Meflin is a druggable target using antibody-drug conjugates in progressive osteosarcoma

The 5-year overall survival rate of patients with recurrent osteosarcoma (OS) has remained less than 30%, which is attributed to the persistence and growth of OS cells with high chemoresistance, tumorigenicity and metastatic potential. However, the characteristics of recurrent OS cells and therapeutic strategies remain unexplored. In the present study, we found that Meflin, a membrane protein previously identified as a specific marker of mesenchymal stromal/stem cells, was highly expressed in tumor cells of patients with progressive OS. Interestingly, OS cells resistant to doxorubicin showed upregulated Meflin expression and high tumorigenicity. Meflin expression was correlated with that of cancer stem cell markers such as multidrug resistance-associated protein 1. In addition, Meflin is involved in bone morphogenetic protein signaling by binding to its cognate receptor and regulating anchorage-independent sphere formation in OS cells. This suggests that Meflin expression may be associated with the acquisition of tumor-initiating or stem-like features. We generated antibody-drug conjugates (ADCs) consisting of anti-Meflin antibodies covalently linked to the cytotoxic agent monomethyl auristatin E (anti-Meflin ADCs). Anti-Meflin ADCs were internalized and exhibited remarkable cytotoxicity in cultured Meflin-positive OS cells and antitumor efficacy in OS murine models. Importantly, they did not show any obvious adverse effects in wild-type mice. Collectively, these data provide evidence that anti-Meflin ADCs warrant further development as novel therapeutic targets for Meflin-positive refractory or recurrent OS.