Development of a leucine-rich repeat-containing protein 15-targeted radio-immunotheranostic approach to deplete pro-tumorigenic mechanisms and immunotherapy resistance
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.
Authors
- Wahed Zedan (ORCID: https://orcid.org/0000-0002-0287-5367)
- Bilal Ahmed Siddiqui (ORCID: https://orcid.org/0000-0002-6806-1294)
- Noah Federman (ORCID: https://orcid.org/0000-0002-2627-6772)
- Mohamed Altai (ORCID: https://orcid.org/0000-0002-7624-0313)
- Sumit Kumar Subudhi (ORCID: https://orcid.org/0000-0001-5208-7732)
- Thomas G. Graeber (ORCID: https://orcid.org/0000-0001-8574-9181)
- A. Hasson
- Johannes Czernin
- Haley Marks (ORCID: https://orcid.org/0000-0001-7407-2582)
- Robert D. Damoiseaux (ORCID: https://orcid.org/0000-0002-7611-7534)
- Alexander Ridley
- Lars Breuer (ORCID: https://orcid.org/0000-0002-7797-9662)
- Laurent A. Bentolila (ORCID: https://orcid.org/0000-0002-8758-1594)
- Diane S. Abou (ORCID: https://orcid.org/0000-0002-3005-9623)
- Henan Zhu (ORCID: https://orcid.org/0000-0003-1617-0146)
- Julie E. Park (ORCID: https://orcid.org/0000-0002-3053-9969)
- Daniel L.J. Thorek (ORCID: https://orcid.org/0000-0003-2437-1239)
- Jens Thomas Siveke (ORCID: https://orcid.org/0000-0002-8772-4778)
- David H. Ulmert (ORCID: https://orcid.org/0000-0002-7871-2281)
- Marcella Safi
- Xia Yang (ORCID: https://orcid.org/0000-0002-3971-038X)
- Constance Yuen (ORCID: https://orcid.org/0000-0001-9714-9001)
- Claire M. Storey (ORCID: https://orcid.org/0000-0003-0792-1569)
- Enna Ulmert
- Susanne Geres
- Michael W. Cheng (ORCID: https://orcid.org/0000-0002-1869-2557)
- Ken Herrmann
- Marija Trajkovic-Arsic
- Urpo Lamminmäki
- Liqun Mao (ORCID: https://orcid.org/0000-0001-9704-3995)
- Katharina Lückerath
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- California NanoSystems Institute (US)
- University of Turku (FI)
- University of California, Los Angeles (US)
- German Cancer Research Center (DE)
- Lund University (SE)
- Washington University in St. Louis (US)
- Heidelberg University (DE)
- UCLA Health (US)
- UCLA Medical Center (US)
- University Hospital Heidelberg (DE)
- Los Angeles Medical Center (US)
- Broad Center (US)
- Molecular Theranostics (United States) (US)
- University of Duisburg-Essen (DE)
Publication Details
- Journal
- Signal Transduction and Targeted Therapy
- Published
- 2025-09-29
- DOI
- https://doi.org/10.1038/s41392-025-02410-9
- Citations
- 2
- Primary Topic
- Neuroblastoma Research and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 2.78
Funders
- Prostate Cancer Foundation
- Children's Discovery Institute
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Cancerfonden
- Lunds Universitet
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet
- Barncancerfonden
- Deutschen Konsortium für Translationale Krebsforschung
- National Institutes of Health
- Center for AIDS Research, University of Washington
- National Cancer Institute
- Jonsson Comprehensive Cancer Center
- David Geffen School of Medicine, University of California, Los Angeles
- UCLA AIDS Institute
- California NanoSystems Institute