Cure of Micrometastatic B-Cell Lymphoma in a SCID Mouse Model Using<sup>213</sup>Bi-Anti-CD20 Monoclonal Antibody
Gregory T. Havlena, Nirav S. Kapadia, Peng Huang, Hong Song, James Engles, Martin W. Brechbiel, George Sgouros, Richard L. Wahl
Abstract
We studied the feasibility of using the α-emitting <sup>213</sup>Bi-anti-CD20 therapy with direct bioluminescent tracking of micrometastatic human B-cell lymphoma in a SCID mouse model. <b>Methods:</b> 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 <sup>213</sup>Bi-rituximab were compared with various controls, including no treatment, free <sup>213</sup>Bi radiometal, unlabeled rituximab, and <sup>213</sup>Bi-labeled anti-HER2/<i>neu</i> (non–CD20-specific antibody). <sup>213</sup>Bi-rituximab was also compared in vivo with the low-energy β-emitter <sup>131</sup>I-tositumomab and the high-energy β-emitter <sup>90</sup>Y-rituximab. <b>Results:</b> In vitro studies showed dose-dependent target-specific killing of lymphoma cells with <sup>213</sup>Bi-rituximab. Multiple in vivo studies showed significant and specific tumor growth delays with <sup>213</sup>Bi-rituximab versus free <sup>213</sup>Bi, <sup>213</sup>Bi-labeled control antibody, or unlabeled rituximab. Redosing of <sup>213</sup>Bi-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 <sup>90</sup>Y-rituximab group, progressed. With 3,700 kBq of <sup>213</sup>Bi-rituximab, 75% of the mice survived and all but 1 survivor was cured. With 2,035 kBq of <sup>131</sup>I-tositumomab, 75% of the mice were tumor-free by bioluminescent imaging and 62.5% survived. <b>Conclusion:</b> Cure of micrometastatic NHL is achieved in most animals treated 4 d after intravenous tumor inoculation using either <sup>213</sup>Bi-rituximab or <sup>131</sup>I-tositumomab, in contrast to the lack of cures with unlabeled rituximab or <sup>90</sup>Y-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.