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

Abstract

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 68 Ga and 177 Lu for PET imaging and targeted therapy. The therapeutic potential of 177 Lu-DTPA-sdAb was compared with that of 177 Lu-DTPA-rituximab and unlabeled rituximab in mice bearing hCD20 pos tumors. Radiolabeled with 68 Ga, sdAb 9079 showed specific tumor uptake, with very low accumulation in nontarget organs, except kidneys. The tumor uptake of 177 Lu-DTPA-sdAb 9079 after 1.5 h was 3.4 AE 1.3% ID/g, with T/B and T/M ratios of 13.3 AE 4.6 and 32.9 AE 15.6. Peak tumor accumulation of 177 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 AE 0.1 and 7.1 AE 2.4). Treatment of mice with 177 Lu-DTPA-sdAb 9079 significantly prolonged median survival compared with control groups and was as effective as treatment with rituximab or its 177 Lu-labeled variant. Taken together, sdAb 9079 displays promising features as a theranostic drug to treat CD20 pos lymphomas.

Same-Day Imaging Using Small Proteins: Clinical Experience and Translational Prospects in Oncology

“…Both methodologies provided appreciably higher uptake of radiometals in tumors than in kidneys, with the peptide nucleic acid-mediated approach resulting in better tumor retention. (13,15,16,18) and with permission of (13).) B 5 bladder; K 5kidney; L 5 liver.…”

Nanobodies: Next Generation of Cancer Diagnostics and Therapeutics

“…Notably, the HER2-CAIX combination synergistically enhanced the T/B ratio and could also detect lung metastases ( 22 ). Additionally, 89 Zr-HER3 ( 23 ), 18 F-HER2 ( 24 ), and 68 Ga-NOTA-CD20 ( 25 ) nanobodies have demonstrated success in various tumor models. Pant et al ( 26 ) developed a novel implementation of anti-EGFR-nanobody-dendritic polyglycerols (dPGs), demonstrating enhanced accumulation in vivo .…”

Targeted Nanobody-Based Molecular Tracers for Nuclear Imaging and Image-Guided Surgery

“…A major application field for nanobody-based radiotracers is cancer imaging. Radiolabeled nanobodies targeting tumor biomarkers such as the epidermal growth factor receptor (EGFR), carcinoembryonic antigen (CEA), mesothelin, prostate-specific membrane antigen (PSMA), CD20, or HER2 showed high specific tumor uptake (ranging typically between 2 and 10% IA/g, depending on the expression level of the target) in preclinical tumor models as soon as 1 h after administration, with tumor-to-blood ratios of up to 10–30 (Figure 1B,C) [23,35,38,41,42,45,48,49,53,54,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71]. Of particular interest is the anti-HER2 nanobody 2Rs15d that has been selected as a lead compound for clinical translation.…”