Cardillo Thomas M, Rossi Diane L, Zalath Maria B, Liu Donglin, Arrojo Roberto, Sharkey Robert M, Chang Chien-Hsing, Goldenberg David M
Immunomedics, Inc., Morris Plains, NJ 07950, USA.
Currently employed with FrontAim Biomedicines Inc., Princeton, NJ 08540, USA.
Oncotarget. 2020 Oct 27;11(43):3849-3862. doi: 10.18632/oncotarget.27766.
Sacituzumab govitecan (SG) is an antibody-drug conjugate composed of a humanized anti-Trop-2 IgG antibody conjugated a hydrolysable linker to SN-38, the topoisomerase I-inhibitory active component of irinotecan. We investigated whether Trop-2-expression and homologous recombination repair (HRR) of SN-38-mediated double-strand DNA (dsDNA) breaks play a role in the sensitivity of triple-negative breast cancer (TNBC) to SG. Activation of HRR pathways, as evidenced by Rad51 expression, was assessed in SG-sensitive cell lines with low and moderate Trop-2-expression (SK-MES-1 squamous cell lung carcinoma and HCC1806 TNBC, respectively), compared to a low Trop-2-expressing, less SG-sensitive TNBC cell line (MDA-MB-231). Further, two Trop-2-transfectants of MDA-MB-231, C13 and C39 (4- and 25-fold higher Trop-2, respectively), were treated in mice with SG to determine whether increasing Trop-2 expression improves SG efficacy. SG mediated >2-fold increase in Rad51 in MDA-MB-231 but had no effect in SK-MES-1 or HCC1806, resulting in lower levels of dsDNA breaks in MDA-MB-231. SG and saline produced similar effects in parental MDA-MB-231 tumor-bearing mice (median survival time (MST) = 21d and 19.5d, respectively). However, in mice bearing higher Trop-2-expressing C13 and C39 tumors after Trop-2 transfection, SG provided a significant survival benefit, even compared to irinotecan (MST = 97d 35d for C13, and 81d 28d for C39, respectively; < 0.0007). These results suggest that SG could provide better clinical benefit than irinotecan in patients with HRR-proficient tumors expressing high levels of Trop-2, as well as to patients with HRR-deficient tumors expressing low/moderate levels of Trop-2.
戈沙妥珠单抗（SG）是一种抗体药物偶联物，由人源化抗Trop-2 IgG抗体与可水解连接子连接SN-38（伊立替康的拓扑异构酶I抑制活性成分）组成。我们研究了Trop-2表达以及SN-38介导的双链DNA（dsDNA）断裂的同源重组修复（HRR）是否在三阴性乳腺癌（TNBC）对SG的敏感性中发挥作用。与低表达Trop-2、对SG敏感性较低的TNBC细胞系（MDA-MB-231）相比，在低表达和中等表达Trop-2的SG敏感细胞系（分别为SK-MES-1肺鳞状细胞癌和HCC1806 TNBC）中评估了由Rad51表达所证明的HRR途径的激活情况。此外，用SG处理MDA-MB-231的两种Trop-2转染细胞系C13和C39（Trop-2分别高4倍和25倍）的小鼠，以确定增加Trop-2表达是否能提高SG疗效。SG使MDA-MB-231中的Rad51增加超过2倍，但对SK-MES-1或HCC1806没有影响，导致MDA-MB-231中的dsDNA断裂水平降低。SG和生理盐水对携带亲本MDA-MB-231肿瘤的小鼠产生相似的效果（中位生存时间（MST）分别为21天和19.5天）。然而，在Trop-2转染后携带高表达Trop-2的C13和C39肿瘤的小鼠中，SG提供了显著的生存益处，甚至与伊立替康相比也是如此（C13的MST = 97天对35天，C39的MST = 81天对28天；P < 0.0007）。这些结果表明，SG在表达高水平Trop-2的HRR功能正常的肿瘤患者以及表达低/中等水平Trop-2的HRR缺陷肿瘤患者中可能比伊立替康提供更好的临床益处。
