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@ARTICLE{Cremer:829380,
      author       = {Cremer, Christian and Braun, Hanna and Mladenov, Radoslav
                      and Schenke, Lea and Cong, Xiaojing and Jost, Edgar and
                      Brümmendorf, Tim H. and Fischer, Rainer and Carloni, Paolo
                      and Barth, Stefan and Nachreiner, Thomas},
      title        = {{N}ovel angiogenin mutants with increased cytotoxicity
                      enhance the depletion of pro-inflammatory macrophages and
                      leukemia cells ex vivo},
      journal      = {Cancer immunology immunotherapy},
      volume       = {64},
      number       = {12},
      issn         = {1432-0851},
      address      = {Berlin},
      publisher    = {Springer},
      reportid     = {FZJ-2017-03093},
      pages        = {1575 - 1586},
      year         = {2015},
      abstract     = {Immunotoxins are fusion proteins that combine a targeting
                      component such as an antibody fragment or ligand with a
                      cytotoxic effector component that induces apoptosis in
                      specific cell populations displaying the corresponding
                      antigen or receptor. Human cytolytic fusion proteins (hCFPs)
                      are less immunogenic than conventional immunotoxins because
                      they contain human pro-apoptotic enzymes as effectors.
                      However, one drawback of hCFPs is that target cells can
                      protect themselves by expressing endogenous inhibitor
                      proteins. Inhibitor-resistant enzyme mutants that maintain
                      their cytotoxic activity are therefore promising effector
                      domain candidates. We recently developed potent variants of
                      the human ribonuclease angiogenin (Ang) that were either
                      more active than the wild-type enzyme or less susceptible to
                      inhibition because of their lower affinity for the
                      ribonuclease inhibitor RNH1. However, combining the
                      mutations was unsuccessful because although the enzyme
                      retained its higher activity, its susceptibility to RNH1
                      reverted to wild-type levels. We therefore used molecular
                      dynamic simulations to determine, at the atomic level, why
                      the affinity for RNH1 reverted, and we developed strategies
                      based on the introduction of further mutations to once again
                      reduce the affinity of Ang for RNH1 while retaining its
                      enhanced activity. We were able to generate a novel Ang
                      variant with remarkable in vitro cytotoxicity against HL-60
                      cells and pro-inflammatory macrophages. We also demonstrated
                      the pro-apoptotic potential of Ang-based hCFPs on cells
                      freshly isolated from leukemia patients.},
      cin          = {GRS Jülich ; German Research School for Simulation
                      Sciences / IAS-5},
      ddc          = {610},
      cid          = {I:(DE-Juel1)GRS-20100316 / I:(DE-Juel1)IAS-5-20120330},
      pnm          = {899 - ohne Topic (POF3-899)},
      pid          = {G:(DE-HGF)POF3-899},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000365176600008},
      pubmed       = {pmid:26472728},
      doi          = {10.1007/s00262-015-1763-8},
      url          = {https://juser.fz-juelich.de/record/829380},
}