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Background Although high-dose interleukin-2 (IL-2) has been approved for the treatment of certain cancers since 1992, widespread use has been limited due to systemic toxicity, including cytokine release syndrome and vascular leak syndrome. Versions of IL-2 with reduced potency have been studied but reduce efficacy as well as toxicity. We have developed Daiad TM-2/15 as a de-novo designed, highly potent IL-2/IL-15 agonist (Neo-2/15) that is targeted and conditionally activated to deliver anti-tumor activity to the tumor microenvironment without systemic immune activation.Methods A logic gate was engineered by splitting Neo-2/15 into two separate pieces, one comprising three alpha helices and the other one helix. The individual domains are unable to bind or activate the IL-2 receptor complex, but recombine into Neo-2/15 when the two pieces are brought into close proximity. By fusing each portion of the cytokine mimetic to a single domain antibody, we created two distinct modules, which together constitute Daiad-2/15.Results We have developed Daiad-2/15 variants that target antigens on the surface of specific T cells, leading to IL-2R signaling and activation in a target-dependent manner. In vitro, Daiad-2/15 treatment activates T cells that express the targeted antigen, with a 10,000 fold lower threshold for signaling compared to antigen-negative T cells. Furthermore, Daiad-2/15 does not trans-activate target-negative cells, even when present in an admixed culture. Finally, Daiad technology enables an ‘and’ logic gate by targeting each of the inactive domains to different targets, such that immune cell activation and proliferation only occur when both targets are present on the same cell.Conclusions Together, our data suggest that Daiad-2/15 could potentiate the systemic delivery of a highly potent immune agonist to specific immune cells within the tumor microenvironment and draining lymph nodes in the absence of significant systemic toxicity.