Journal of Thoracic Oncology 2018 June 26 [Link]
Schunselaar LM, Monkhorst K, van der Noort V, Wijdeven R, Peters D, Zwart W, Neefjes J, Baas P
The prognosis for patients with mesothelioma is poor, which urges the need for the development of better treatment options. Antibody drug conjugates (ADCs) are gaining interest as a therapeutic strategy in mesothelioma. 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 biopsies, 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 out of 12 (primary) cell lines. Most biopsies 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 out 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 out of three ADCs were capable of killing the mesothelioma cells, the third ADC required additional lysosomal neutralization for its effect. 5T4-based ADC would be a selective strategy for the treatment of mesothelioma.