Data from Theranostic Radiolabeled Anti-CD20 sdAb for Targeted Radionuclide Therapy of Non-Hodgkin Lymphoma

Abstract

<div>Abstract<p>Anti-CD20 radioimmunotherapy is an effective approach for therapy of relapsed or refractory CD20<sup>pos</sup> lymphomas, but faces limitations due to poor tumor penetration and undesirable pharmacokinetics of full antibodies. Camelid single-domain Ab fragments (sdAb) might circumvent some of the limitations of radiolabeled full antibodies. In this study, a set of hCD20-targeting sdAbs was generated, and their capacity to bind hCD20 was evaluated <i>in vitro</i> and <i>in vivo</i>. A lead sdAb, sdAb 9079, was selected on the basis of its specific tumor targeting and significant lower kidney accumulation compared with other sdAbs. SdAb 9079 was then radiolabeled with <sup>68</sup>Ga and <sup>177</sup>Lu for PET imaging and targeted therapy. The therapeutic potential of <sup>177</sup>Lu-DTPA-sdAb was compared with that of <sup>177</sup>Lu-DTPA-rituximab and unlabeled rituximab in mice bearing hCD20<sup>pos</sup> tumors. Radiolabeled with <sup>68</sup>Ga, sdAb 9079 showed specific tumor uptake, with very low accumulation in nontarget organs, except kidneys. The tumor uptake of <sup>177</sup>Lu-DTPA-sdAb 9079 after 1.5 h was 3.4 ± 1.3% ID/g, with T/B and T/M ratios of 13.3 ± 4.6 and 32.9 ± 15.6. Peak tumor accumulation of <sup>177</sup>Lu-DTPA-rituximab was about 9 times higher, but concomitantly with high accumulation in nontarget organs and very low T/B and T/M ratios (0.8 ± 0.1 and 7.1 ± 2.4). Treatment of mice with <sup>177</sup>Lu-DTPA-sdAb 9079 significantly prolonged median survival compared with control groups and was as effective as treatment with rituximab or its <sup>177</sup>Lu-labeled variant. Taken together, sdAb 9079 displays promising features as a theranostic drug to treat CD20<sup>pos</sup> lymphomas. <i>Mol Cancer Ther; 16(12); 2828–39. ©2017 AACR</i>.</p></div>