Comparative efficacy of ¹⁷⁷Lu and ⁹⁰Y 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 (⁹⁰Y) and lutetium-177 (¹⁷⁷Lu) 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 ⁹⁰Y has been successfully applied in a number of preclinical and clinical radioimmunotherapy settings, there have been few published pretargeting studies with ¹⁷⁷Lu. We therefore compared the therapeutic potential of targeting either ⁹⁰Y or ¹⁷⁷Lu 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 antibodystreptavidin conjugate (1F5-SA) and an ⁹⁰Y- or ¹⁷⁷Lu-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 ⁹⁰Y (1.3 Gy/MBq) as for ¹⁷⁷Lu (0.6 Gy/MBq). More importantly, therapy with ⁹⁰Y-DOTAbiotin was dramatically more effective than with ¹⁷⁷Lu-DOTA-biotin, with 100% of Ramos xenograft-bearing mice cured with 37 MBq ⁹⁰Y, whereas 0% were cured using identical amounts of ¹⁷⁷Lu-DOTA-biotin. Similar results were observed in mice bearing Granta xenografts, with 80% of the mice cured with ⁹⁰Y-PRIT and 0% cured with ¹⁷⁷Lu-PRIT. Toxicities were comparable with both isotopes. Conclusion ⁹⁰Y was therapeutically superior to ¹⁷⁷Lu for streptavidin-biotin PRIT approaches in these human lymphoma xenograft models