Drug Design, Development and Therapy (Aug 2018)
A novel multifunctional anti-CEA-IL15 molecule displays potent antitumor activities
Abstract
Yue Liu,1,2 Yanlan Wang,1,2 Jieyu Xing,1,2 Yumei Li,1,2 Jiayu Liu,1,2 Zhong Wang1,2 1School of Pharmaceutical Sciences, 2Center for Cellular and Structural Biology, Sun Yat-Sen University, Guangzhou, People’s Republic of China Introduction: Interleukin-15 (IL-15) is an immunomodulatory cytokine. It can activate and expand cytotoxic CD8 T lymphocytes and natural killer cells, leading to potent antitumor effects. Various forms of IL-15 are now in different stages of development for cancer immunotherapy. One of the major issues with IL-15 or IL15–IL15Rα fusion is high toxicity due to systemic activation of immune cells. Materials and methods: In this study, we engineered a nanobody–cytokine fusion molecule, anti-CEA-IL15, in which an anti-CEA nanobody was linked to an IL15Rα–IL15 fusion. The nanobody–cytokine fusion exhibited multiple mechanisms to kill tumor cells, including promoting immune cell proliferation and directing antibody-dependent cytotoxicity against CEA-positive tumor cells. Results: In xenograft models, anti-CEA-IL15 was localized in the tumor microenvironment and exhibited more potent antitumor activities than non-targeting IL-15, supporting potential application of this multifunctional fusion molecule in tumor immunotherapy. Conclusion: We generated and validated a tumortargeting fusion protein, anti-CEA-IL15, which has potent cytokine activity to activate and mobilize the immune system to fight cancer cells. Such strategies may also be applied to other cytokines and tumor-targeting molecules to increase antitumor efficacy. Keywords: immunotherapy, IL-15, nanobody, CEA, antibody–cytokine fusion
