Conventional and pretargeted radioimmunotherapy using bismuth-213 to target and treat non-Hodgkin lymphomas expressing CD20: a preclinical model toward optimal consolidation therapy to eradicate minimal residual disease

Radioimmunotherapy (RIT) with alpha-emitting radionuclides is an attractive approach for the treatment of minimal residual disease because the short path lengths and high energies of alpha-particles produce optimal cytotoxicity at small target sites while minimizing damage to surrounding normal tissues. Pretargeted RIT (PRIT) using antibody-streptavidin (Ab-SA) constructs and radiolabeled biotin allows rapid, specific localization of radioactivity at tumor sites, making it an optimal method to target alpha-emitters with short half-lives, such as bismuth-213 (Bi-213). Athymic mice bearing Ramos lymphoma xenografts received anti-CD20 1F5(scFv)(4)SA fusion protein (FP), followed by a dendrimeric clearing agent and [Bi-213] DOTA-biotin. After 90 minutes, tumor uptake for 1F5(scFv) 4SA was 16.5% +/- 7.0% injected dose per gram compared with 2.3% +/- .9% injected dose per gram for the control FP. Mice treated with anti-CD20 PRIT and 600 mu Ci [Bi-213] DOTA-biotin exhibited marked tumor growth delays compared with controls (mean tumor volume .01 +/- .02 vs. 203.38 +/- 83.03 mm(3) after 19 days, respectively). The median survival for the 1F5(scFv) 4SA group was 90 days compared with 23 days for the control FP (P < .0001). Treatment was well tolerated, with no treatment-related mortalities. This study demonstrates the favorable biodistribution profile and excellent therapeutic efficacy attainable with Bi-213-labeled anti-CD20 PRIT. (Blood. 2010;116(20):4231-4239)