New therapeutic strategies based on biasing IL-2 mutants for cancers and autoimmune diseases

Interleukin-2 (IL-2) is an immunomodulatory multifunctional cytokine. High-dose IL-2 was first approved by the U.S. Food and Drug Administration (FDA) in the 1990s for the treatment of metastatic renal cell carcinoma and metastatic melanoma. However, the short half-life of IL-2 and its toxicity caused by high-dose IL-2 limit the clinical use of IL-2. Recently, the development of cell-type-selective engineered IL-2 products become a hot research filed, mainly because IL-2 stimulates both regulatory T cells (Treg) and effector T cells (Teff) in vivo. The selective effect of IL-2 on Treg and Teff can be improved by designing biased IL-2 mutants, which showed reduced toxicity while being more effective in stimulating anti-tumor effector immunity or ameliorating autoimmune diseases. In this review we summarize the biological properties of IL-2 mutants reported so far. The design process and principle of IL-2 mutants, IL-2 mutant antibody complexes and IL-2 fusion proteins were discussed, which provided research basis for the design and application of IL-2 mutants in the future.