| RRC ID |
67183
|
| 著者 |
Yokota K, Serada S, Tsujii S, Toya K, Takahashi T, Matsunaga T, Fujimoto M, Uemura S, Namikawa T, Murakami I, Kobayashi S, Eguchi H, Doki Y, Hanazaki K, Naka T.
|
| タイトル |
Anti-Glypican-1 Antibody-drug Conjugate as Potential Therapy Against Tumor Cells and Tumor Vasculature for Glypican-1-Positive Cholangiocarcinoma.
|
| ジャーナル |
Mol Cancer Ther
|
| Abstract |
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. Immunohistochemical 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. Monomethyl auristatin F-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.
|
| 巻・号 |
20(9)
|
| ページ |
1713-1722
|
| 公開日 |
2021-9-1
|
| DOI |
10.1158/1535-7163.MCT-21-0015
|
| PII |
1535-7163.MCT-21-0015
|
| PMID |
34224365
|
| MeSH |
Animals
Apoptosis
Bile Duct Neoplasms / blood supply
Bile Duct Neoplasms / drug therapy*
Bile Duct Neoplasms / metabolism
Bile Duct Neoplasms / pathology
Cell Proliferation
Cholangiocarcinoma / blood supply
Cholangiocarcinoma / drug therapy*
Cholangiocarcinoma / metabolism
Cholangiocarcinoma / pathology
Female
Glypicans / antagonists & inhibitors*
Glypicans / immunology
Humans
Immunoconjugates / pharmacology*
Mice
Mice, SCID
Neovascularization, Pathologic / immunology
Neovascularization, Pathologic / metabolism
Neovascularization, Pathologic / pathology
Neovascularization, Pathologic / prevention & control*
Prognosis
Survival Rate
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
|
| IF |
5.615
|
| リソース情報 |
| ヒト・動物細胞 |
SSP-25(RCB1293)
TFK-1(RCB2537) |
