Liver Research Center, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence, RI, USA.
Liver Research Center, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence, RI, USA; Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150081, Heilongjiang Province, PR China.
Cancer Lett. 2019 May 1;449:87-98. doi: 10.1016/j.canlet.2019.02.006. Epub 2019 Feb 12.
Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy with very limited treatment options. Antibody drug conjugates (ADCs) are promising cytotoxic agents capable of highly selective delivery. Aspartate-β-hydroxylase (ASPH) is a type II transmembrane protein highly expressed in PDACs (97.1%) but not normal pancreas. We investigated anti-tumor effects of an ADC guided by a human monoclonal antibody (SNS-622) against ASPH in human PDAC cell lines and derived subcutaneous (s.c.) xenograft as well as a patient-derived xenograft (PDX) murine model with spontaneous pulmonary metastasis. The cytotoxic effects exhibited by several candidate payloads linked to SNS-622 antibody targeting ASPH PDACs were analyzed. After i.v. administration of SNS-622-emtansine (DM1) ADC, the primary PDAC tumor growth and progression (number and size of pulmonary metastases) were determined. The PDAC cell lines, s.c. and PDX tumors treated with ADC were tested for cell proliferation, cytotoxicity and apoptosis by MTS and immunohistochemistry (IHC) assays. SNS-622-DM1 construct has demonstrated optimal anti-tumor effects in vitro. In the PDX model of human PDAC, SNS-622-DM1 ADC exerted substantially inhibitory effects on tumor growth and pulmonary metastasis through attenuating proliferation and promoting apoptosis.
胰腺导管腺癌 (PDAC) 是一种极具侵袭性的恶性肿瘤，治疗选择非常有限。抗体药物偶联物 (ADC) 是一种有前途的细胞毒性药物，能够实现高度选择性递送。天冬氨酸-β-羟化酶 (ASPH) 是一种在 PDAC 中高度表达的 II 型跨膜蛋白 (97.1%)，但在正常胰腺中不表达。我们研究了一种针对 ASPH 的人源单克隆抗体 (SNS-622) 引导的 ADC 在人 PDAC 细胞系和衍生的皮下 (s.c.) 异种移植以及具有自发性肺转移的患者来源异种移植 (PDX) 小鼠模型中的抗肿瘤作用。分析了几种候选有效载荷与 SNS-622 抗体靶向 PDACs 的 ASPH 结合后的细胞毒性作用。在静脉注射 SNS-622-emtansine (DM1) ADC 后，确定主要 PDAC 肿瘤的生长和进展 (肺转移的数量和大小)。通过 MTS 和免疫组织化学 (IHC) 检测评估用 ADC 治疗的 PDAC 细胞系、s.c. 和 PDX 肿瘤的细胞增殖、细胞毒性和细胞凋亡情况。SNS-622-DM1 构建体在体外表现出最佳的抗肿瘤作用。在人 PDAC 的 PDX 模型中，SNS-622-DM1 ADC 通过减弱增殖和促进凋亡，对肿瘤生长和肺转移产生了实质性的抑制作用。
