Robust antitumor activity of a de novo interleukin-21 mimic
A long-standing goal of cancer immunotherapy is to activate cytotoxic antitumor T cells across a broad range of affinities and dampen suppressive regulatory T (Treg) cell responses, but current approaches achieve these goals with limited success. Here, we report a de novo IL-21 mimic, 21h10, designed to have augmented stability and high signaling potency in both humans and mice. In multiple animal models, 21h10 showed robust antitumor activity, exceeding that of native IL-21 for murine melanoma, inducing a rapid regression of murine adenocarcinoma, and exhibiting potent activity in an orthotopic pancreatic cancer model that is refractory to conventional immunotherapies. In the tumor microenvironment, 21h10 induced highly cytotoxic antitumor T cells from clonotypes with a range of affinities for endogenous tumor antigens, driving high expression of interferon-?? (IFN-??) and granzyme B compared to native IL-21, while in the CD4+  T cell compartment, the frequency of IFN-??+ Th1 cells was increased while Foxp3+ Treg cells were reduced. Thus, 21h10 is a highly active IL-21 mimic with human-mouse cross-reactivity that potentiates low-affinity antitumor responses and has considerable translational potential. Overall design: RNA-Seq analyses using mouse CD8+ T cells that were pre-activated with anti-CD3 + anti-CD28, and cultured in complete RPMI media for 48 hours at 37°C. Cells were rested overnight, and then either without stimulation or stimulated with either mIL-21 or 21h10 for 24h.