Designing Human IL -12 to Reduce Its Toxicity

Abstract

Cancer is a set of multiple diseases, characterized by uncontrollable abnormal growth of cell that has the ability to invade and destroy normal body tissue. Although radiation therapy and chemotherapy are in routine practice, the success rate is limited attracting immunotherapy to complement the treatment regime. Several cytokines are in the list of cancer immunotherapy and IL-12 (interleukin-12) is considered a very potent drug for the treatment of cancer. IL-12 plays very essential role in regulating both innate and adaptive immune responses. It is a heterodimer made up of p35 and p40 subunits. While p40 helps in the binding of IL-12 with its receptor, p35 activates the signalling pathway. Although effective, multiple doses of administration of IL-12 have been shown to induce systemic toxicity, thus limiting use in clinical trials. When IL-12 is administered, it stimulates CD8+ T and NK cells, which are cytotoxic in nature, produces a high level of IFN-γ that leads to the lethal inflammatory syndrome. Our focus in this study is to design IL-12 molecule by creating potential mutations so that its anti-tumor properties are retained but toxic effects are minimized. Here, we have made attempt to modulate the signalling of IL-12 by manipulating the interaction of IL-12 with its receptor. For this, we used various in silico methods including web servers and softwares to mutate IL-12. Mutation of p35 subunit, docking of mutated and wild type subunits and prediction of structures of IL-12 receptor β1 and β2 has been done. We expect that the engineered IL-12 based on our in silico design would affect the overt IFN- γ and might serve as a safe drug for cancer immunotherapy.