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<p>Leucine-rich repeat containing 15 (LRRC15) has emerged as an attractive biomarker and target for cancer therapy. Transforming growth factor-β (TGFβ) induces the expression of this plasma membrane protein specifically in aggressive and treatment resistant tumor cells derived from mesenchymal stem cells, with minimal expression observed in non-neoplastic tissues. We have developed a humanized monoclonal antibody, DUNP19, that specifically binds with high affinity to a phylogenetically conserved LRRC15 epitope and is rapidly internalized upon LRRC15 binding. In multiple subcutaneous and orthotopic tumor xenograft mouse models, Lutetium-177 labeled DUNP19 ([<sup>177</sup>Lu]Lu-DUNP19) enabled non-invasive imaging and molecularly precise radiotherapy to LRRC15-expressing cancer cells and murine cancer-associated fibroblasts, effectively halting tumor progression and prolonging survival with minimal toxicity. Transcriptomic analyses of [<sup>177</sup>Lu]Lu-DUNP19-treated tumors reveal a loss of pro-tumorigenic mechanisms, including a previously reported TGFβ-induced LRRC15+ signature associated with immunotherapy resistance. In a syngeneic tumor model, administration of [<sup>177</sup>Lu]Lu-DUNP19 significantly potentiated checkpoint-blockade therapy, yielding durable complete responses. Together, these results demonstrate that radio-theranostic targeting of LRRC15 with DUNP19 is a compelling precision medicine platform for image-guided diagnosis, eradication, and reprogramming of LRRC15+ tumor tissue that drives immuno-resistance and disease aggressiveness in a wide range of currently untreatable malignancies.</p>

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Development of a leucine-rich repeat-containing protein 15-targeted radio-immunotheranostic approach to deplete pro-tumorigenic mechanisms and immunotherapy resistance

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月30日

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  • Claire M. Storey,
  • Mohamed Altai,
  • Katharina Lückerath,
  • Wahed Zedan,
  • Henan Zhu,
  • Lara Breuer,
  • Marija Trajkovic-Arsic,
  • Julie Park,
  • Abbie Hasson,
  • Jens Siveke,
  • Diane Abou,
  • Haley Marks,
  • Enna Ulmert,
  • Alexander Ridley,
  • Marcella Safi,
  • Urpo Lamminmäki,
  • Constance Yuen,
  • Susanne Geres,
  • Liqun Mao,
  • Michael Cheng,
  • Sumit K. Subudhi,
  • Bilal A. Siddiqui,
  • Noah Federman,
  • Johannes Czernin,
  • Ken Herrmann,
  • Laurent Bentolila,
  • Xia Yang,
  • Thomas G. Graeber,
  • Robert Damoiseaux,
  • Daniel Thorek,
  • David Ulmert

摘要

Leucine-rich repeat containing 15 (LRRC15) has emerged as an attractive biomarker and target for cancer therapy. Transforming growth factor-β (TGFβ) induces the expression of this plasma membrane protein specifically in aggressive and treatment resistant tumor cells derived from mesenchymal stem cells, with minimal expression observed in non-neoplastic tissues. We have developed a humanized monoclonal antibody, DUNP19, that specifically binds with high affinity to a phylogenetically conserved LRRC15 epitope and is rapidly internalized upon LRRC15 binding. In multiple subcutaneous and orthotopic tumor xenograft mouse models, Lutetium-177 labeled DUNP19 ([177Lu]Lu-DUNP19) enabled non-invasive imaging and molecularly precise radiotherapy to LRRC15-expressing cancer cells and murine cancer-associated fibroblasts, effectively halting tumor progression and prolonging survival with minimal toxicity. Transcriptomic analyses of [177Lu]Lu-DUNP19-treated tumors reveal a loss of pro-tumorigenic mechanisms, including a previously reported TGFβ-induced LRRC15+ signature associated with immunotherapy resistance. In a syngeneic tumor model, administration of [177Lu]Lu-DUNP19 significantly potentiated checkpoint-blockade therapy, yielding durable complete responses. Together, these results demonstrate that radio-theranostic targeting of LRRC15 with DUNP19 is a compelling precision medicine platform for image-guided diagnosis, eradication, and reprogramming of LRRC15+ tumor tissue that drives immuno-resistance and disease aggressiveness in a wide range of currently untreatable malignancies.