Anti-cancer Immunologic Function of Recombinant Interleukin-18

Abstract

Interleukin-18 (IL-18) is a cytokine species that can be used as a tumor suppressor protein in animal model and this protein can be applied to patients safely. In this study, we have developed the engineered types of human IL-18 including E6K T63A and E6K+T63A based on protein-receptor interaction. When the testing of the ability of each engineered IL-18 in interferon (IFN)-y induction was performed, the result showed the higher activity of E6K+T63A IL-18 than native, T63A and E6K IL- 18 around 16, 4.2 and 1.7 times, respectively. Moreover, results from the animal study demonstrated that mice treated with E6K+T63A IL-18 exhibited the lowest tumor volume, and expanded the survival period of this group of mice. This may be mediated by the recruitment of Th1 and cytotoxic T lymphocyte (CTL) to the tumor mass effected by our engineered IL-18 since flow cytometry revealed the higher proportion of Th1 and CTL cells in the tumor region when compared to the control group. Molecular dynamic simulation was also used to investigate the role of inter- and intra-molecular alterations of the protein after mutations were performed, and it has been revealed that the mutation affected the key residues containing region of IL- 18, leading to the effective interaction between our engineered IL-18 and its receptors. Although these structural changes occurred with the higher activity, root mean square deviation and root mean square fluctuation demonstrated that the overall structure still be the same. This all confirms the performance of our engineered type of IL-18 to be a candidate as a cancer therapeutic agent.