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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

Garden State Cancer Center, Belleville; and Immunomedics, Inc., Morris Plains, New Jersey

Tumor targeting and therapeutic efficacy of ¹⁷⁷Lu-labeled monoclonal antibody (mAb) RS7 (antiepithelial glycoprotein-1) was evaluated in a human nonsmall cell lung carcinoma xenograft model. The potential of ¹⁷⁷Lu-labeled RS7 was compared with that of RS7 labeled with ⁹⁰Y and a residualizing form of ¹³¹I. Methods: A 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) conjugate of RS7 was used for radiolabeling with ¹⁷⁷Lu-acetate or ^88/90Y-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 ⁹⁰Y-DOTA-RS7 (3.9 MBq [105 µCi]) and ¹⁷⁷Lu-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 ¹³¹I-RS7. Results: Radiolabeling of RS7-DOTA conjugate with ¹⁷⁷Lu-acetate was facile. ¹⁷⁷Lu-DOTA-RS7 displayed biodistribution results that were nearly identical to that of the ⁸⁸Y analog in a paired-label study. The mean percentage injected doses per gram (%ID/g) for ¹⁷⁷Lu-RS7 and ⁸⁸Y-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 cm³, was shown using doses of ¹⁷⁷Lu-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 ¹⁷⁷Lu-DOTA-RS7 was markedly more effective than the ¹⁷⁷Lu-DOTA control antibody. A comparison of the therapeutic efficacies of ¹⁷⁷Lu-DOTA-RS7 and ⁹⁰Y-DOTA-RS7, using mice with established tumors with an initial mean tumor volume of 0.85 cm³, indicated similar tumor growth inhibition and similar tumor regrowth profiles. The therapy data were similar to those obtained with residualizing ¹³¹I-RS7 obtained at the same time. Conclusion: ¹⁷⁷Lu-RS7 is an effective radioimmunoconjugate for radioimmunotherapy. With its radiophysical properties similar to those of ¹³¹I, coupled with its facile and stable attachment to mAb, ¹⁷⁷Lu promises to be an alternative to ¹³¹I, and a complement to ⁹⁰Y, in radioimmunotherapy.

Key Words: ¹⁷⁷Lu • ⁹⁰Y • ¹³¹I • residualizing labels • radioimmunotherapy

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