Antitumor effect of humanized anti‑tissue factor antibody‑drug conjugate in a model of peritoneal disseminated pancreatic cancer

Tsumura,Ryo; Anzai,Takahiro; Manabe,Shino; Takashima,Hiroki; Koga,Yoshikatsu; Yasunaga,Masahiro; Matsumura,Yasuhiro

doi:10.3892/or.2020.7850

Antitumor effect of humanized anti‑tissue factor antibody‑drug conjugate in a model of peritoneal disseminated pancreatic cancer

Authors:
- Ryo Tsumura
- Takahiro Anzai
- Shino Manabe
- Hiroki Takashima
- Yoshikatsu Koga
- Masahiro Yasunaga
- Yasuhiro Matsumura
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Affiliations: Division of Developmental Therapeutics, EPOC, National Cancer Center, Kashiwanoha, Kashiwa, Chiba 277‑8577, Japan, Laboratory of Functional Molecule Chemistry, Pharmaceutical Department and Institute of Medicinal Chemistry, Hoshi University, Ebara, Shinagawa, Tokyo 142‑8501, Japan, Department of Immune Medicine, National Cancer Center Research Institute, Tsukiji, Chuo‑ku, Tokyo 104‑0045, Japan
Published online on: November 12, 2020 https://doi.org/10.3892/or.2020.7850
Pages: 329-336

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Abstract

Tissue factor (TF) is an attractive target for cancer therapy due to its overexpression in multiple types of malignancies. In addition, TF has been reported to play functional roles in both cancer development and metastasis. Several groups have already developed antibody‑drug conjugates (ADCs) against TF for use as cancer treatments, and have demonstrated their efficacies in conventional subcutaneous xenograft models and patient‑derived xenograft models. However, no previous studies have investigated the effectiveness of anti‑TF ADC in an advanced‑stage cancer model. The present study developed an original humanized anti‑TF monoclonal antibody conjugated with monomethyl auristatin E, and evaluated its in vivo efficacy in a pancreatic cancer xenograft model with peritoneal dissemination. In vitro assays demonstrated that the anti‑TF ADC had potent binding affinity and cytotoxic activity against human pancreatic cancer cells that strongly expressed TF antigens. The anti‑TF ADC also exhibited greater antitumor effect than that of a control ADC in conventional subcutaneous xenograft models, with efficacy depending on the TF expression in the tumor tissues. Furthermore, the anti‑TF ADC significantly inhibited tumor growth in an orthotopic xenograft model, and extended the survival period in a murine peritoneal dissemination model. These results indicated that anti‑TF ADC has the potential to be an effective treatment not only for primary tumors, but also for those that are widely disseminated. Therefore, it can be concluded that ADC targeting TF may be a promising agent for advanced pancreatic cancer therapy.

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