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Comparison of Immunoscintigraphy, Efficacy, and Toxicity of Conventional and Pretargeted Radioimmunotherapy in CD20-Expressing Human Lymphoma Xenografts

¹ Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
² Department of Radiation Oncology, University of Washington, Seattle, Washington
³ Department of Medicine, University of Washington, Seattle, Washington
⁴ NeoRx Corporation, Seattle, Washington
⁵ Department of Bioengineering, University of Washington, Seattle, Washington
⁶ Department of Biological Structure, University of Washington, Seattle, Washington

Pretargeted radioimmunotherapy (RIT) using streptavidin (sAv)-conjugated antibodies before radiolabeled-biotin is a promising approach to improve absorbed dose ratios and achieve high durable remission rates with diminished systemic toxicity. This study compared the immunoscintigraphy, toxicity, and therapeutic efficacy of pretargeted RIT with conventional RIT using an anti-CD20 antibody. Methods: Athymic mice bearing Ramos human Burkitt’s lymphoma xenografts were injected intraperitoneally with a 1F5-sAv conjugate followed 24 h later by a galactosylated, biotinylated clearing agent (CA) and, finally, 3 h later by ¹¹¹In- or ⁹⁰Y-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-biotin. The comparison groups consisted of mice injected with conventional, directly labeled ¹¹¹In- or ⁹⁰Y-1F5. Results: Rapid tumor uptake of radioactivity within 2 h was observed with the pretargeting approach, resulting in high-contrast tumor images at 24 h with minimal blood-pool radioactivity. Although conventional radiolabeled antibodies produced clear tumor images at 24 h, a large amount of radioactivity was present in the blood pool. The tumor-to-blood ratio was 3.5:1 with pretargeting compared with 0.4:1 with conventional ¹¹¹In-1F5. Pretargeted RIT with 29.6 MBq (800 µCi) ⁹⁰Y-DOTA-biotin cured 100% of mice with tolerable toxicity, whereas conventional RIT with ⁹⁰Y-1F5 at a dose of 14.8 MBq (400 µCi) produced no cures, induced profound pancytopenia, and was lethal to all mice. Conclusion: These results suggest that anti-CD20 pretargeted RIT may be superior to conventional radiolabeled antibodies in terms of radioimmunoscintigraphy, toxicity, and therapeutic efficacy for treatment of B-cell lymphomas.

Key Words: immunoscintigraphy • CD20 • pretargeting • streptavidin • biotin • lymphoma

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