A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Development of a leucine-rich repeat-containing protein 15-targeted radio-immunotheranostic approach to deplete pro-tumorigenic mechanisms and immunotherapy resistance
Tekijät: Storey, Claire M.; Altai, Mohamed; Lückerath, Katharina; Zedan, Wahed; Zhu, Henan; Breuer, Lara; Trajkovic-Arsic, Marija; Park, Julie; Hasson, Abbie; Siveke, Jens; Abou, Diane; Marks, Haley; Ulmert, Enna; Ridley, Alexander; Safi, Marcella; Lamminmäki, Urpo; Yuen, Constance; Geres, Susanne; Mao, Liqun; Cheng, Michael; Subudhi, Sumit K.; Siddiqui, Bilal A.; Federman, Noah; Czernin, Johannes; Herrmann, Ken; Bentolila, Laurent; Yang, Xia; Graeber, Thomas G.; Damoiseaux, Robert; Thorek, Daniel; Ulmert, David
Kustantaja: Springer Nature
Julkaisuvuosi: 2025
Lehti:: Signal Transduction and Targeted Therapy
Artikkelin numero: 319
Vuosikerta: 10
ISSN: 2095-9907
eISSN: 2059-3635
DOI: https://doi.org/10.1038/s41392-025-02410-9
Verkko-osoite: https://doi.org/10.1038/s41392-025-02410-9
Rinnakkaistallenteen osoite: https://research.utu.fi/converis/portal/detail/Publication/504638328
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.
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This study was supported in part by the Outsmarting Osteosarcoma Hero Award (Because of Sydney), the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research Rose Hill Foundation Innovator Award. The study was further supported by NCI R01CA201035, R01CA240711, R01CA229893, DoD W81XWH-18-1-0223, UCLA SPORE in Prostate Cancer (P50 CA092131), JCCC Cancer support grant from NIH P30 CA016042 (PI: Teitell), Knut and Alice Wallenberg Foundation, Bertha Kamprad Foundation, David H. Koch Prostate Cancer Foundation Young Investigator Award, Swedish Research Council, Swedish Cancer Society, SIPEA Foundation, Swedish Childhood Cancer Foundation, John and Augusta Perssons Foundation, Royal Physiographic Society of Lund, Franke and Margareta Bergqvist Foundation, Crafoord Foundation, Lund University Medical Faculty research time allocation award, IngaBritt and Arne Lundberg Research Foundation, the German Research Foundation (552440240), the German Cancer Consortium (DKTK) and the German Federal Ministry of Education and Research (BMBF; grant no. 01KD2206A/SATURN3). We also acknowledge funding support from the Children’s Discovery Institute of the St. Louis Children’s Hospital. Confocal laser scanning microscopy was performed at the Advanced Light Microscopy/Spectroscopy Laboratory (RRID: SCR_022789) and the Leica Microsystems Center of Excellence at the California NanoSystems Institute at UCLA with funding support from NIH Shared Instrumentation Grant S10OD025017. Flow cytometry was performed in the UCLA Jonsson Comprehensive Cancer Center (JCCC) and Center for AIDS Research Flow Cytometry Core Facility that is supported by National Institutes of Health awards P30 CA016042 and 5P30 AI028697, and by the JCCC, the UCLA AIDS Institute, the David Geffen School of Medicine at UCLA, the UCLA Chancellor’s Office, and the UCLA Vice Chancellor’s Office of Research.
