Recently, we have introduced Fc-optimized antibodies targeting CD135/FLT3 and CD133 to induce superior antibody-dependent cellular cytotoxicity (ADCC) of NK cells against acute myeloid leukemia (AML), with the CD135 compound having completed Phase I testing in a clinical trial (NCT02789254; Heitmann JS et al, J Hematol Oncol. 2023). To enhance the ability of antibodies to induce ADCC, NK cell immunity can be further enhanced using cytokines such as IL-15, which is currently at the focus of numerous efforts for cancer treatment. However, the use of clinically effective doses of IL-15 is hampered by significant side effects due to unspecific immune activation. Here we report on modified immunocytokines (MICs) consisting of Fc-optimized CD133 and CD135 antibodies fused to a mutant IL-15 with abolished binding to the IL-15 receptor alpha (MIC133/MIC135). In MIC constructs, binding of the antibody substitutes for trans presentation of IL-15, which is physiologically required for stimulation of the IL-15 receptor beta/gamma on NK cells. Comparative analysis revealed that CD135 is expressed at significantly higher levels on primary AML cells and is less susceptible to antigen shift than CD133. Functional analyses using primary AML cells as targets showed that MIC135 induced target-restricted NK cell anti-leukemia reactivity to a significantly greater extent than the Fc-optimized FLYSYN antibody. Notably, beyond improving target cell killing, in stark contrast to FLYSYN, MIC135 induced prominent NK cell proliferation, and Off-target toxicity analyses confirmed the target-antigen-dependent activity of MIC135 compared to anti-CD135 immunocytokines with wild-type IL-15 (IC135). In addition, MIC135 did not induce adverse effects against healthy FLT3-expressing cells. Taken together, MIC135 induces NK cell reactivity against leukemia cells in a highly target cell-restricted manner and shows higher efficacy than Fc-optimized antibodies, making it a promising treatment option for AML.