peritoneum combined with administration of interferon (IFN)to upregulate TAG-72 antigen produces a higher relative tumor uptake in intraperitoneal tumor nodules compared to blood, and to determine the relative tumor efficacy at the maximum tolerated dose of 131|- or 177Lu-HuCC49deltaCH2 ve. 131|- or 177Lu- HuCC49.
The specific aims are to: 1)radiolabel the Mabs HUCC49deltaCH2 with 131| using the direct lodoGen procedure or the indirect ATE procedure and with 177LU using the PA-DOTA or CHX-A DTPA bifunctional chelating agent; 2)characterize the immuno reactivity, and in vitro and in vivo stabilities of 131|- and 177Lu-labeled Mabs HuCC49 and HuCC49deltaCH2; 3)compare the tumor localization and biodistribution of 131|- and 177LU-labeled Mabs HuCC49 and HuCC49deltaCH2 in thymic nude mice bearing an intraperitoneal human cancer xenograft model at various times after injection; 4) upregulate the expression of TAG-72 antigen in human ovarian and colon caner following administration of IFN by bolus, gene transfer, or continuous slow release , in order to improve tumor localization and therapy with radiolabled Mabs HuCC49 and HuCC49deltaCh2; and 5) compare the relative therapeutic efficacy of 131|- and 177 Lu-labeled MabsHuCC49 and HuCC49deltaCH2; in thymic nude mice bearing intraperitneal human cancer xenografts at escalating radionuclide doses at comparable maximum tolerated doses. We hypothesize that the use of HuCC49deltaCH2 antibody in combination with Ifn will result in highintraperitoneal tumor binding following tingraperitoneal injection relative to HuCC49 antibody, but a much more rapid clearance from blood. It remains to be determine whether regionally administered CH2 deleted antibody administered into the peritoneum will produce a greater therapeutic effect against intraperitoneal cancer at its maximum tolerated dose compared to intact antibody. The experiments descried in this proposal will provide answers to these questions. These studies would establish the rationale for human clinical RIT trials in patients with intraperitoneal cancer using HuCC49deltaCH2 and the optimum method of administration of IFN.
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