Division of Developmental Therapeutics, EPOC, National Cancer Center, Kashiwa, Japan.
Synthetic Cellular Chemistry Laboratory, RIKEN, Wako, Japan.
Cancer Sci. 2019 Oct;110(10):3296-3305. doi: 10.1111/cas.14146. Epub 2019 Aug 29.
Tissue factor (TF) is known to be overexpressed in various cancers including pancreatic cancer. The upregulation of TF expression has been observed not only in tumor cells, but also in tumor stromal cells. Because of the potential of TF as a delivery target, several studies investigated the effectiveness of Ab-drug conjugates (ADCs) against TF for cancer therapy. However, it is still unclear whether anti-TF ADC can exert toxicity against both tumor cells and tumor stromal cells. Here, we prepared ADC using a rat anti-mouse TF mAb (clone.1157) and 2 types of in vivo murine pancreatic cancer models, one s.c. and other orthotopic with an abundant tumor stroma. We also compared the feasibility of bis-alkylating conjugation (bisAlk) with that of conventional maleimide-based conjugation (MC). In the s.c. models, anti-TF ADC showed greater antitumor effects than control ADC. The results also indicated that the bisAlk linker might be more suitable than the MC linker for cancer treatments. In the orthotopic model, anti-TF ADC showed greater in vivo efficacy and more extended survival time control ADC. Treatment with anti-TF ADC (20 mg/kg, three times a week) did not affect mouse body weight changes in any in vivo experiment. Furthermore, immunofluorescence staining indicated that anti-TF ADC delivered agents not only to TF-positive tumor cells, but also to TF-positive tumor vascular endothelial cells and other tumor stromal cells. We conclude that anti-TF ADC should be a selective and potent drug for pancreatic cancer therapy.
组织因子（TF）在包括胰腺癌在内的各种癌症中表达过度。TF 表达的上调不仅在肿瘤细胞中观察到，而且在肿瘤基质细胞中也观察到。由于 TF 作为一种递药靶标的潜力，一些研究调查了针对 TF 的抗体药物偶联物（ADC）在癌症治疗中的有效性。然而，抗 TF ADC 是否能对肿瘤细胞和肿瘤基质细胞都产生毒性仍不清楚。在这里，我们使用大鼠抗小鼠 TF mAb（克隆。1157）和 2 种体内小鼠胰腺癌模型，一种皮下和另一种富含肿瘤基质的原位，制备了 ADC。我们还比较了双烷基化连接（bisAlk）与传统马来酰亚胺基连接（MC）的可行性。在皮下模型中，抗 TF ADC 比对照 ADC 显示出更强的抗肿瘤效果。结果还表明，bisAlk 接头可能比 MC 接头更适合癌症治疗。在原位模型中，抗 TF ADC 显示出更强的体内疗效和更长的生存时间控制 ADC。在任何体内实验中，抗 TF ADC（20mg/kg，每周 3 次）治疗均未影响小鼠体重变化。此外，免疫荧光染色表明，抗 TF ADC 不仅递送到 TF 阳性肿瘤细胞，而且递送到 TF 阳性肿瘤血管内皮细胞和其他肿瘤基质细胞。我们得出结论，抗 TF ADC 应该是一种用于胰腺癌治疗的选择性和有效药物。
