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.
Oncol Rep. 2021 Jan;45(1):329-336. doi: 10.3892/or.2020.7850. Epub 2020 Nov 12.
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.
组织因子（TF）在多种恶性肿瘤中过度表达，因此成为癌症治疗的一个有吸引力的靶点。此外，TF 已被报道在癌症的发生和转移中发挥功能作用。已经有几个小组针对 TF 开发了抗体药物偶联物（ADC）用于癌症治疗，并在传统的皮下异种移植模型和患者来源的异种移植模型中证明了它们的疗效。然而，以前没有研究调查过抗 TF ADC 在晚期癌症模型中的有效性。本研究开发了一种原创的人源化抗 TF 单克隆抗体与单甲基澳瑞他汀 E 偶联，并在具有腹膜扩散的胰腺癌异种移植模型中评估了其体内疗效。体外试验表明，抗 TF ADC 对 TF 抗原强烈表达的人胰腺癌细胞具有强大的结合亲和力和细胞毒性。与对照 ADC 相比，抗 TF ADC 在传统的皮下异种移植模型中也表现出更强的抗肿瘤作用，其疗效取决于肿瘤组织中的 TF 表达。此外，抗 TF ADC 显著抑制了原位异种移植模型中的肿瘤生长，并延长了小鼠腹膜扩散模型中的生存期。这些结果表明，抗 TF ADC 不仅有可能成为原发性肿瘤的有效治疗方法，而且还有可能成为广泛扩散的肿瘤的有效治疗方法。因此，可以得出结论，针对 TF 的 ADC 可能是治疗晚期胰腺癌的一种有前途的药物。
