Comparative efficacy of 177Lu and 90Y for anti-CD20 pretargeted radioimmunotherapy in murine lymphoma xenograft models

Abstract

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 antibody-streptavidin 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-DOTA-biotin 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.

Fig 1. Comparative biodistributions of radioactivity in mice bearing subcutaneous Ramos xenografts.

Mice were injected with 1.4 nmol 1F5-SA (A and B) or HB8181-SA (C and D), together with 400 μg of HB8181. Circulating MAb-SA was cleared by administration of 5.8 nmol of NAGB 20 hours p.i. Four hours later, 2.4 nmol of either ¹⁷⁷Lu- (A and C) or ⁹⁰Y-labeled (B and D) DOTA-biotin was injected. Tissues were harvested 4, 24, 48, or 120 hours p.i. and the radioactive content expressed as %IA/g (± SD; n = 5) after corrections for decay and background. *Error bar extends to 19.4%IA/g.

Fig 2. Autoradiographs acquired using the novel iQID camera.

Panels show the distribution of ¹⁷⁷Lu (A, C, and E) and ⁹⁰Y (B, D, and F) 24 hours after injection of labeled DOTA-biotin in 1F5-SA-pretargeted tumor (A and B), liver (C and D), and kidney (E and F) cryosections. The scales apply to all panels; the color bar represents relative pixel intensity normalized to the mean for the tumor sections and the white scale bar indicates 5 mm.

Fig 3. Regression of Ramos and Granta xenografts in athymic mice after either ¹⁷⁷Lu- or ⁹⁰Y-PRIT.

Mice were injected with 1.4 nmol of 1F5-SA or HB8181-SA, together with 400 μg of HB8181. Circulating MAb-SA was cleared by administration of 5.8 nmol of NAGB after 20 hours, followed by 15–37 MBq of either ¹⁷⁷Lu- or ⁹⁰Y-labeled DOTA-biotin (2.4 nmol) 4 hours later. Ten xenograft mice per tumor model served as control group (PBS only). The curves were truncated at the time of euthanasia of the first mouse in each treatment group (mm³ ± SD; n = 10).

Fig 4. Kaplan-Meier survival curves of mice carrying either Ramos or Granta xenografts after ¹⁷⁷Lu-/ ⁹⁰Y-PRIT.

Athymic nude mice were i.v. injected with 300 μg of 1F5-SA or HB8181-SA, together with 400 μg of HB8181, followed 20 hours later by 50 μg of NAGB. Four hours later, ¹⁷⁷Lu- or ⁹⁰Y-labeled DOTA-biotin was administered: 15, 30, or 37 MBq for Ramos xenografts; 37 MBq for Granta (n = 10). Control groups received no treatment (PBS only).

Fig 5. Radiation-induced toxicity in non-xenografted mice after treatment with 37 MBq of ¹⁷⁷Lu- or ⁹⁰Y-PRIT.

1F5-SA (300 μg) was co-injected with 400 μg of HB8181, followed 20 hours later by 50 μg of NAGB. Four hours later, 37 MBq of either ¹⁷⁷Lu- or ⁹⁰Y-labeled DOTA-biotin was administered. The control group received no injections. (WBC (A) and PLT (B) counts ± SD; n = 10).