FRACTIONATED RADIOIMMUNOTHERAPY OF HUMAN COLON-CARCINOMA XENOGRAFTS WITH I-131-LABELED MONOCLONAL-ANTIBODY CC49

Radiolabeled monoclonal antibodies (MoAbs) have been used for radioimm unotherapy (RIT) of human colon cancer xenografts in an attempt to dev elop promising clinical approaches to improving therapy success, Sever al strategies have been investigated to accomplish this task while dec reasing toxicity, The CC49 antibody was selected for the present studi es because of its relatively high affinity constant (16.2 x 10(9) M(-1 )) for the high molecular weight TAG-72 mucinous antigen secreted by h uman colon cancer cells, In previous studies, when CC49 was labeled wi th I-131, it demonstrated a substantial therapeutic advantage over the lower affinity antibody (B72.3) reactive with TAG-72, One of the chie f problems in achieving cures with RIT is that hematological toxicity limits the quantity of radionuclide that can be administered, In other studies of dose fractionation using athymic nude mice and I-131-label ed intact MoAbs reactive with human colon cancer xenografts, multiple administrations at approximately 1-week intervals were found to produc e more prolonged tumor growth inhibition and less toxicity than single administrations. The purpose of this study was to investigate the the rapeutic efficacy and toxicity of I-131-labeled CC49 MoAb administered with short fractionation schedules against human colon cancer xenogra fts to determine the optimal treatment schedule, with the ultimate aim of applying this approach in clinical trials. The results reported he re demonstrate that in an animal colon cancer xenograft model, RIT del ivered in a fractionated schedule clearly presents a therapeutic advan tage, For example, one administration of 600 mu Ci I-131-labeled CC49 to LS174T tumor-bearing mice was lethal to approximately 25% of mice b ut produced no tumor regressions, Fractionation of this dose to two ad ministrations of 300 mu Ci I-131-labeled CC49 at a 3-day interval resu lted in tumor regression in approximately 30% of the animals, accompan ied by a similar 25% death rate, The administration of 300 mu Ci I-131 -labeled CC49 at a 7-day interval resulted in 15% animal lethality, bu t no complete tumor regressions, When three administrations of 300 mu Ci I-131-labeled CC49 were given over a 1-week period on days 0, 3, an d 7, tumor regressions occurred in approximately 40% of the animals, a ccompanied by a 30% death rate, Moreover, three administrations of 300 mu Ci I-131-labeled CC49 resulted in 20% tumor recurrence, whereas tw o administrations of I-131-labeled CC49 resulted in 60% tumor recurren ce, The data in the present study concerning the concentration of I-12 5-labeled CC49 in LS174T tumors following one or two treatments with I -131-labeled CC49 at a 3-day interval suggest that a higher concentrat ion of radiolabeled antibody was maintained in the tumor for a longer period of time than would have occurred with a single administration o f I-131-labeled CC49. The studies reported here demonstrate that fract ionated administrations of I-131-labeled CC49 at short time intervals can clearly elicit both tumor regressions and cures with limited toxic ity in a model using relatively large established human colon carcinom a xenografts, The results of the present study suggest that initial tr ials in humans should be designed with the goal of determining a fract ionation interval of a nonimmunogenic genetically engineered or human antibody that reduces bone marrow toxicity but permits similar tumor u ptake of each radiolabeled antibody injection.