Dual Activation of CD8+ and CD4+ T cells by a PD-1 targeted IL-15 Mutein in Viral Infection

Immune checkpoint inhibitors have transformed cancer therapy, yet many patients fail to achieve durable responses, in part due to insufficient T cell reinvigoration. Cytokines remain promising additions to immunotherapy to improve response rates; however, the low therapeutic index and associated side effects have hindered progress. In response to these challenges, immunocytokines, engineered fusion proteins that combine the specificity of antibodies with the immune-stimulatory properties of cytokines, have been employed to enable targeted delivery of cytokine signals to immune cells or the tumor microenvironment to minimize pathological consequences. Here, we describe SAR445877 (SAR’877), a novel PD-1-targeted immunocytokine that fuses a high-affinity anti-PD-1 antibody with a detuned IL-15/IL-15Rα sushi domain complex. SAR’877 simultaneously blocks PD-1/PD-L1 and PD-1/PD-L2 interactions and delivers IL-15 signals selectively to PD-1+ T cells. This design enhances the proliferation and activation of antigen-experienced CD8⁺ and CD4⁺ T cells, as well as NK cells, while limiting systemic inflammatory cytokine release. Mechanistically, SAR’877 preferentially activates STAT5 signaling in PD-1⁺ lymphocytes and restores effector function in exhausted T cells in vitro. A murine surrogate of SAR’877 accelerated viral clearance and reinvigorated exhausted T cells in the chronic LCMV Clone-13 infection model. In multiple syngeneic tumor models, the surrogate induced robust anti-tumor immunity by expanding cytotoxic CD8⁺ T cells and promoting Th1 polarization. Notably, SAR’877 outperformed combination therapy with anti-PD-1 and untargeted IL-15, underscoring the therapeutic potential of targeted IL-15 delivery to PD-1+ cells. These findings position SAR’877 as a promising next-generation checkpoint immunotherapy that augments efficacy while reducing cytokine-associated toxicities.