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
リソース情報
ヒト・動物細胞 PK-8(RCB2700) TE-8(RCB2098) TE-14(RCB2101)