Division of Oncogenomics, Oncode Institute within Netherlands Cancer Institute, Amsterdam, The Netherlands.
Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
J Thorac Oncol. 2018 Oct;13(10):1577-1587. doi: 10.1016/j.jtho.2018.06.008. Epub 2018 Jun 27.
The prognosis for patients with mesothelioma is poor, which prompts the need for the development of better treatment options. Antibody drug conjugates (ADCs) are gaining interest as a therapeutic strategy in mesothelioma. Trophoblast glycoprotein (5T4) is an oncofetal protein overexpressed in mesothelioma with low expression in normal tissue and therefore a good candidate for ADC treatment. Here, we evaluated and manipulated 5T4 as a suitable antigen for ADC targeted therapy in patients with mesothelioma.
Expression of the 5T4 antigen is evaluated in (primary) mesothelioma cell lines and biopsy specimens, and correlated with clinical outcome. Internalization was assessed in 5T4 expressing cells. The cytotoxicity of three different 5T4-targeting ADCs was tested on (primary) mesothelioma cells.
5T4 was expressed in 10 of 12 (primary) cell lines. Most biopsy specimens stained positive for the 5T4 antigen, with marked differences in staining intensity and percentage of positive cells. High expression correlated with long progression-free survival. Both free antibody and ADCs targeting 5T4 were internalized and entered lysosomal compartments. Cytotoxicity experiments showed that cell lines with a high expression for 5T4 were sensitive to two of three ADCs. Lack of efficacy for the third ADC could be restored by neutralizing lysosomal compartments with chloroquine.
The 5T4 antigen is expressed in mesothelioma and 5T4-based ADCs are internalized in lysosomes. Two of three ADCs were capable of killing the mesothelioma cells; the third ADC required additional lysosomal neutralization for its effect. 5T4-based ADCs would be a selective strategy for the treatment of mesothelioma.
间皮瘤患者的预后较差，这促使我们需要开发更好的治疗方法。抗体药物偶联物（ADC）作为间皮瘤的治疗策略引起了关注。滋养层细胞表面抗原 5（Trophoblast glycoprotein 5，5T4）是一种在间皮瘤中过表达的癌胚蛋白，在正常组织中低表达，因此是 ADC 治疗的理想候选物。在此，我们评估并操纵 5T4 作为间皮瘤患者 ADC 靶向治疗的合适抗原。
评估 5T4 抗原在（原代）间皮瘤细胞系和活检标本中的表达，并与临床结果相关联。在表达 5T4 的细胞中评估内化作用。测试三种不同的 5T4 靶向 ADC 对（原代）间皮瘤细胞的细胞毒性。
12 种（原代）细胞系中有 10 种表达 5T4。大多数活检标本对 5T4 抗原呈阳性染色，染色强度和阳性细胞百分比有明显差异。高表达与无进展生存期延长相关。游离抗体和靶向 5T4 的 ADC 均被内化并进入溶酶体腔室。细胞毒性实验表明，5T4 高表达的细胞系对两种 ADC 敏感。用氯喹中和溶酶体腔室可以恢复第三种 ADC 的疗效。
5T4 抗原在间皮瘤中表达，5T4 为基础的 ADC 被内化到溶酶体中。三种 ADC 中有两种能够杀死间皮瘤细胞；第三种 ADC 则需要额外的溶酶体中和才能发挥作用。基于 5T4 的 ADC 是治疗间皮瘤的一种有选择性的策略。
