Cure of Micrometastatic B-Cell Lymphoma in a SCID Mouse Model Using 213Bi-Anti-CD20 Monoclonal Antibody

Abstract

We studied the feasibility of using the α-emitting ²¹³Bi-anti-CD20 therapy with direct bioluminescent tracking of micrometastatic human B-cell lymphoma in a SCID mouse model. Methods: A highly lethal SCID mouse model of minimal-tumor-burden disseminated non-Hodgkin lymphoma (NHL) was established using human Raji lymphoma cells transfected to express the luciferase reporter. In vitro and in vivo radioimmunotherapy experiments were conducted. Single- and multiple-dose regimens were explored, and results with ²¹³Bi-rituximab were compared with various controls, including no treatment, free ²¹³Bi radiometal, unlabeled rituximab, and ²¹³Bi-labeled anti-HER2/neu (non-CD20-specific antibody). ²¹³Bi-rituximab was also compared in vivo with the low-energy β-emitter ¹³¹I-tositumomab and the high-energy β-emitter ⁹⁰Y-rituximab. Results: In vitro studies showed dose-dependent target-specific killing of lymphoma cells with ²¹³Bi-rituximab. Multiple in vivo studies showed significant and specific tumor growth delays with ²¹³Bi-rituximab versus free ²¹³Bi, ²¹³Bi-labeled control antibody, or unlabeled rituximab. Redosing of ²¹³Bi-rituximab was more effective than single dosing. With a single dose of therapy given 4 d after intravenous tumor inoculation, disease in all untreated controls, and in all mice in the 925-kBq ⁹⁰Y-rituximab group, progressed. With 3,700 kBq of ²¹³Bi-rituximab, 75% of the mice survived and all but 1 survivor was cured. With 2,035 kBq of ¹³¹I-tositumomab, 75% of the mice were tumor-free by bioluminescent imaging and 62.5% survived. Conclusion: Cure of micrometastatic NHL is achieved in most animals treated 4 d after intravenous tumor inoculation using either ²¹³Bi-rituximab or ¹³¹I-tositumomab, in contrast to the lack of cures with unlabeled rituximab or ⁹⁰Y-rituximab or if there was a high tumor burden before radioimmunotherapy. α-emitter-labeled anti-CD20 antibodies are promising therapeutics for NHL, although a longer-lived α-emitter may be of greater efficacy.

Keywords: 213Bi; B-cell non-Hodgkin lymphoma; alpha emitter; animal model; bioluminescence; radioimmunotherapy.