High Shed Antigen Levels within Tumors: An Additional Barrier to Immunoconjugate Therapy

Shedding of cell surface antigens is an important biological process that is used by cells to modulate responses to signals in the extracellular environment. Because antibody-based therapies of cancer target cell surface antigens, it is important to understand more about the shedding process and how it affects tumor responses to this type of therapy. Up to now most attention has been focused on measuring the concentration of shed antigens in the blood and using these to determine the presence of a tumor and as a measure of response. The recent finding that the concentration of the tumor antigen mesothelin is extremely high within the interstitial space of tumors, where it can block antibody action, and that the concentration of shed mesothelin within the tumor is lowered by chemotherapy has important implications for the successful treatment of solid tumors by immunoconjugates and whole antibodies.