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.

• Authors: Satoko Matsuzaki, Satoshi Serada, Kosuke Hiramatsu, Satoshi Nojima, Shinya Matsuzaki, Yutaka Ueda, Tomoharu Ohkawara, Seiji Mabuchi, Minoru Fujimoto, Eiichi Morii, Kiyoshi Yoshino, Tadashi Kimura, Tetsuji Naka
• Journal: International journal of cancer (Int J Cancer) Vol. 142 Issue 5 Pg. 1056-1066 (03 01 2018) ISSN: 1097-0215 [Electronic] United States
• PMID: 29055044 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 UICC.

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• GPC1 protein, human
• Glypicans
• Immunoconjugates
• Oligopeptides
• monomethylauristatin F

Topics

• Adult
• Aged
• Animals
• Antibodies, Monoclonal (administration & dosage, chemistry)
• Antineoplastic Agents (chemistry, therapeutic use)
• Apoptosis
• Carcinoma, Squamous Cell (drug therapy, immunology, pathology)
• Cell Proliferation
• Female
• Glypicans (antagonists & inhibitors, immunology)
• Humans
• Immunoconjugates (chemistry, therapeutic use)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred NOD
• Mice, SCID
• Middle Aged
• Molecular Targeted Therapy
• Oligopeptides (administration & dosage, chemistry)
• Prognosis
• Tumor Cells, Cultured
• Uterine Cervical Neoplasms (drug therapy, immunology, pathology)
• Xenograft Model Antitumor Assays
• Young Adult