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@ARTICLE{Klimovich:300329,
      author       = {B. Klimovich and L. Anton and J. Jung and Y. Lim and B. Lee
                      and J. Won and L. Zekri and A. Chashchina and M. Pflügler
                      and J. S. Heitmann and G. Jung and H. Salih$^*$},
      title        = {{CLEC}12{A}-directed immunocytokine with target
                      cell-restricted {IL}-15 activity for treatment of acute
                      myeloid leukemia.},
      journal      = {Frontiers in immunology},
      volume       = {16},
      issn         = {1664-3224},
      address      = {Lausanne},
      publisher    = {Frontiers Media},
      reportid     = {DKFZ-2025-00775},
      pages        = {1561823},
      year         = {2025},
      abstract     = {Despite recent advancements, acute myeloid leukemia (AML)
                      remains a therapeutic challenge. While monoclonal antibodies
                      (mAbs) leveraging natural killer (NK) cells through
                      antibody-dependent cellular cytotoxicity show great
                      potential, none have gained clinical approval for AML.
                      Immunocytokines have emerged as a promising strategy to
                      overcome the limited efficacy of therapeutic antibodies.
                      IL-15 stimulates activation, proliferation cytotoxic
                      activity of NK cells, but its clinical use is prevented by
                      short half-life, poor accumulation in the tumor, and
                      toxicity due to systemic off-target immune activation. Here
                      we report on the generation and preclinical characterization
                      of modified immunocytokines consisting of an Fc-optimized
                      CLEC12A (CLL-1) antibody fused to an IL-15 moiety with E46K
                      mutation. The mutation abrogates binding to IL-15Rα,
                      thereby enabling substitution of physiological
                      trans-presentation by target binding and thus conditional
                      IL-15Rβ/γ stimulation to reduce systemic toxicity. An
                      optimal CLEC12A binder was selected from a range of murine
                      mAbs, based on analysis of AML cell lines and leukemic cells
                      from patients. This antibody was then used to construct an
                      immunocytokine (MIC12) that subsequently was characterized
                      functionally. Analysis of NK cell activation, cytokine
                      release, proliferation and anti-leukemia reactivity
                      demonstrated that MIC12 induced superior target cell killing
                      and NK cell expansion compared to Fc-optimized CLEC12A
                      antibody, with efficacy being dependent on target antigen
                      binding. Our results show that novel immunocytokines with
                      conditional IL-15 activity are capable of inducing potent NK
                      cell responses against AML cells and identify MIC12 as
                      promising therapeutic candidate for leukemia treatment.},
      keywords     = {AML (Other) / CLL-1 (Other) / Clec12A (Other) /
                      Fc-optimized antibodies (Other) / IL-15 (Other) / NK cells
                      (Other) / immunocytokines (Other)},
      cin          = {TU01},
      ddc          = {610},
      cid          = {I:(DE-He78)TU01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40213559},
      pmc          = {pmc:PMC11983603},
      doi          = {10.3389/fimmu.2025.1561823},
      url          = {https://inrepo02.dkfz.de/record/300329},
}