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Int J Cancer. 2018 Mar 1;142(5):1056-1066. doi: 10.1002/ijc.31124. Epub 2017 Oct 31.

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

Author information

1
Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Yamadaoka Suita, Osaka, Japan.
2
Laboratory of Immune Signal, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan.
3
Center for Intractable Immune Disease, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan.
4
Department of Pathology, Osaka University Graduate School of Medicine, Yamadaoka Suita, Osaka, Japan.

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.

KEYWORDS:

antibody-drug conjugate; glypican-1; uterine cervical cancer

PMID:
29055044
DOI:
10.1002/ijc.31124
[Indexed for MEDLINE]
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