論文 - 詳細
| RRC ID | 67282 |
|---|---|
| 著者 | Munekage E, Serada S, Tsujii S, Yokota K, Kiuchi K, Tominaga K, Fujimoto M, Kanda M, Uemura S, Namikawa T, Nomura T, Murakami I, Hanazaki K, Naka T. |
| タイトル | A glypican-1-targeted antibody-drug conjugate exhibits potent tumor growth inhibition in glypican-1-positive pancreatic cancer and esophageal squamous cell carcinoma. |
| ジャーナル | Neoplasia |
| Abstract |
An antibody-drug conjugate (ADC) is a promising therapeutic modality because selective and effective delivery of an anti-cancer drug is achieved by drug-conjugated antibody-targeting cancer antigen. Glypican 1 (GPC1) is highly expressed in malignant tumors, including pancreatic ductal adenocarcinoma (PDAC) and esophageal squamous cell carcinoma (ESCC). Herein, we describe the usefulness of GPC1-targeting ADC. Humanized anti-GPC1 antibody (clone T2) was developed and conjugated with monomethyl auristatin E (MMAE) via maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (mc-vc-PABC) linkers (humanized GPC1-ADC[MMAE]). Humanized GPC1-ADC(MMAE) inhibited the growth of GPC1-positive PDAC and ESCC cell lines via inducing cycle arrest in the G2/M phase and apoptosis in vitro. The binding activity of humanized GPC1-ADC(MMAE) with GPC1 was comparable with that of the unconjugated anti-GPC1 antibody. The humanized GPC1-ADC(MMAE) was effective in GPC1-positive BxPC-3 subcutaneously xenografted mice but not in GPC1-negative BxPC-3-GPC1-KO xenografted mice. To assess the bystander killing activity of the humanized GPC1-ADC(MMAE), a mixture of GPC1-positive BxPC-3 and GPC1-negative BxPC-3-GPC1-KO-Luc cells were subcutaneously inoculated, and a heterogenous GPC1-expressing tumor model was developed. The humanized GPC1-ADC(MMAE) inhibited the tumor growth and decreased the luciferase signal, measured with an in vivo imaging system (IVIS), which suggests that the suppression of the BxPC-3-GPC1-KO-Luc population. The humanized GPC1-ADC(MMAE) also inhibited the established liver metastases of BxPC-3 cells and significantly improved the overall survival of the mice. It exhibited a potent antitumor effect on the GPC1-positive PDAC and ESCC patient-derived xenograft (PDX) models. Our preclinical data demonstrate that GPC1 is a promising therapeutic target for ADC. |
| 巻・号 | 23(9) |
| ページ | 939-950 |
| 公開日 | 2021-9-1 |
| DOI | 10.1016/j.neo.2021.07.006 |
| PII | S1476-5586(21)00061-0 |
| PMID | 34332450 |
| PMC | PMC8340053 |
| MeSH | Animals Antibodies, Monoclonal / administration & dosage Antibodies, Monoclonal / metabolism Antibodies, Monoclonal, Humanized / administration & dosage Antibodies, Monoclonal, Humanized / metabolism* Antigens, Neoplasm / metabolism Cell Line, Tumor Cell Survival / drug effects Cell Survival / physiology Esophageal Neoplasms / drug therapy Esophageal Neoplasms / immunology Esophageal Neoplasms / metabolism* Esophageal Squamous Cell Carcinoma / drug therapy Esophageal Squamous Cell Carcinoma / immunology Esophageal Squamous Cell Carcinoma / metabolism* Glypicans / antagonists & inhibitors Glypicans / metabolism* Growth Inhibitors / administration & dosage Growth Inhibitors / metabolism Humans Immunoconjugates / administration & dosage Immunoconjugates / metabolism* Mice Mice, Knockout Mice, SCID Mice, Transgenic Pancreatic Neoplasms / drug therapy Pancreatic Neoplasms / immunology Pancreatic Neoplasms / metabolism* Xenograft Model Antitumor Assays / methods |
| IF | 5.696 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 5 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 3.0 |
| リソース情報 | |
| ヒト・動物細胞 | PK-8(RCB2700) TE-8(RCB2098) TE-14(RCB2101) |