Background: Esophageal cancer is a highly aggressive neoplasm. Targeted therapy has been proven to be a promising way for cancer therapy. Here, we report a novel anti-CD147 antibody for esophageal cancer therapy, which is a chimeric antibody with modified glycoform in Fc region. Methods: ADCC assay was used to explore the antitumor efficacy of Metuzumab against esophageal cancer in vitro. Wound healing assay and Boyden Chamber invasion assay were performed to explore whether Metuzumab could inhibit migration and invasion of esophageal cancer in vitro. Insulin-like growth factors 1 (IGF-1) and PI3k/Akt was assayed for elaborating antagonistic mechanism of Metuzumab in migration and invasion of esophageal cancer cells. Subcutaneous xenograft nude mouse model was used to investigate the antitumor efficacy of Metuzumab against esophageal cancer in vivo. The esophageal cancer tissue microarrays (TMA) was examined for identification of association of CD147 with lymph node metastasis, and the footpad xenograft nude mouse model was used to explore whether Metuzumab could inhibit lymph node metastasis of esophageal cancer in vivo. Results: The results showed that Metuzumab exhibited higher ADCC compared to the wild type antibody cHAb18. Metuzumab inhibited migration and invasion of esophageal cancer through blockade of CD147 in vitro. The results of Western blot showed Metuzumab might inhibit migration and invasion of esophageal cancer cells through suppressing activation of PI3k/Akt and expression of IGF-1. Experiments in vivo showed that Metuzumab exhibited significant antitumor efficacy and inhibited lymph node metastasis of esophageal cancer in xenograft models. The immunochemical staining of TMA showed CD147 was high-expressed on various kinds of esophageal cancer tissues and associated with the grade of lymph node-metastasis. Conclusions: The in vitro and in vivo study demonstrated dual effects of Metuzumab in effectively mediating ADCC by activating effector cells, and inhibiting metastasis of esophageal cancer through blockade the function of CD147, providing justification for moving Metuzumab forward to clinical development in esophageal cancer.

中文翻译：

---

抗CD147抗体对食道癌治疗的双重作用。

背景：食管癌是一种高度侵袭性的肿瘤。靶向治疗已被证明是一种有前途的癌症治疗方法。在这里，我们报道了一种用于食道癌治疗的新型抗CD147抗体，它是一种在Fc区具有修饰糖型的嵌合抗体。方法：采用ADCC法研究美妥珠单抗对食管癌的体外抗肿瘤作用。进行伤口愈合试验和Boyden Chamber浸润试验，以探讨美妥珠单抗能否在体外抑制食管癌的迁移和浸润。分析了胰岛素样生长因子1（IGF-1）和PI3k / Akt阐明美妥珠单抗在食管癌细胞迁移和侵袭中的拮抗机制。使用皮下异种移植裸鼠模型来研究美妥珠单抗在体内对食道癌的抗肿瘤功效。检查了食管癌组织芯片（TMA），以鉴定CD147与淋巴结转移的关联，并使用脚垫异种移植裸鼠模型探讨美妥珠单抗能否抑制体内食管癌的淋巴结转移。结果：结果表明，与野生型抗体cHAb18相比，Metuzumab表现出更高的ADCC。Metuzumab通过在体外阻断CD147抑制食道癌的迁移和侵袭。Western blot结果显示，美妥珠单抗可能通过抑制PI3k / Akt的激活和IGF-1的表达来抑制食管癌细胞的迁移和侵袭。体内实验表明，在异种移植模型中，Metuzumab表现出显着的抗肿瘤功效并抑制食道癌的淋巴结转移。TMA的免疫化学染色显示CD147在各种食道癌组织中高表达，并与淋巴结转移的程度有关。结论：体外和体内研究证明了美妥珠单抗通过激活效应细胞并通过阻断CD147的功能抑制食管癌的转移而有效介导ADCC的双重作用，为将美妥珠单抗推向食管癌的临床发展提供了依据。TMA的免疫化学染色显示CD147在各种食道癌组织中高表达，并与淋巴结转移的程度有关。结论：体外和体内研究证明了美妥珠单抗通过激活效应细胞并通过阻断CD147的功能抑制食管癌的转移而有效介导ADCC的双重作用，为将美妥珠单抗推向食管癌的临床发展提供了依据。TMA的免疫化学染色显示CD147在各种食道癌组织中高表达，并与淋巴结转移的程度有关。结论：体外和体内研究证明了美妥珠单抗通过激活效应细胞并通过阻断CD147的功能抑制食管癌的转移而有效介导ADCC的双重作用，为将美妥珠单抗推进食管癌的临床发展提供了依据。