Cholangiocarcinoma is a highly malignant cancer. Many patients need systemic chemotherapy to prevent tumor development and recurrence; however, their prognosis is poor due to the lack of effective therapy. Therefore, a new treatment option is urgently required. We recently identified glypican-1 (GPC1) as a novel cancer antigen of esophageal squamous cell carcinoma. We also demonstrated the efficacy and safety of GPC1-targeted ADC (GPC1–ADC) conjugating anti-GPC1 mAb possessing high internalization activity with monomethyl auristatin F (MMAF), which is a potent tubulin polymerizing inhibitor. In this study, we confirmed that GPC1 was highly expressed in cholangiocarcinoma cells and tissues. IHC analysis of 49 extrahepatic cholangiocarcinoma patient tumor specimens revealed high expression of GPC1 in 47% of patients. These patients demonstrated significantly poorer prognosis compared with the low-expression group in terms of disease-free survival and overall survival ( P < 0.05). GPC1 was also expressed in tumor vessels of cholangiocarcinoma, but not on the vessels of nontumor tissues. MMAF-conjugated GPC1–ADC showed potent tumor growth inhibition against GPC1-positive cholangiocarcinoma cells in vitro and in vivo . In a GPC1 knockout xenograft model, GPC1–ADC partially inhibited tumor growth. Vascular endothelial cells in tumor tissues of GPC1-negative xenograft mice expressed GPC1 and were arrested in the G2–M phase of cell cycle by GPC1–ADC. GPC1–ADC exhibits direct as well as indirect antitumor effects via inhibition of tumor angiogenesis. Our preclinical data highlight GPC1–ADC as a promising therapy for GPC1-positive cholangiocarcinoma.

中文翻译：

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抗 Glypican-1 抗体-药物偶联物作为抗 Glypican-1 阳性胆管癌的肿瘤细胞和肿瘤血管系统的潜在疗法

胆管癌是一种高度恶性的癌症。许多患者需要全身化疗来预防肿瘤的发展和复发；然而，由于缺乏有效的治疗，他们的预后很差。因此，迫切需要一种新的治疗方案。我们最近将 glypican-1 (GPC1) 鉴定为食管鳞状细胞癌的一种新型癌抗原。我们还证明了 GPC1 靶向 ADC (GPC1-ADC) 与抗 GPC1 mAb 偶联的有效性和安全性，该抗体具有高内化活性，单甲基 auristatin F (MMAF) 是一种有效的微管蛋白聚合抑制剂。在这项研究中，我们证实 GPC1 在胆管癌细胞和组织中高表达。对 49 例肝外胆管癌患者肿瘤标本的 IHC 分析显示 GPC1 在 47% 的患者中高表达。与低表达组相比，这些患者的无病生存期和总生存期明显较差（P < 0.05）。GPC1也在胆管癌的肿瘤血管中表达，但不在非肿瘤组织的血管中表达。MMAF 结合的 GPC1-ADC 在体外和体内对 GPC1 阳性胆管癌细胞显示出有效的肿瘤生长抑制作用。在 GPC1 敲除异种移植模型中，GPC1-ADC 部分抑制了肿瘤生长。GPC1 阴性异种移植小鼠肿瘤组织中的血管内皮细胞表达 GPC1，并被 GPC1-ADC 抑制在细胞周期的 G2-M 期。GPC1-ADC 通过抑制肿瘤血管生成表现出直接和间接的抗肿瘤作用。我们的临床前数据强调 GPC1-ADC 作为 GPC1 阳性胆管癌的有希望的疗法。