Generation and evaluation of a chimeric antibody against coxsackievirus and adenovirus receptor for cancer therapy
Generation and evaluation of a chimeric antibody against coxsackievirus and adenovirus receptor for cancer therapy
复制标题
用于癌症治疗的柯萨奇病毒和腺病毒受体嵌合抗体的产生和评估
DOI：
10.1111/cas.14196
复制
发表时间：
2019
期刊：
影响因子：
5.7
通讯作者：
Kawada M
中科院分区：
文献类型：
--
作者：
Sakamoto S;Inoue H;Kaneko MK;Ogasawara S;Kajikawa M;Urano S;Ohba S;Kato Y;Kawada M
柯萨奇病毒和腺病毒受体(CAR)是一种与腺病毒感染相关的单程跨膜蛋白。CAR参与了上皮紧密连接的形成，并在一些癌症中促进了肿瘤的生长。此前，我们研制了针对人CAR的鼠单抗，并发现其中一种名为mu6G10A的抗体显著抑制了人类癌细胞异种移植瘤的生长。在此，我们从mu6G10A中制备并鉴定了鼠-人嵌合抗CAR抗体(Ch6G10A)。CH6G10A具有结合活性、诱导抗体依赖的细胞毒作用和补体依赖的细胞毒作用，体内对表达CAR的前列腺癌DU-145细胞具有抗肿瘤活性。此外，肿瘤组织芯片分析证实，CAR在包括小细胞肺癌在内的神经内分泌肺癌中高表达，ch6G10A治疗有效地抑制了NCI-H69小细胞肺癌裸鼠皮下移植瘤的生长。此外，mu6G10A治疗有效地抑制了人小细胞肺癌DMS273细胞高转移亚系小鼠异种移植模型的体内原位肿瘤生长和远处转移形成。这些结果表明，使用治疗性抗体对CAR进行靶向治疗可能对包括小细胞肺癌在内的几种癌症类型有效。
Coxsackievirus and adenovirus receptor (CAR) is a single‐pass transmembrane protein that is associated with adenoviral infection. CAR is involved in the formation of epithelial tight junctions and promotes tumor growth in some cancers. Previously, we developed mouse monoclonal antibodies against human CAR and found that one, mu6G10A, significantly inhibited tumor growth in xenografts of human cancer cells. Herein, we generated and characterized a mouse‐human chimeric anti‐CAR antibody (ch6G10A) from mu6G10A. ch6G10A had binding activity, inducing antibody‐dependent cellular cytotoxicity and complement‐dependent cytotoxicity, and in vivo anti‐tumor activity against CAR‐expressing prostate cancer DU‐145 cells. In addition, cancer tissue array analysis confirmed that CAR is highly expressed in neuroendocrine lung cancers including small cell lung cancer, and treatment with ch6G10A effectively inhibited in vivo subcutaneous tumor growth of NCI‐H69 small cell lung cancer cells in nude mice. Moreover, treatment with mu6G10A effectively inhibited both in vivo orthotopic tumor growth and distant metastatic formation in mouse xenograft models of a highly metastatic subline of human small cell lung cancer DMS273 cells. These results suggest that targeting therapy to CAR with a therapeutic antibody might be effective against several cancer types including small cell lung cancer.