Recombinant Interleukin-12 for Immunotherapy: A Double-Sided Sword

The innate and adaptive immune responses are closely linked and mutually reinforcing. The type of adaptive immune response is strongly influenced by the cytokines produced by innate immune cells. Interleukin-12 (IL-12) plays a key role in linking innate immunity to an adaptive T helper-1 (Th1) response against pathogens and tumor cells, thereby counteracting an imbalanced Th2 immune response. These properties make IL-12 a powerfull candidate to revert the Th2 dominance into a polarized immune response, e.g., in the tumor environment. Due to the heterodimeric structure, recombinant IL-12 fusion proteins provide the potential to create agonistic as well as antagonistic derivatives. The latter IL-12 derivatives block IL-12 activity by competitive binding to the receptor, e.g., to repress chronic inflammatory processes. Here we discuss functional properties of recombinant IL-12 constructs for use in immunotherapy, particularly (i) the agonistically acting IL-12(p40-p35) protein designed to boost anti-tumor immunity by reverting Th2 dominance and by increasing the effector functions of tumor infiltrating T- and NK-cells, and (ii) the antagonistically acting IL-12(p40)2 dimer protein designed to block IL-12 functions in chronic inflammatory diseases. Despite their limitations, both types of recombinant IL-12 derivatives have significant implications for the immunotherapy of malignant diseases as well as of bowel disease.