Full antagonist of the IL-7 receptor suppresses chronic inflammation in non-human primate models by controlling antigen-specific memory T cells

Abstract
Targeting the expansion of pathogenic memory immune cells holds promise as a therapeutic strategy for preventing chronic autoimmune attacks. Interleukin 7 (IL-7), a critical cytokine produced by epithelial and stromal cells, plays a vital role in supporting the development, homeostasis, and metabolism of T-lymphocytes. Nearly all mature conventional T lymphocytes express the IL-7 receptor (IL-7R), with the notable exception of naturally occurring regulatory T-cells (Tregs). This creates a rare opportunity to selectively target harmful effector cells while sparing essential regulatory T-cells. In our recent study, we demonstrated that the therapeutic efficacy of anti-IL-7Rα antagonist monoclonal antibodies (mAbs) in a non-human primate model of memory T cell-induced chronic inflammation relies on the recognition of an epitope that overlaps both the IL-7 binding domain (site 1) and the receptor heterodimerization region (site-2b) (Nat Commun, 9(1):4483). We observed that “site-1-only” mAbs inhibited IL-7-induced JAK/STAT signaling but instead activated PI3K and Erk signaling, showing limited effectiveness in vivo. In contrast, “site-1 + 2b” mAbs acted as full antagonists, exhibiting potent long-term activity in controlling skin inflammation. Their mechanism of action involved SCH900353 neutralizing IFN-γ-producing antigen-specific memory T cells without inducing lymphopenia or causing functional or metabolic defects in polyclonal T-cells, a common side effect seen in previous rodent studies.