Radiolabeled
monoclonal antibodies (MoAbs) have been used for
radioimmunotherapy (RIT) of human
colon cancer xenografts in an attempt to develop promising clinical approaches to improving
therapy success. Several strategies have been investigated to accomplish this task while decreasing toxicity. The
CC49 antibody was selected for the present studies 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 human
colon cancer cells. In previous studies, when CC49 was labeled with 131I, it demonstrated a substantial therapeutic advantage over the lower affinity antibody (
B72.3) reactive with
TAG-72. One of the chief 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 131I-labeled intact MoAbs reactive with human
colon cancer xenografts, multiple administrations at approximately 1-week intervals were found to produce more prolonged
tumor growth inhibition and less toxicity than single administrations. The purpose of this study was to investigate the therapeutic efficacy and toxicity of 131I-labeled CC49 MoAb administered with short fractionation schedules against human
colon cancer xenografts to determine the optimal treatment schedule, with the ultimate aim of applying this approach in clinical trials. The results reported here demonstrate that in an animal
colon cancer xenograft model, RIT delivered in a fractionated schedule clearly presents a therapeutic advantage. For example, one administration of 600 microCi 131I-labeled CC49 to LS174T
tumor-bearing mice was lethal to approximately 25% of mice but produced no
tumor regressions. Fractionation of this dose to two administrations of 300 microCi 131I-labeled CC49 at a 3-day interval resulted in
tumor regression in approximately 30% of the animals, accompanied by a similar 25% death rate. The administration of 300 microCi 131I-labeled CC49 at a 7-day interval resulted in 15% animal lethality, but no complete
tumor regressions. When three administrations of 300 microCi 131I-labeled CC49 were given over a 1-week period on days 0, 3, and 7,
tumor regressions occurred in approximately 40% of the animals, accompanied by a 30% death rate. Moreover, three administrations of 300 microCi 131I-labeled CC49 resulted in 20%
tumor recurrence, whereas two administrations of 131I-labeled CC49 resulted in 60%
tumor recurrence.(ABSTRACT TRUNCATED AT 400 WORDS)