Background: Use of IL-2 (Proleukin) remains limited due to its short half-life, toxicity, and its ability to preferentially activate Tregs resulting in unwanted immune suppression. Approaches to reduce binding to CD25 (IL2α), such as pegylation techniques, also results in reduced affinity to CD122 (IL2β). To bypass these limitations, we engineered MDNA11, an IL-2 Superkine containing core mutations to diminish binding to CD25 while increasing affinity to CD122. To increase half-life, MDNA11 was fused to an albumin scaffold, which is known to allow accumulation at the tumor site. Methods: MDNA11 was evaluated using in vitro and in vivo studies that included: IL-2 signaling in human PBMCs, Biacore binding analyses, PK studies in mice, and efficacy studies in syngeneic tumor models with or without immune checkpoint inhibitors (ICIs). In addition, dose-range finding studies in cynomolgus monkeys (NHP) were performed to characterize the safety and PK/PD profiles of MDNA11. Results: MDNA11 displayed enhanced STAT5 signaling in human NK and naïve CD8 T-cells with diminished Treg activity. In mice, the terminal half-life of MDNA11 was 24-fold longer than IL-2. As a result, MDNA11 triggered effective tumor growth control, as monotherapy or in combination with ICI, in multiple tumor models in spite of q1wk dosing for two weeks. MDNA11 administration to mice with pre-established CT26 colon cancer resulted in tumor-free animals and induced strong memory response and protection against subsequent re-challenges. MDNA11 also inhibited the growth of B16F10 melanomas, which translated into a durable increase in tumor infiltrating CD8 T-cells. When tested in NHP, MDNA11 led to increased circulating CD8 T-cells lasting for almost 14 days with limited effects on Tregs and eosinophils (the latter being a source of IL-5 causing vascular leak syndrome). High doses resulted in mild side effects that were transient and reversible even following repeated dosing. Conclusions: The long-acting MDNA11 Superkine has superior potency over IL-2 at activating naïve CD8 T-cells and NK cells, while exhibiting diminished Treg activation. This molecule potently inhibited tumor growth and induced durable regression and long-term memory response. Studies in NHP showed prolonged proliferation of immune effector cells lasting almost two weeks post-MDNA11 administration. The sum of these data underscores the potency of MDNA11 to trigger the host’s immune response to control or eradicate established tumors.