Modulating Mesothelin Shedding to Improve Therapy

Many tumor-specific or tumor-associated antigens have been discovered, but only a few of them have been successfully used for cancer therapy. Not only are the pharmacological properties of therapeutic drug molecules critical to the clinical success, the biological nature of the target antigens has a big influence on the therapeutic outcome. In searching for good drug targets for cancer, our lab discovered a cell surface protein called mesothelin in the 1990s. It is highly expressed in many tumors such as mesothelioma, ovarian cancer, pancreatic cancer and lung cancer. However, it only has minor expression in normal mesothelial cells lining the pleura, pericardium and peritoneum. This expression pattern makes it an attractive target. We designed a mesothelin targeted immunotoxin called SS1P in which the Fv portion of an anti-mesothelin antibody is fused to a truncated portion of Pseudomonas exotoxin A (PE38). The cell-killing mechanism of immunotoxin involves three general steps. i) The SS1P immunotoxin molecule binds to mesothelin on the cell surface; ii) SS1P enters the cell through a mesothelin-mediated internalization process and its PE portion is translocated to the cytosol; and iii) the PE molecule causes ADP-ribosylation of EF-2, leading to arrest of protein synthesis and apoptosis. SS1P turns out to be very toxic to mesothelioma cells, yet is well tolerated by patients in spite of low level mesothelin expression in normal tissue. We observed several minor responses in our phase I clinical trials [1]. Depending on the cell-killing mechanism, the cytotoxicity of an immunotoxin can be significantly affected by the target properties, such as the signaling pathway involved, the cell surface target density, target internalization rate, target-mediated membrane traffic pathway, etc. Mesothelin is a GPI-anchored protein without an intracellular tail. Its physiological ligand has not been identified and it is not known if mesothelin is involved in any signaling pathway. Mesothelin has been shown to bind to another cell surface protein, MUC16. Mesothelin has several features, which make it useful for cancer therapy. Mesothelin is well-internalized, making it a good target for immunotoxins. Mesothelin is actively shed from the cell surface, generating an antigen pool in the circulation and in the tumor interstitial space. The measurement of serum levels of shed mesothelin is used as a criterion in the diagnosis of mesothelioma and ovarian cancer in patients. Mesothelin in the tumor interstitial space will inevitably interact with its targeting agents during the process of tumor penetration. To better understand …