An IL-12 partial agonist sustains intratumoral lymphocyte activation and detoxifies systemic IL-12 therapy.

Interleukin-12 (IL-12) is a proinflammatory T cell- and natural killer (NK) cell-activating cytokine with potent preclinical anti-tumor efficacy, but clinical toxicity has limited its use as an immunotherapy. In a mouse tumor model, wild-type IL-12 induces NK cell hyperactivation and cytokine storm followed by rapid NK cell loss. To avoid NK hyperactivation, we engineered an IL-12-Fc with attenuated IL-12Rβ1 binding (STK-026) to preferentially target activated T cells expressing high levels of IL-12 receptors. STK-026 avoids NK cell hyperactivation but supports sustained T cell activation, interferon γ (IFNγ) production, and intratumoral infiltration of tumor-infiltrating lymphocytes (TILs), macrophages, and cytotoxic NK cells. STK-026 induces tumor control in immune-competent mice, with a substantial therapeutic window between efficacy and toxicity. STK-026 also controls "cold" tumors and synergizes with anti-PD-1 treatment. In non-human primates, STK-026 avoids toxicity associated with IL-12 treatment but sustains effector T cell and NK cell activation. In summary, STK-026 provides anti-tumor efficacy without acute toxicity, expanding the therapeutic index of IL-12 treatment.