A glypican-1-targeted antibody-drug conjugate exhibits potent tumor growth inhibition in glypican-1-positive pancreatic cancer and esophageal squamous cell carcinoma

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

doi:10.1016/j.neo.2021.07.006

A glypican-1-targeted antibody-drug conjugate exhibits potent tumor growth inhibition in glypican-1-positive pancreatic cancer and esophageal squamous cell carcinoma

Neoplasia. 2021 Sep;23(9):939-950. doi: 10.1016/j.neo.2021.07.006. Epub 2021 Jul 28.

Authors

Affiliations

¹ Department of Surgery, Kochi University, Nankoku, Kochi, Japan; Department of Clinical Immunology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan.
² Department of Clinical Immunology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan; Institute for Biomedical Sciences Molecular Pathophysiology, Iwate Medical University, Yahaba, Iwate, Japan. Electronic address: serada@kochi-u.ac.jp.
³ Department of Medical course, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan.
⁴ Department 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, Japan.
⁵ Institute for Biomedical Sciences Molecular Pathophysiology, Iwate Medical University, Yahaba, Iwate, Japan.
⁶ Department of Surgery, Kochi University, Nankoku, Kochi, Japan.
⁷ Animal Models of Human Diseases, National Institute of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan.
⁸ Department of Pathology, School of Medicine, Kochi University, Nankoku, Kochi, Japan.
⁹ Department 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. Electronic address: naka@kochi-u.ac.jp.

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.

Keywords: Antibody-drug conjugate; Esophageal squamous cell carcinoma; Glypican-1; Pancreatic cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

Antibodies, Monoclonal
Antibodies, Monoclonal, Humanized
Antigens, Neoplasm
GPC1 protein, human
Glypicans
Growth Inhibitors
Immunoconjugates