A monoclonal antibody W1 blocks mesothelin-mediated tumor progression.

Mesothelin (MSLN) represents an attractive and potential biomarker for targeted cancer therapy. Although MSLN has been implicated in mediating tumorigenesis, its precise physiological function remains incompletely elucidated. Moreover, only a limited number of antibodies have been reported to directly inhibit its function in tumor progression. In this study, we confirmed that the N-terminal domain 1 (D1) of MSLN serves as the key region responsible for mediating binding to tumor cells and promoting migration and invasion through the activation of the matrix metalloproteinase-7 (MMP7) pathway. We further identified two monoclonal antibodies, W1 and A12H, which specifically bind to D1 and domain 3 (D3) of MSLN, respectively. W1 effectively inhibits the interaction between D1 and tumor cells, thereby suppressing cell migration and invasion via interference with MSLN-mediated signaling pathways. In contrast, A12H, which targets D3, does not exhibit a similar functional blockade. Additionally, W1 significantly reduces the tumor burden in mice bearing MSLN-positive tumor cells. Together, these findings provide mechanistic insights into the role of D1 in driving tumor progression and reinforce the potential of MSLN as a therapeutic biomarker. The antibody W1 emerges as a promising candidate, offering novel perspectives for developing immunotherapeutic strategies against MSLN-related cancers.