Mesothelin (MSLN) Region III (MSLN (Region III))

Mesothelin (MSLN) is a 40 kDa glycosylphosphatidylinositol (GPI)-anchored glycoprotein that is highly expressed in several malignancies, including mesothelioma, ovarian, and pancreatic cancers [1.2.1, 1.4.2]. The protein is structurally divided into three distinct domains, with Region III (residues 487–598) being the membrane-proximal portion [1.2.3, 1.3.2]. While the exact physiological function of mesothelin remains unclear, it is known to facilitate tumor cell adhesion and metastasis through its interaction with MUC16 (CA125) at the N-terminal Region I [1.3.2, 1.4.3]. Region III has emerged as a strategic therapeutic target because it is not involved in MUC16 binding, thereby avoiding ligand competition that can hinder drug efficacy [1.3.2]. Furthermore, targeting this membrane-proximal region is hypothesized to enhance the potency of chimeric antigen receptor (CAR) T cells and bispecific antibodies by optimizing the distance of the immunological synapse [1.3.2, 1.5.1]. Current therapeutic developments focusing on Region III include monoclonal antibodies like YP218 and various CAR-T cell constructs designed to minimize the interference of shed mesothelin [1.3.1, 1.3.2]. Despite its promise, targeting mesothelin carries risks of on-target off-tumor toxicity, particularly inflammation of the mesothelial linings in the pleura and peritoneum [1.2.2, 1.4.5].

Other names

MSLNCAK1 antigenPre-pro-megakaryocyte-potentiating factorC-terminal mesothelinMembrane-proximal mesothelin domain

Binding to the membrane-proximal Region III of mesothelin to induce immune-mediated cytotoxicity (e.g., via CAR-T cells or bispecific antibodies) while avoiding competition with the MUC16 ligand and reducing the decoy effect of shed mesothelin [1.3.1, 1.3.2].