Recent advances in structural investigations of cancer antigen mesothelin and its interactions with therapeutic antibodies

The tumor-associated antigen mesothelin is highly expressed in many human cancers, while its expression in normal tissues is limited. Its interaction with the cancer antigen 125 promotes heterotypic cell adhesion and tumor metastasis. Mesothelin-targeted immunotherapies are being intensively investigated, which is aided by growing structural knowledge of the protein and its interactions with antibodies. Recent studies have produced a complete atomic model showing mesothelin as a compact, right-handed, conformationally flexible solenoid composed of nine layers of helices, with glycans attached at all three predicted N-glycosylation sites. Structural analyses reveal that most therapeutic antibodies target the rigid and immunogenic N-terminal domain, while a few bind to middle domain or C-terminal linear tail, revealing correlation between immunogenicity and structural stability. Crystallographic studies have also extended to the interactions between mesothelin and CA-125. These structural advances offer insights into the potential function of mesothelin and guidance for further development of therapeutic antibodies.