Glypican-1-targeted antibody-drug conjugate shows therapeutic efficacy in lung squamous cell carcinoma
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Updated: May 9, 2026
A GPC3-targeting Bispecific Antibody, GPC3-S-Fab, with Potent Cytotoxicity
Published on: July 12, 2018
Haruhiko Yokoyama1, Satoshi Serada2, Masashi Yamashita1
1Iwate Medical University School of Medicine, Yahaba, Japan.
Background:
Lung squamous cell carcinoma (LUSC) is the second most common subtype of lung cancer. Although immune checkpoint inhibitors have improved outcomes, overall survival remains poor, and treatment responses vary markedly. This study aimed to evaluate the preclinical efficacy of an antibody-drug conjugate (ADC)-targeting glypican-1 (GPC1), a cell-surface proteoglycan overexpressed in LUSC.
Methods:
GPC1-ADC consisted of a humanized anti-GPC1 antibody conjugated to monomethyl auristatin E through a maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl linker. GPC1 expression was assessed by immunohistochemistry using a lung cancer tissue microarray. Antitumor activity of GPC1-ADC was evaluated in vitro using GPC1-positive LUSC cell lines and in vivo using both subcutaneous and bone metastasis xenograft models derived from HARA cells.
Results:
High GPC1 expression was observed in 18 of 20 (90%) primary LUSC cases and 7 of 10 (70%) lymph node metastases. In vitro, GPC1-ADC suppressed proliferation of GPC1-positive LUSC cells by inducing G2/M cell cycle arrest and caspase-3-dependent apoptosis. The bystander killing activity of the GPC1-ADC was identified using a co-culture system of two LUSC cell lines, one with high and the other with low GPC1 expression. In vivo, intravenous GPC1-ADC significantly suppressed tumor growth in GPC1-positive HARA xenografts. In a bone metastasis model using HARA CMV-Luc cells, GPC1-ADC markedly reduced bioluminescent tumor burden and prolonged survival without causing body-weight loss.
Conclusion:
GPC1-ADC demonstrated potent and specific antitumor activity across multiple preclinical models of LUSC with high GPC1 expression. These findings support GPC1-ADC as a promising novel therapeutic candidate for patients with LUSC.
Insights
A novel antibody-drug conjugate targeting glypican-1 (GPC1) shows significant preclinical antitumor activity in lung squamous cell carcinoma (LUSC). This GPC1-ADC suppressed tumor growth and prolonged survival in models, offering a promising new therapy for LUSC patients.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Lung squamous cell carcinoma (LUSC) is a common lung cancer subtype with poor survival rates despite current treatments.
- Existing therapies like immune checkpoint inhibitors show variable responses, highlighting the need for novel therapeutic strategies.
- Glypican-1 (GPC1) is a cell-surface proteoglycan overexpressed in LUSC, making it a potential therapeutic target.
Purpose of the Study:
- To evaluate the preclinical efficacy of a novel antibody-drug conjugate (ADC) targeting glypican-1 (GPC1) in lung squamous cell carcinoma (LUSC).
- To assess the antitumor activity of GPC1-ADC in vitro and in vivo models of LUSC.
- To determine the expression levels of GPC1 in primary LUSC and metastatic tissues.
Main Methods:
- Developed a GPC1-ADC comprising an anti-GPC1 antibody linked to monomethyl auristatin E.
- Assessed GPC1 expression in LUSC tissues using immunohistochemistry.
- Evaluated GPC1-ADC's in vitro efficacy on GPC1-positive LUSC cell lines and in vivo antitumor activity in subcutaneous and bone metastasis xenograft models.
Main Results:
- High GPC1 expression was detected in 90% of primary LUSC cases and 70% of lymph node metastases.
- GPC1-ADC demonstrated potent in vitro activity by inducing cell cycle arrest and apoptosis in GPC1-positive LUSC cells, with bystander killing effects.
- In vivo studies showed significant tumor growth suppression, marked reduction in bone tumor burden, and prolonged survival in GPC1-positive xenografts without weight loss.
Conclusions:
- GPC1-ADC exhibits strong and specific antitumor activity in preclinical LUSC models with high GPC1 expression.
- The findings support GPC1-ADC as a potential new therapeutic agent for LUSC.
- Further clinical investigation of GPC1-ADC for LUSC treatment is warranted.
