Therapeutic efficacy evaluation of radioimmunotherapy with 90Y-labeled anti-podoplanin antibody NZ-12 for mesothelioma
Therapeutic efficacy evaluation of radioimmunotherapy with 90Y-labeled anti-podoplanin antibody NZ-12 for mesothelioma
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DOI：
10.1111/cas.13979
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发表时间：
2019-05-01
期刊：
影响因子：
5.7
通讯作者：
Higashi, Tatsuya
中科院分区：
文献类型：
--
作者：
Sudo, Hitomi;Tsuji, Atsushi B.;Higashi, Tatsuya
Podoplanin是一种I型跨膜唾液粘蛋白样糖蛋白，在恶性间皮瘤中高度表达。鼠-人嵌合抗体NZ-12对人podoplanin具有高亲和力和抗体依赖的细胞毒性，可用于放射免疫治疗（RIT）以增强抗肿瘤效果。在本研究中，我们评价了放射性标记的NZ-12的体内和体外性质以及在NCI-H226（H226）恶性间皮瘤异种移植小鼠模型中使用Y-90标记的NZ-12的RIT的抗肿瘤作用。In-111标记的NZ-12以高亲和力特异性结合H226细胞，并且在H226肿瘤中积累高，但在主要器官中积累低。用Y-90标记的NZ-12进行RIT可显著抑制肿瘤生长，延长生存期，且体重无减轻，无明显副作用。在人间皮瘤标本中观察到更高的podoplanin表达水平，表明与H226肿瘤异种移植物相比，Y-90标记的NZ-12在患者中的肿瘤积累更高。我们的研究结果表明，Y-90标记的NZ-12是一个有前途的RIT代理作为一个新的治疗选择恶性间皮瘤，值得进一步的临床研究，以评估患者的剂量和疗效。
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 invivo and invitro properties of radiolabeled NZ-12 and the antitumor effect of RIT with Y-90-labeled NZ-12 in an NCI-H226 (H226) malignant mesothelioma xenograft mouse model. In-111-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-90-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-90-labeled NZ-12 in patients compared with the H226 tumor xenografts. Our findings suggest that Y-90-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.