(1) Munekage E (2) Serada S (3) Tsujii S (4) Yokota K (5) Kiuchi K (6) Tominaga K (7) Fujimoto M (8) Kanda M (9) Uemura S (10) Namikawa T (11) Nomura T (12) Murakami I (13) Hanazaki K (14) Naka T

Neoplasia

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.

Author Info: (1) Department of Surgery, Kochi University, Nankoku, Kochi, Japan; Department of Clinical Immunology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan. (2) Department

Author Info: (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 Surgery, Kochi University, Nankoku, Kochi, Japan; Department of Clinical Immunology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan. (4) Department of Surgery, Kochi University, Nankoku, Kochi, Japan; Department of Clinical Immunology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan. (5) Department of Medical course, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan. (6) Department of Medical course, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan. (7) 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. (8) Institute for Biomedical Sciences Molecular Pathophysiology, Iwate Medical University, Yahaba, Iwate, Japan. (9) Department of Surgery, Kochi University, Nankoku, Kochi, Japan. (10) Department of Surgery, Kochi University, Nankoku, Kochi, Japan. (11) Animal Models of Human Diseases, National Institute of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan. (12) Department of Pathology, School of Medicine, Kochi University, Nankoku, Kochi, Japan. (13) Department of Surgery, Kochi University, Nankoku, Kochi, Japan. (14) 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.

Citation: Neoplasia 2021 Jul 28 23:939-950 Epub07/28/2021

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/34332450

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