Department of Molecular Imaging and Theranostics, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology (QST-NIRS), Chiba, Japan.
Department of Diagnostic Radiology, Kyoto University Hospital, Kyoto, Japan.
Cancer Sci. 2019 May;110(5):1653-1664. doi: 10.1111/cas.13979. Epub 2019 Mar 12.
Podoplanin is a type I transmembrane sialomucin-like glycoprotein that is highly expressed in malignant mesothelioma. The rat-human chimeric antibody NZ-12 has high affinity for human podoplanin and antibody-dependent cellular cytotoxicity and is applicable for radioimmunotherapy (RIT) to enhance the antitumor effect. In the present study, we evaluated the in vivo and in vitro properties of radiolabeled NZ-12 and the antitumor effect of RIT with Y-labeled NZ-12 in an NCI-H226 (H226) malignant mesothelioma xenograft mouse model. In-labeled NZ-12 bound specifically to H226 cells with high affinity, and accumulation was high in H226 tumors but low in major organs. RIT with Y-labeled NZ-12 significantly suppressed tumor growth and prolonged survival without body weight loss and obvious adverse effects. Higher podoplanin expression levels were observed in human mesothelioma specimens, suggesting higher tumor accumulation of Y-labeled NZ-12 in patients compared with the H226 tumor xenografts. Our findings suggest that Y-labeled NZ-12 is a promising RIT agent as a new therapeutic option for malignant mesothelioma that warrants further clinical studies to evaluate the dosimetry and efficacy in patients.
波形蛋白是一种高度表达于恶性间皮瘤的 I 型跨膜唾液酸糖蛋白样糖蛋白。鼠-人嵌合抗体 NZ-12 对人波形蛋白具有高亲和力和抗体依赖性细胞细胞毒性，适用于放射免疫治疗 (RIT) 以增强抗肿瘤作用。在本研究中，我们评估了放射性标记的 NZ-12 的体内和体外特性，以及 Y 标记的 NZ-12 在 NCI-H226（H226）恶性间皮瘤异种移植小鼠模型中的 RIT 的抗肿瘤作用。 I 标记的 NZ-12 特异性高亲和力地与 H226 细胞结合，在 H226 肿瘤中积累量高，但在主要器官中积累量低。用 Y 标记的 NZ-12 进行 RIT 可显著抑制肿瘤生长并延长生存时间，而不会导致体重减轻和明显的不良反应。在人类间皮瘤标本中观察到更高的波形蛋白表达水平，提示与 H226 肿瘤异种移植相比，患者中 Y 标记的 NZ-12 具有更高的肿瘤积累。我们的研究结果表明， Y 标记的 NZ-12 是一种很有前途的 RIT 药物，可作为恶性间皮瘤的新治疗选择，值得进一步进行临床研究以评估患者的剂量学和疗效。
