{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE323nnn/GSE323389/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Mus musculus"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE323389"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Dual Activation of CD8+ and CD4+ T cells by a PD-1 targeted IL-15 Mutein in Viral Infection","description":"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.","dates":{"publication":"2026/04/21"},"accession":"GSE323389","cross_references":{"GSM":["GSM9564845","GSM9564846","GSM9564844","GSM9564847"],"GPL":["34290"],"GSE":["323389"],"taxon":["Mus musculus"]}}