Comparative Efficacy of (177)Lu and (90)Y for Anti-CD20 Pretargeted Radioimmunotherapy in Murine Lymphoma Xenograft Models

PURPOSE: Pretargeted radioimmunotherapy (PRIT) is a multi-step method of selectively delivering high doses of radiotherapy to tumor cells while minimizing exposure to surrounding tissues. Yttrium-90 ((90)Y) and lutetium-177 ((177)Lu) are two of the most promising beta-particle emitting radionuclides used for radioimmunotherapy, which despite having similar chemistries differ distinctly in terms of radiophysical features. These differences may have important consequences for the absorbed dose to tumors and normal organs. Whereas (90)Y has been successfully applied in a number of preclinical and clinical radioimmunotherapy settings, there have been few published pretargeting studies with (177)Lu. We therefore compared the therapeutic potential of targeting either (90)Y or (177)Lu to human B-cell lymphoma xenografts in mice. METHODS: Parallel experiments evaluating the biodistribution, imaging, dosimetry, therapeutic efficacy, and toxicity were performed in female athymic nude mice bearing either Ramos (Burkitt lymphoma) or Granta (mantle cell lymphoma) xenografts, utilizing an anti-CD20 antibody-streptavidin conjugate (1F5-SA) and an (90)Y- or (177)Lu-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-biotin second step reagent. RESULTS: The two radionuclides displayed comparable biodistributions in tumors and normal organs; however, the absorbed radiation dose delivered to tumor was more than twice as high for (90)Y (1.3 Gy/MBq) as for (177)Lu (0.6 Gy/MBq). More importantly, therapy with (90)Y-DOTA-biotin was dramatically more effective than with (177)Lu-DOTA-biotin, with 100% of Ramos xenograft-bearing mice cured with 37 MBq (90)Y, whereas 0% were cured using identical amounts of (177)Lu-DOTA-biotin. Similar results were observed in mice bearing Granta xenografts, with 80% of the mice cured with (90)Y-PRIT and 0% cured with (177)Lu-PRIT. Toxicities were comparable with both isotopes. CONCLUSION: (90)Y was therapeutically superior to (177)Lu for streptavidin-biotin PRIT approaches in these human lymphoma xenograft models.