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) |