Anti-Glypican-1 Antibody–drug Conjugate as Potential Therapy Against Tumor Cells and Tumor Vasculature for Glypican-1–Positive Cholangiocarcinoma

Abstract

Cholangiocarcinoma is a highly malignant cancer. Many patients need systemic chemotherapy to prevent tumor development and recurrence; however, their prognosis is poor due to the lack of effective therapy. Therefore, a new treatment option is urgently required. We recently identified glypican-1 (GPC1) as a novel cancer antigen of esophageal squamous cell carcinoma. We also demonstrated the efficacy and safety of GPC1-targeted ADC (GPC1–ADC) conjugating anti-GPC1 mAb possessing high internalization activity with monomethyl auristatin F (MMAF), which is a potent tubulin polymerizing inhibitor. In this study, we confirmed that GPC1 was highly expressed in cholangiocarcinoma cells and tissues. IHC analysis of 49 extrahepatic cholangiocarcinoma patient tumor specimens revealed high expression of GPC1 in 47% of patients. These patients demonstrated significantly poorer prognosis compared with the low-expression group in terms of disease-free survival and overall survival (P < 0.05). GPC1 was also expressed in tumor vessels of cholangiocarcinoma, but not on the vessels of nontumor tissues. MMAF-conjugated GPC1–ADC showed potent tumor growth inhibition against GPC1-positive cholangiocarcinoma cells in vitro and in vivo. In a GPC1 knockout xenograft model, GPC1–ADC partially inhibited tumor growth. Vascular endothelial cells in tumor tissues of GPC1-negative xenograft mice expressed GPC1 and were arrested in the G2–M phase of cell cycle by GPC1–ADC. GPC1–ADC exhibits direct as well as indirect antitumor effects via inhibition of tumor angiogenesis. Our preclinical data highlight GPC1–ADC as a promising therapy for GPC1-positive cholangiocarcinoma.

Plasmon‐Enhanced Single Extracellular Vesicle Analysis for Cholangiocarcinoma Diagnosis

“…[ 63 ] Moreover, we compared the candidate markers in our proteomics data of CCA cell lines with those in benign cells. This analysis led to the following candidate markers: EpCAM, [ 53 ] EGFR, [ 54 ] MUC1, [ 51,52 ] PD‐L1, [ 55 ] WNT2, [ 56 ] GPC1, [ 57 ] and CD44v6. [ 58,59 ] We first performed cellular analysis on these candidate markers and EV putative markers (CD63, CD9, and CD81) using CCA cell lines (SNU308, SNU478, and SNU1196) and normal human cholangiocyte cell line (H69).…”

“…To choose relevant CCA markers, we first reviewed the literature on biomarkers reported for CCA. [51][52][53][54][55][56][57][58][59][60][61] We narrowed down the list based on the cross-reference with the EV biomarker database (Vesiclepedia) [62] and a human protein atlas. [63] Moreover, we compared the candidate markers in our proteomics data of CCA cell lines with those in benign cells.…”

Promising Highly Targeted Therapies for Cholangiocarcinoma: A Review and Future Perspectives

“…There have been three preclinical trials of ADCs for CCA using murine models whose targeted antigens were human epidermal growth factor receptor 2 (HER2) [23], mucin 1 (MUC1) [24], and glypican-1 (GPC1) [25] (Table 1). HER2 is a member of the EGFR family.…”

“…GPC1, a cancer antigen, is a heparan sulfate proteoglycan that is linked to the cell surface by a glycosylphosphatidylinositol anchor and promotes tumor growth, metastasis, and invasion by acting as a co-receptor [36]. Yokota et al reported high expression of GPC1 in 47% of patients with ECC by immunohistochemical staining and that MMAFconjugated anti-GPC1 antibodies showed potent tumor growth inhibition against GPC1positive CCA cells in vitro and in vivo [25]. MMAF is a tubulin-polymerizing inhibitor and is also clinically used as a payload in ADCs for relapsed or refractory multiple myeloma.…”

Tumor Microenvironment and its Implications for Antitumor Immunity in Cholangiocarcinoma: Future Perspectives for Novel Therapies

“…Thus, targeting GPC1 by ADC (Antibody-drug conjugates) can effectively inhibit the development of CCA. Grow 37 . CD105 is highly expressed in vascular endothelial cells of pCCA, and it is an independent poor prognostic factor, which can serve as a feasible target for clinical treatment 38 .…”