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@ARTICLE{PfeiferSerrahima:212443,
      author       = {J. Pfeifer Serrahima and C. Zhang$^*$ and P. Oberoi$^*$ and
                      M. Bodden and J. Röder and C. Arndt and A. Feldmann and A.
                      Kiefer and M. Prüfer and I. Kühnel and T. Tonn$^*$ and M.
                      Bachmann$^*$ and W. S. Wels$^*$},
      title        = {{M}ultivalent adaptor proteins specifically target {NK}
                      cells carrying a universal chimeric antigen receptor to
                      {E}rb{B}2 ({HER}2)-expressing cancers.},
      journal      = {Cancer immunology immunotherapy},
      volume       = {72},
      number       = {9},
      issn         = {0340-7004},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DKFZ-2023-00162},
      pages        = {2905-2918},
      year         = {2023},
      note         = {2023 Sep;72(9):2905-2918},
      abstract     = {Chimeric antigen receptor (CAR)-engineered immune effector
                      cells constitute a promising approach for adoptive cancer
                      immunotherapy. Nevertheless, on-target/off-tumor toxicity
                      and immune escape due to antigen loss represent considerable
                      challenges. These may be overcome by adaptor CARs that are
                      selectively triggered by bispecific molecules that crosslink
                      the CAR with a tumor-associated surface antigen. Here, we
                      generated NK cells carrying a first- or second-generation
                      universal CAR (UniCAR) and redirected them to tumor cells
                      with so-called target modules (TMs) which harbor an ErbB2
                      (HER2)-specific antibody domain for target cell binding and
                      the E5B9 peptide recognized by the UniCAR. To investigate
                      differential effects of the protein design on activity, we
                      developed homodimeric TMs with one, two or three E5B9
                      peptides per monomer, and binding domains either directly
                      linked or separated by an IgG4 Fc domain. The adaptor
                      molecules were expressed as secreted proteins in Expi293F
                      cells, purified from culture supernatants and their
                      bispecific binding to UniCAR and ErbB2 was confirmed by flow
                      cytometry. In cell killing experiments, all tested TMs
                      redirected NK cell cytotoxicity selectively to
                      ErbB2-positive tumor cells. Nevertheless, we found
                      considerable differences in the extent of specific cell
                      killing depending on TM design and CAR composition, with
                      adaptor proteins carrying two or three E5B9 epitopes being
                      more effective when combined with NK cells expressing the
                      first-generation UniCAR, while the second-generation UniCAR
                      was more active in the presence of TMs with one E5B9
                      sequence. These results may have important implications for
                      the further development of optimized UniCAR and target
                      module combinations for cancer immunotherapy.},
      keywords     = {Chimeric antigen receptor (Other) / ErbB2 (Other) / HER2
                      (Other) / NK-92 (Other) / Natural killer cells (Other) /
                      UniCAR (Other)},
      cin          = {FM01 / DD01},
      ddc          = {610},
      cid          = {I:(DE-He78)FM01-20160331 / I:(DE-He78)DD01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36688995},
      doi          = {10.1007/s00262-023-03374-x},
      url          = {https://inrepo02.dkfz.de/record/212443},
}