A glypican-1-targeted antibody-drug conjugate exhibits potent tumor growth inhibition in glypican-1-positive pancreatic cancer and esophageal squamous cell carcinoma
| Autor: | Sunao Uemura, Minoru Fujimoto, Kazuhiro Hanazaki, Kenji Tominaga, Keita Kiuchi, Satoshi Serada, Tetsuji Naka, Taisei Nomura, Keiichiro Yokota, Shigehiro Tsujii, Ichiro Murakami, Mizuki Kanda, Eri Munekage, Tsutomu Namikawa |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Antibody-drug conjugate Immunoconjugates Esophageal Neoplasms endocrine system diseases Cell Survival Population Clone (cell biology) Mice Transgenic Mice SCID Antibodies Monoclonal Humanized chemistry.chemical_compound Mice Glypicans Antigens Neoplasm Esophageal squamous cell carcinoma Pancreatic cancer Cell Line Tumor medicine Animals Humans education RC254-282 Original Research Mice Knockout education.field_of_study biology Chemistry Antibodies Monoclonal Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease Xenograft Model Antitumor Assays Growth Inhibitors digestive system diseases Pancreatic Neoplasms body regions Monomethyl auristatin E Apoptosis Cell culture Cancer research biology.protein Antibody Glypican-1 |
| Zdroj: | Neoplasia: An International Journal for Oncology Research, Vol 23, Iss 9, Pp 939-950 (2021) Neoplasia (New York, N.Y.) |
| ISSN: | 1476-5586 |
| Popis: | Highlights • The authors developed a humanized anti-glypican-1 (GPC1) monoclonal antibody (clone T2) and produced an antibody-drug conjugate (ADC) linked to monomethyl auristatin E (MMAE). The ADC potently inhibited the growth of GPC1-positive pancreatic ductal adenocarcinoma and esophageal squamous cell carcinoma in vitro and in vivo, and exhibited bystander killing activity. Humanized GPC1-ADC(MMAE) was effective against BxPC-3-Luc#2 pancreatic cancer liver metastases in mice. Humanized GPC1-ADC(MMAE) may provide a promising therapeutic strategy for GPC1-positive tumors. 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. |
| Databáze: | OpenAIRE |
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