Radioimmunotherapy of a human lung cancer xenograft with monoclonal antibody RS7: Evaluation of Lu-177 and comparison of its efficacy with that of Y-90 and residualizing I-131

Tumor targeting and therapeutic efficacy of Lu-177-labeled monoclonal antib ody (mAb) RS7 (antiepithelial glycoprotein-1) was evaluated in a human nons mall cell lung carcinoma xenograft model. The potential of Lu-177-labeled R S7 was compared with that of RS7 labeled with Y-90 and a residualizing form of I-131. Methods: A 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraaceti c acid (DOTA) conjugate of RS7 was used for radiolabeling with Lu-177-aceta te or Y-88/90-acetate. Biodistribution and therapy studies were conducted i n nude mice with subcutaneous Calu-3 xenografts. Therapy studies were perfo rmed using the maxima[ tolerated doses (MTDs) of Y-90-DOTA-RS7 (3.9 MBq [10 5 mu Ci]) and Lu-177-DOTA-RS7 (10.2 MBq [275 mu Ci]) and compared with the data obtained using the MTD (13.0 MBq [350 mu Ci]) of a residualizing form of I-131-RS7. Results: Radiolabeling of RS7-DOTA conjugate with Lu-177-acet ate was facile. Lu-177-DOTA-RS7 displayed biodistribution results that were nearly identical to that of the Y-88 analog in a paired-label study. The m ean percentage injected doses per gram (%ID/g) for Lu-177-RS7 and Y-88-RS7 (in parentheses) in tumor were 38.3 %ID/g (39.1 %ID/g), 63.0 %ID/g (66.0 %I D/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 Lu-177-DOTA-RS7 r anging from 5.6 to 9.3 MBq (150-250 mu Ci) per nude mouse, with no signific ant difference in response rate noted between the doses in this range. Spec ificity of the therapeutic effect was shown in an isotype-matched control e xperiment, in which Lu-177-DOTA-RS7 was markedly more effective than the (L U)-L-177-DOTA control antibody. A comparison of the therapeutic efficacies of Lu-177-DOTA-RS7 and Y-90-DOTA-RS7, using mice with established tumors wi th an initial mean tumor volume of 0.85 cm(3), indicated similar tumor grow th inhibition and similar tumor regrowth profiles. The therapy data were si milar to those obtained with residualizing I-131-RS7 obtained at the same t ime. Conclusion: Lu-177-RS7 is an effective radioimmunoconjugate for radioi mmunotherapy. With its radiophysical properties similar to those of I-131, coupled with its facile and stable attachment to mAb, Lu-177 promises to be an alternative to I-131, and a complement to Y-90, in radioimmunotherapy.