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

Anti-CD20 radioimmunotherapy is an effective approach for therapy of relapsed or refractory CD20^pos 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 in vitro and in vivo. 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 ⁶⁸Ga and ¹⁷⁷Lu for PET imaging and targeted therapy. The therapeutic potential of ¹⁷⁷Lu-DTPA-sdAb was compared with that of ¹⁷⁷Lu-DTPA-rituximab and unlabeled rituximab in mice bearing hCD20^pos tumors. Radiolabeled with ⁶⁸Ga, sdAb 9079 showed specific tumor uptake, with very low accumulation in nontarget organs, except kidneys. The tumor uptake of ¹⁷⁷Lu-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 ¹⁷⁷Lu-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 ¹⁷⁷Lu-DTPA-sdAb 9079 significantly prolonged median survival compared with control groups and was as effective as treatment with rituximab or its ¹⁷⁷Lu-labeled variant. Taken together, sdAb 9079 displays promising features as a theranostic drug to treat CD20^pos lymphomas. Mol Cancer Ther; 16(12); 2828–39. ©2017 AACR.

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