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

Published on Jul 28, 2021in Neoplasia5.696
· DOI :10.1016/J.NEO.2021.07.006
Eri Munekage10
Estimated H-index: 10
(Kōchi University),
Satoshi Serada1
Estimated H-index: 1
(Iwate Medical University)
+ 11 AuthorsTsutomu Namikawa22
Estimated H-index: 22
(Kōchi University)
Sources
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.
📖 Papers frequently viewed together
2006
1 Author (耕作 三村)
References30
Newest
#1Simone R. Potje (USP: University of São Paulo)H-Index: 7
#2Tiago Dal-Cin de Paula (USP: University of São Paulo)H-Index: 3
Last. Lusiane Maria Bendhack (USP: University of São Paulo)H-Index: 25
view all 4 authors...
This review highlights recent findings about the role that endothelial glycocalyx and caveolae play in vascular homeostasis. We describe the structure, synthesis, and function of glycocalyx and caveolae in vascular cells under physiological and pathophysiological conditions. In addition, we cite which alterations in glycocalyx and caveolae are associated with impaired production of nitric oxide and generation of reactive oxygen species. Such alterations could contribute to the development of vas...
Source
#1Dustin UhlenhoppH-Index: 3
#2Eric O. Then (Brooklyn Hospital Center)H-Index: 4
Last. Vinaya GaduputiH-Index: 9
view all 4 authors...
Esophageal cancer is the eighth most common type of cancer worldwide and constitutes the sixth leading cause of cancer deaths. It is characterized by its high mortality rate, poor prognosis at time of diagnosis and variability based on geographic location. Present day, the prevalence of esophageal cancer is in transition. Although esophageal squamous cell carcinoma continues to be the most prevalent type worldwide, esophageal adenocarcinoma is quickly becoming the most prevalent type in develope...
Source
#1Takahiko Nishigaki (Osaka University)H-Index: 6
#2Tsuyoshi Takahashi (Osaka University)H-Index: 37
Last. Tetsuji Naka (Kōchi University)H-Index: 63
view all 21 authors...
Pancreatic cancer (PDAC) is the most lethal malignancy. New treatment options for it are urgently required. The aim was to develop an antibody–drug conjugate (ADC) targeting glypican-1 (GPC-1) as a new therapy for PDAC. We evaluated GPC-1 expression in resected PDAC specimens and PDAC cell lines. We then measured the antitumour effect of anti-GPC-1 monoclonal antibody conjugated with the cytotoxic agent monomethyl auristatin F (MMAF) in vitro and in vivo. GPC-1 was overexpressed in most primary ...
Source
Glypican-1 (GPC-1) is a cell surface heparan sulphate proteoglycan that is critical during normal development, but which is not required for normal homoeostasis in the adult. It is, however, overexpressed in a variety of solid tumours and is known to regulate tumour growth, invasion, metastasis and progression, through modulation of tumour cell biology as well as influence on the tumour microenvironment (TME). The role of GPC-1 in the TME and on the tumour cell is broad, as GPC-1 regulates signa...
Source
#1Prashanth RawlaH-Index: 15
#2Tagore Sunkara (Mercy Medical Center (Baltimore, Maryland))H-Index: 13
Last. Vinaya GaduputiH-Index: 9
view all 3 authors...
Pancreatic cancer is the seventh leading cause of cancer-related deaths worldwide. However, its toll is higher in more developed countries. Reasons for vast differences in mortality rates of pancreatic cancer are not completely clear yet, but it may be due to lack of appropriate diagnosis, treatment and cataloging of cancer cases. Because patients seldom exhibit symptoms until an advanced stage of the disease, pancreatic cancer remains one of the most lethal malignant neoplasms that caused 432,2...
Source
#2Limary M. Cancel (CCNY: City College of New York)H-Index: 15
#3Mariya Mayer (CCNY: City College of New York)H-Index: 2
Last. John M. Tarbell (CCNY: City College of New York)H-Index: 71
view all 6 authors...
BACKGROUND: Previous studies have demonstrated that the glycosaminoglycans (GAGs) heparan sulfate (HS) and hyaluronic acid (HA) are mechanosensors for interstitial flow on cancer cells. The proteins that link the GAGs to the cancer cell for mechanotransduction, however, are not known. OBJECTIVE: To assess whether the HS proteoglycan core proteins, Glypican-1 and Syndecan-1, or the HA receptor, CD44, provides the mechanical linkage to the cell. METHODS: The highly metastatic renal carcinoma cell ...
Source
#1Christopher S. SzotH-Index: 12
#2Saurabh SahaH-Index: 17
Last. Brad St. CroixH-Index: 31
view all 22 authors...
: Although nonmalignant stromal cells facilitate tumor growth and can occupy up to 90% of a solid tumor mass, better strategies to exploit these cells for improved cancer therapy are needed. Here, we describe a potent MMAE-linked antibody-drug conjugate (ADC) targeting tumor endothelial marker 8 (TEM8, also known as ANTXR1), a highly conserved transmembrane receptor broadly overexpressed on cancer-associated fibroblasts, endothelium, and pericytes. Anti-TEM8 ADC elicited potent anticancer activi...
Source
#1Satoko MatsuzakiH-Index: 7
#2Satoshi SeradaH-Index: 31
Last. Tetsuji NakaH-Index: 63
view all 13 authors...
Glypican-1 (GPC1) is highly expressed in solid tumors, especially squamous cell carcinomas (SCCs), and is thought to be associated with disease progression. We explored the use of a GPC1-targeted antibody-drug conjugate (ADC) as a novel treatment for uterine cervical cancer. On immunohistochemical staining, high expression levels of GPC1 were detected in about 50% of uterine cervical cancer tissues and also in a tumor that had relapsed after chemoradiotherapy. Novel anti-GPC1 monoclonal antibodi...
Source
#1Mariko Tanaka (UTokyo: University of Tokyo)H-Index: 15
#2Shumpei Ishikawa (Tokyo Medical and Dental University)H-Index: 36
Last. Masashi Fukayama (UTokyo: University of Tokyo)H-Index: 94
view all 14 authors...
// Mariko Tanaka 1 , Shumpei Ishikawa 2 , Tetsuo Ushiku 1 , Teppei Morikawa 1 , Takayuki Isagawa 3 , Makoto Yamagishi 4 , Hiroyuki Yamamoto 5 , Hiroto Katoh 2 , Kimiko Takeshita 1 , Junichi Arita 6 , Yoshihiro Sakamoto 6 , Kiyoshi Hasegawa 6 , Norihiro Kokudo 7 and Masashi Fukayama 1 1 Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan 2 Department of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan 3 Depart...
Source
#1Haizhen Lu (Peking Union Medical College)H-Index: 4
#2Fangfei Niu (Peking Union Medical College)H-Index: 3
Last. Xiaohang Zhao (Peking Union Medical College)H-Index: 21
view all 6 authors...
Pancreatic ductal adenocarcinoma (PDAC) is the most lethal cancer in humans, with a 5-year survival rate of <5%. Recently, glypican-1 (GPC1)-expressing circulating exosomes were found to be a promising diagnostic tool for PDAC. However, the aberrant expression of GPC1 has not been systematically evaluated in large-scale clinical samples of PDAC. Here, we performed a comprehensive analysis of GPC1 mRNA and protein expression features. Included in this study were 178 PDAC patients from the cancer ...
Source
Cited By0
Newest
This website uses cookies.
We use cookies to improve your online experience. By continuing to use our website we assume you agree to the placement of these cookies.
To learn more, you can find in our Privacy Policy.