A glypican-1-targeted antibody-drug conjugate exhibits potent tumor growth inhibition in glypican-1-positive pancreatic cancer and esophageal squamous cell carcinoma
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...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-09-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558621000610 |
| _version_ | 1818367160331796480 |
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| author | Eri Munekage Satoshi Serada Shigehiro Tsujii Keiichiro Yokota Keita Kiuchi Kenji Tominaga Minoru Fujimoto Mizuki Kanda Sunao Uemura Tsutomu Namikawa Taisei Nomura Ichiro Murakami Kazuhiro Hanazaki Tetsuji Naka |
| author_facet | Eri Munekage Satoshi Serada Shigehiro Tsujii Keiichiro Yokota Keita Kiuchi Kenji Tominaga Minoru Fujimoto Mizuki Kanda Sunao Uemura Tsutomu Namikawa Taisei Nomura Ichiro Murakami Kazuhiro Hanazaki Tetsuji Naka |
| author_sort | Eri Munekage |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T22:47:38Z |
| format | Article |
| id | doaj.art-5785173f07364c98b9918dddf1a8cf79 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 |
| language | English |
| last_indexed | 2024-12-13T22:47:38Z |
| publishDate | 2021-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-5785173f07364c98b9918dddf1a8cf792022-12-21T23:28:42ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862021-09-01239939950A glypican-1-targeted antibody-drug conjugate exhibits potent tumor growth inhibition in glypican-1-positive pancreatic cancer and esophageal squamous cell carcinomaEri Munekage0Satoshi Serada1Shigehiro Tsujii2Keiichiro Yokota3Keita Kiuchi4Kenji Tominaga5Minoru Fujimoto6Mizuki Kanda7Sunao Uemura8Tsutomu Namikawa9Taisei Nomura10Ichiro Murakami11Kazuhiro Hanazaki12Tetsuji Naka13Department of Surgery, Kochi University, Nankoku, Kochi, Japan; Department of Clinical Immunology, Kochi Medical School, Kochi University, Nankoku, Kochi, JapanDepartment of Clinical Immunology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan; Institute for Biomedical Sciences Molecular Pathophysiology, Iwate Medical University, Yahaba, Iwate, Japan; Corresponding authors.Department of Surgery, Kochi University, Nankoku, Kochi, Japan; Department of Clinical Immunology, Kochi Medical School, Kochi University, Nankoku, Kochi, JapanDepartment of Surgery, Kochi University, Nankoku, Kochi, Japan; Department of Clinical Immunology, Kochi Medical School, Kochi University, Nankoku, Kochi, JapanDepartment of Medical course, Kochi Medical School, Kochi University, Nankoku, Kochi, JapanDepartment of Medical course, Kochi Medical School, Kochi University, Nankoku, Kochi, JapanDepartment of Clinical Immunology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan; Division of Allergy and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Yahaba, Iwate, JapanInstitute for Biomedical Sciences Molecular Pathophysiology, Iwate Medical University, Yahaba, Iwate, JapanDepartment of Surgery, Kochi University, Nankoku, Kochi, JapanDepartment of Surgery, Kochi University, Nankoku, Kochi, JapanAnimal Models of Human Diseases, National Institute of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, JapanDepartment of Pathology, School of Medicine, Kochi University, Nankoku, Kochi, JapanDepartment of Surgery, Kochi University, Nankoku, Kochi, JapanDepartment of Clinical Immunology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan; Institute for Biomedical Sciences Molecular Pathophysiology, Iwate Medical University, Yahaba, Iwate, Japan; Division of Allergy and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Yahaba, Iwate, Japan; Corresponding authors.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.http://www.sciencedirect.com/science/article/pii/S1476558621000610Antibody-drug conjugateGlypican-1Pancreatic cancerEsophageal squamous cell carcinoma |
| spellingShingle | Eri Munekage Satoshi Serada Shigehiro Tsujii Keiichiro Yokota Keita Kiuchi Kenji Tominaga Minoru Fujimoto Mizuki Kanda Sunao Uemura Tsutomu Namikawa Taisei Nomura Ichiro Murakami Kazuhiro Hanazaki Tetsuji Naka A glypican-1-targeted antibody-drug conjugate exhibits potent tumor growth inhibition in glypican-1-positive pancreatic cancer and esophageal squamous cell carcinoma Neoplasia: An International Journal for Oncology Research Antibody-drug conjugate Glypican-1 Pancreatic cancer Esophageal squamous cell carcinoma |
| title | A glypican-1-targeted antibody-drug conjugate exhibits potent tumor growth inhibition in glypican-1-positive pancreatic cancer and esophageal squamous cell carcinoma |
| title_full | A glypican-1-targeted antibody-drug conjugate exhibits potent tumor growth inhibition in glypican-1-positive pancreatic cancer and esophageal squamous cell carcinoma |
| title_fullStr | A glypican-1-targeted antibody-drug conjugate exhibits potent tumor growth inhibition in glypican-1-positive pancreatic cancer and esophageal squamous cell carcinoma |
| title_full_unstemmed | A glypican-1-targeted antibody-drug conjugate exhibits potent tumor growth inhibition in glypican-1-positive pancreatic cancer and esophageal squamous cell carcinoma |
| title_short | A glypican-1-targeted antibody-drug conjugate exhibits potent tumor growth inhibition in glypican-1-positive pancreatic cancer and esophageal squamous cell carcinoma |
| title_sort | glypican 1 targeted antibody drug conjugate exhibits potent tumor growth inhibition in glypican 1 positive pancreatic cancer and esophageal squamous cell carcinoma |
| topic | Antibody-drug conjugate Glypican-1 Pancreatic cancer Esophageal squamous cell carcinoma |
| url | http://www.sciencedirect.com/science/article/pii/S1476558621000610 |
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