biostudies-literatureUnknown5(10)Wu JRegeneron PharmaceuticalsThe clinical use of interleukin-2 (IL-2) for cancer immunotherapy is limited by severe toxicity. Emerging IL-2 therapies with reduced IL-2 receptor alpha (IL-2Rα) binding aim to mitigate toxicity and regulatory T cell (Treg) expansion but have had limited clinical success. Here, we show that IL-2Rα engagement is critical for the anti-tumor activity of systemic IL-2 therapy. A "non-α" IL-2 mutein induces systemic expansion of CD8⁺ T cells and natural killer (NK) cells over Tregs but exhibits limited anti-tumor efficacy. We develop a programmed cell death protein 1 (PD-1)-targeted, receptor-masked IL-2 immunocytokine, PD1-IL2Ra-IL2, which attenuates systemic IL-2 activity while maintaining the capacity to engage IL-2Rα on PD-1⁺ T cells. Mice treated with PD1-IL2Ra-IL2 sCell reports. Medicine101747https://www.ebi.ac.uk/biostudies/studies/S-EPMC11513833biostudies-literatureA PD-1-targeted, receptor-masked IL-2 immunocytokine that engages IL-2Rα strengthens T cell-mediated anti-tumor therapies.PMC11513833Wu JMurphy AJCrawford ADavis SMohrs KKrueger PWei YMacdonald LHermann AAhmed HGarg VDiLillo DJWang QUllman EVazzana KWang SYancopoulos GDPatel SGuo CRamos WBhavsar RAdler CLin JCBloch NSmith EYan YNi MHuang TZhang TDudgeon DAntao OQChang AYAmatulli MOlson WCfalseA PD-1-targeted, receptor-masked IL-2 immunocytokine that engages IL-2Rα strengthens T cell-mediated anti-tumor therapies.The clinical use of interleukin-2 (IL-2) for cancer immunotherapy is limited by severe toxicity. Emerging IL-2 therapies with reduced IL-2 receptor alpha (IL-2Rα) binding aim to mitigate toxicity and regulatory T cell (Treg) expansion but have had limited clinical success. Here, we show that IL-2Rα engagement is critical for the anti-tumor activity of systemic IL-2 therapy. A "non-α" IL-2 mutein induces systemic expansion of CD8⁺ T cells and natural killer (NK) cells over Tregs but exhibits limited anti-tumor efficacy. We develop a programmed cell death protein 1 (PD-1)-targeted, receptor-masked IL-2 immunocytokine, PD1-IL2Ra-IL2, which attenuates systemic IL-2 activity while maintaining the capacity to engage IL-2Rα on PD-1⁺ T cells. Mice treated with PD1-IL2Ra-IL2 s2024-01-01T00:00:00Z2024 Oct2026-07-15T17:40:40.486Z2025-04-04T00:29:15.149ZS-EPMC115138333932641010.1016/j.xcrm.2024.101747