Radioimmunotherapy of a Human Lung Cancer Xenograft with Monoclonal Antibody RS7: Evaluation of 177Lu and Comparison of Its Efficacy with That of 90Y and Residualizing 131I

Tumor targeting and therapeutic efficacy of 177 Lu-labeled monoclonal antibody (mAb) RS7 (antiepithelial glycoprotein-1) was evaluated in a human nonsmall cell lung carcinoma xenograft model. The potential of 177 Lu-labeled RS7 was compared with that of RS7 labeled with 90 Y and a residualizing form of 131 I. Methods: A 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) conjugate of RS7 was used for radiolabeling with 177 Lu-acetate or 88/90 Y-acetate. Biodistribution and therapy studies were conducted in nude mice with subcutaneous Calu-3 xenografts. Therapy studies were performed using the maximal tolerated doses (MTDs) of 90 Y-DOTA-RS7 (3.9 MBq [105 μCi]) and 177 Lu-DOTA-RS7 (10.2 MBq [275 μCi]) and compared with the data obtained using the MTD (13.0 MBq [350 μCi]) of a residualizing form of 131 I-RS7. Results: Radiolabeling of RS7-DOTA conjugate with 177 Lu-acetate was facile. 177 Lu-DOTA-RS7 displayed biodistribution results that were nearly identical to that of the 88 Y analog in a paired-label study. The mean percentage injected doses per gram (%ID/g) for 177 Lu-RS7 and 88 Y-RS7 (in parentheses) in tumor were 38.3 %ID/g (39.1 %ID/g), 63.0 %ID/g (66.0 %ID/g), 63.0 %ID/g (65.8 %ID/ g), and 34.0 %ID/g (34.9 %ID/g) on days 1, 3, 7, and 14, respectively. Elimination of established tumors, with an initial mean tumor volume of 0.24 cm 3 , was shown using doses of 177 Lu-DOTA-RS7 ranging from 5.6 to 9.3 MBq (150-250 μCi) per nude mouse, with no significant difference in response rate noted between the doses in this range. Specificity of the therapeutic effect was shown in an isotype-matched control experiment, in which 177 Lu-DOTA-RS7 was markedly more effective than the 177 Lu-DOTA control antibody. A comparison of the therapeutic efficacies of 177 Lu-DOTA-RS7 and 90 Y-DOTA-RS7, using mice with established tumors with an initial mean tumor volume of 0.85 cm 3 , indicated similar tumor growth inhibition and similar tumor regrowth profiles. The therapy data were similar to those obtained with residualizing 131 I-RS7 obtained at the same time. Conclusion: 177 Lu-RS7 is an effective radioimmunoconjugate for radioimmunotherapy. With its radiophysical properties similar to those of 131 I, coupled with its facile and stable attachment to mAb, 177 Lu promises to be an alternative to 131 I, and a complement to 90 Y, in radioimmunotherapy.