Division of Surgical Oncology, Department of Surgery, Moores Cancer Center, University of California San Diego, La Jolla, California.
Tanabe Research Laboratories U.S.A. Inc., San Diego, California.
Clin Cancer Res. 2021 Apr 1;27(7):2100-2110. doi: 10.1158/1078-0432.CCR-20-3210. Epub 2021 Jan 15.
Pancreatic cancer is an aggressive disease associated with a poor 5-year overall survival. Most patients are ineligible for surgery due to late diagnosis and are treated primarily with chemotherapy with very limited success. Pancreatic cancer is relatively insensitive to chemotherapy due to multiple factors, including reduced bioavailability of drugs to tumor cells. One strategy to improve drug efficacy with reduced toxicity is the development of antibody-drug conjugates (ADC), which have now been used successfully to treat both solid and liquid tumors. Here, we evaluate the efficacy of TR1801-ADC, a newly developed ADC composed of a MET antibody conjugated to the highly potent pyrrolobenzodiazepine toxin-linker, tesirine.
We first evaluated MET expression and subcellular localization in pancreatic cancer cell lines, human tumors, and patient-derived xenografts (PDX). We then tested TR1801-ADC efficacy in pancreatic cancer cell lines. Preclinical evaluation of TR1801-ADC efficacy was conducted on PDXs selected on the basis of their MET expression level.
We show that MET is highly expressed and located at the plasma membrane of pancreatic cancer cells. We found that TR1801-ADC induces a specific cytotoxicity in pancreatic cancer cell lines and a profound tumor growth inhibition, even in a gemcitabine-resistant tumor. We also noted synergism between TR1801-ADC and gemcitabine and an improved response to the combination .
Together, these results suggest the promise of agents such as TR1801-ADC as a novel approach to the treatment of pancreatic cancer.
胰腺癌是一种侵袭性疾病，其 5 年总生存率较差。由于诊断较晚，大多数患者不适合手术，主要采用化疗治疗，但效果非常有限。由于多种因素，包括药物向肿瘤细胞的生物利用度降低，胰腺癌对化疗相对不敏感。一种降低毒性提高药物疗效的策略是开发抗体药物偶联物（ADC），现已成功用于治疗实体瘤和液体瘤。在这里，我们评估了由 MET 抗体与高活性吡咯并苯并二氮杂卓毒素 - 连接子 tesirine 偶联而成的新型 ADC 药物 TR1801-ADC 的疗效。
我们首先评估了胰腺癌细胞系、人类肿瘤和患者来源的异种移植瘤（PDX）中 MET 的表达和亚细胞定位。然后，我们在胰腺癌细胞系中测试了 TR1801-ADC 的疗效。根据 MET 表达水平选择 PDX 进行 TR1801-ADC 疗效的临床前评估。
我们表明 MET 在胰腺癌细胞中高度表达并位于质膜上。我们发现 TR1801-ADC 可诱导胰腺癌细胞系产生特异性细胞毒性，并显著抑制肿瘤生长，即使在吉西他滨耐药肿瘤中也是如此。我们还注意到 TR1801-ADC 与吉西他滨之间具有协同作用，并且联合用药的反应得到改善。
这些结果表明，像 TR1801-ADC 这样的药物具有治疗胰腺癌的潜力。
