Anti‐glypican‐1 antibody‐drug conjugate exhibits potent preclinical antitumor activity against glypican‐1 positive uterine cervical cancer

Abstract

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 antibodies were developed, and clone 01a033 was selected as the best antibody for targeted delivery of the cytotoxic agent monomethyl auristatin F (MMAF) into GPC1-positive cells. The anti-GPC1 antibody was conjugated with MMAF. On flow cytometry, HeLa and ME180 cervical cancer cells highly expressed GPC1, however, RMG-I ovarian clear cell cancer cell line showed weak expression. The GPC1-ADC was rapidly internalized into GPC1-expressing cells in vitro and was potently cytotoxic to cancer cells highly expressing GPC1. There were no inhibitory effects on cancer cells with low expression of GPC1. In a murine xenograft model, GPC1-ADC also had significant and potent tumor growth inhibition. GPC1-ADC-mediated G2/M phase cell cycle arrest was detected, indicating that the dominant antitumor effect in vivo was MMAF-mediated. The toxicity of GPC-ADC was tolerable within the therapeutic dose range in mice. Our data showed that GPC1-ADC has potential as a promising therapy for uterine cervical cancer.

Glypican-1 immunohistochemistry does not separate mesothelioma from pulmonary adenocarcinoma

“…Glypican-1 expression by IHC has been described in several tumor types, including gliomas [10], cervical squamous cell carcinoma and adenocarcinoma [11], breast cancer [12], and pancreatic cancer [13,14], and is associated with a worse prognosis in glioblastomas [15], esophageal squamous cell carcinoma [16], and pancreatic ductal adenocarcinoma [14]. These reports raise caution about the utility of glypican-1 as a diagnostic marker given the wide breadth of tumors that can demonstrate staining.…”

Near-Infrared Molecular Imaging of Glioblastoma by Miltuximab®-IRDye800CW as a Potential Tool for Fluorescence-Guided Surgery

“…That study examined serum chemistry, blood counts, and histopathology on organs (liver, lung, heart, kidneys, brain, spleen, and testis) in mice treated with anti-GPC-1 antibody (50 mg/kg) or an isotype control antibody and found no pathology associated with targeting of GPC-1 [41]. In a similar study designed to assess safety, treatment of immune-competent mice with 50 mg/kg anti-GPC-1 cytotoxic antibody drug conjugate (ADC) did not reveal any safety signal [53].…”

Identification of a Novel Epithelial-mesenchymal Transition Gene Signature Regulated by KEAP1-NRF2 Pathway in Esophageal Carcinoma

“…Additionally, it has been suggested that GPC1 plays an important role in regulating TGF-β-mediated EMT and stemness, and could be a potential future therapeutic target to prevent progression of gastric cancer (29). It has been pointed out that GPC1 is over-expressed and implies a poor prognosis in several cancers including, ESCA, uterine cervical cancer, pancreatic cancer, and methothelioma (30)(31)(32)(33)(34). Altogether, the above evidence suggests an oncogenic role of the 5-gene signature in many cancers.…”