In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel, Brussels, Belgium.
Laboratory of Molecular and Cellular Therapy, Department of Biomedical Sciences, Vrije Universiteit Brussel, Brussels, Belgium.
Mol Cancer Ther. 2017 Dec;16(12):2828-2839. doi: 10.1158/1535-7163.MCT-17-0554. Epub 2017 Oct 20.
Anti-CD20 radioimmunotherapy is an effective approach for therapy of relapsed or refractory CD20 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 and 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 Ga and Lu for PET imaging and targeted therapy. The therapeutic potential of Lu-DTPA-sdAb was compared with that of Lu-DTPA-rituximab and unlabeled rituximab in mice bearing hCD20 tumors. Radiolabeled with Ga, sdAb 9079 showed specific tumor uptake, with very low accumulation in nontarget organs, except kidneys. The tumor uptake of 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 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 Lu-DTPA-sdAb 9079 significantly prolonged median survival compared with control groups and was as effective as treatment with rituximab or its Lu-labeled variant. Taken together, sdAb 9079 displays promising features as a theranostic drug to treat CD20 lymphomas. .
抗 CD20 放射免疫疗法是治疗复发或难治性 CD20 淋巴瘤的有效方法，但由于全抗体肿瘤穿透性差和不理想的药代动力学而受到限制。骆驼科单域 Ab 片段（sdAb）可能规避一些放射性标记全抗体的局限性。在这项研究中，生成了一组靶向 hCD20 的 sdAb，并评估了它们与 hCD20 结合的能力，并基于其特异性肿瘤靶向和与其他 sdAb 相比显著较低的肾脏积累，选择了一种先导 sdAb，sdAb 9079。然后，用 Ga 和 Lu 对 sdAb 9079 进行放射性标记，用于 PET 成像和靶向治疗。将 Lu-DTPA-sdAb 的治疗潜力与 Lu-DTPA-rituximab 和未标记的 rituximab 在携带 hCD20 肿瘤的小鼠中进行了比较。用 Ga 放射性标记后，sdAb 9079 显示出特异性肿瘤摄取，除肾脏外，非靶器官的积累非常低。Lu-DTPA-sdAb 9079 在 1.5 小时后的肿瘤摄取率为 3.4±1.3%ID/g，T/B 和 T/M 比值分别为 13.3±4.6 和 32.9±15.6。Lu-DTPA-rituximab 的峰值肿瘤摄取量约高 9 倍，但同时伴有非靶器官的高积累和非常低的 T/B 和 T/M 比值（0.8±0.1 和 7.1±2.4）。与对照组相比，用 Lu-DTPA-sdAb 9079 治疗小鼠可显著延长中位生存期，并且与 rituximab 或其 Lu 标记变体一样有效。综上所述，sdAb 9079 作为治疗 CD20 淋巴瘤的治疗药物具有良好的应用前景。
