Recent Advances in Structural Investigations of Cancer Antigen Mesothelin and Its Interactions with Therapeutic Antibodies

The tumor-associated antigen mesothelin is present at high levels on the cell surface of many human cancers, while its expression in normal tissues is limited. The binding of mesothelin to the cancer antigen 125 (CA-125, also known as MUC16) can lead to heterotypic cell adhesion and tumor metastasis within the pleural and peritoneal cavities. Immunotherapeutic strategies targeting mesothelin are being intensively investigated, which is aided with a growing body of structural knowledge of the protein and its interaction with various antibodies and biological partners. In this review, we summarize experimental studies on the structures of mesothelin, which have resulted in a complete atomic model. Mesothelin is best described as a compact, right-handed, and conformationally flexible solenoid composed of 9-layers of helices, with each layer resembling ARM/HEAT family protein folds. Glycan attachments have been confirmed in the structure for all three predicted N-glycosylation sites. Structural investigations of mesothelin with various bound therapeutic antibodies confirmed that available antibodies target mainly the N-terminal rigid and immunogenic domain, while a few are made to bind middle domain and C-terminal linear tail, revealing correlation between immunogenicity and structural stability as well as unique epitopes at atomic resolution. Crystallographic studies have also extended to the interactions between mesothelin and CA-125. These advances in structural investigation of mesothelin provide atomic models for the 3D organization of this protein and its interactions with antibodies. It offers insights into the potential function of mesothelin and guidance for further development of therapeutic antibodies.