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@ARTICLE{Altai:299009,
      author       = {M. Altai and Á. Nagy and P. Granit and W. Zedan and M.
                      Cerezo-Magaña and J. Park and K. Lückerath$^*$ and S.
                      Geres and M. Sydoff and D. L. J. Thorek and K. Westerlund
                      and D. Ulmert and A. E. Karlström},
      title        = {{O}ptimizing peptide nucleic acid-based pretargeting for
                      enhanced targeted radionuclide therapy.},
      journal      = {Journal of controlled release},
      volume       = {381},
      issn         = {0168-3659},
      address      = {New York, NY [u.a.]},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2025-00419},
      pages        = {113551},
      year         = {2025},
      note         = {Volume 381, 10 May 2025, 113551},
      abstract     = {Radiolabeled targeting agents have emerged as valuable
                      tools for the treatment of disseminated cancer. Monoclonal
                      antibodies (mAbs) are widely employed as carriers for
                      diagnostic and therapeutic radionuclides due to their
                      exceptional specificity and affinity. However, their
                      prolonged circulatory half-life can diminish diagnostic
                      efficacy and increase radiation exposure to non-target
                      tissues in therapeutic applications, resulting in
                      dose-limiting toxicities. To overcome this limitation,
                      pretargeting technologies emerge as promising strategies to
                      enhance tumor-to-background ratio and reduce radiation
                      exposure of healthy tissues. Our previous work introduced a
                      pretargeting concept leveraging the specific interaction
                      between two peptide nucleic acid (PNA) probes, HP1 and HP2,
                      as the recognition mechanism. This early iteration of the
                      PNA-based concept showed limited efficacy when used with
                      mAb-based vectors. To improve its performance, we
                      re-engineered the primary and secondary targeting agents by
                      incorporating newly designed PNA-probes. As the primary
                      targeting agent, we functionalized trastuzumab (T), a
                      well-characterized human epidermal growth factor receptor 2
                      (HER2)-targeting IgG1 mAb, with a 9-mer PNA probe (HP9).
                      Both FcIII-based covalent UV-light crosslinking and
                      enzyme-mediated glyco-engineering click-chemistry methods
                      were applied to generate trastuzumab-PNA conjugates
                      T-FcIII-HP9 and T-gly-HP9, respectively. As a
                      radionuclide-carrying secondary agent, we utilized a 9-mer
                      complementary PNA probe, HP16, which forms a stable duplex
                      with HP9 as well as displaying favorable in vivo kinetics.
                      Biacore and flow cytometry assessment of the HP9-conjugated
                      trastuzumab agents demonstrated retained HER2-binding
                      properties. The secondary HP16 probe, labeled with either a
                      dye or a radionuclide, showed cell surface accumulation
                      contingent on the presence of HP9 on the primary
                      HER2-targeting agents. In vivo, T-gly-HP9 exhibited
                      significantly longer blood circulation half-life and
                      superior tumor uptake compared to T-FcIII-HP9. Further,
                      therapeutic dosing with [177Lu]-HP16 of trastuzumab-HP9
                      pretargeted HER2+ tumor models resulted in significantly
                      delayed disease progression and extended survival compared
                      to untreated subjects. Furthermore, pretargeted [177Lu]-HP16
                      exhibited comparable efficacy to [177Lu]-trastuzumab in both
                      delaying disease progression and prolonging survival. In
                      conclusion, the optimization of our PNA-based pretargeting
                      system has resulted in exceptional in vivo targeting
                      characteristics and therapeutic efficacy, validating the
                      potential of this novel approach.},
      keywords     = {Antibody (Other) / Peptide nucleic acid (Other) /
                      Pretargeting (Other) / Radiotherapy (Other) / Site-specific
                      labeling (Other)},
      cin          = {ED01},
      ddc          = {610},
      cid          = {I:(DE-He78)ED01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39986477},
      doi          = {DOI:10.1016/j.jconrel.2025.02.047},
      url          = {https://inrepo02.dkfz.de/record/299009},
}