Introduction: 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. Methods: 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. Results: 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. Conclusions: 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.

中文翻译：

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5T4 与间皮瘤的有利结果和抗体药物偶联物的靶点相关

简介：间皮瘤患者的预后很差，这提示需要开发更好的治疗方案。抗体药物偶联物 (ADC) 作为间皮瘤的治疗策略越来越受到关注。滋养细胞糖蛋白 (5T4) 是一种在间皮瘤中过度表达的癌胚蛋白，在正常组织中的表达较低，因此是 ADC 治疗的良好候选者。在这里，我们评估和操作 5T4 作为一种合适的抗原，用于间皮瘤患者的 ADC 靶向治疗。方法：在（初级）间皮瘤细胞系和活检标本中评估 5T4 抗原的表达，并与临床结果相关联。在 5T4 表达细胞中评估内化。在（原代）间皮瘤细胞上测试了三种不同的 5T4 靶向 ADC 的细胞毒性。结果：5T4 在 12 个（原代）细胞系中的 10 个中表达。大多数活检标本的 5T4 抗原染色呈阳性，染色强度和阳性细胞百分比存在显着差异。高表达与无进展生存期长相关。靶向 5T4 的游离抗体和 ADC 都被内化并进入溶酶体区室。细胞毒性实验表明，5T4 高表达的细胞系对三种 ADC 中的两种敏感。可以通过用氯喹中和溶酶体区室来恢复第三个 ADC 的有效性。结论：5T4 抗原在间皮瘤中表达，基于 5T4 的 ADC 被内化在溶酶体中。三个 ADC 中有两个能够杀死间皮瘤细胞；第三个 ADC 需要额外的溶酶体中和才能发挥作用。