Development of a leucine-rich repeat-containing protein 15-targeted radio-immunotheranostic approach to deplete pro-tumorigenic mechanisms and immunotherapy resistance
(2025) In Signal Transduction and Targeted Therapy 10(1).- Abstract
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... (More)
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.
(Less)
- author
- organization
- publishing date
- 2025-12
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Signal Transduction and Targeted Therapy
- volume
- 10
- issue
- 1
- article number
- 319
- publisher
- Springer Nature
- external identifiers
-
- scopus:105017544008
- pmid:41022704
- ISSN
- 2095-9907
- DOI
- 10.1038/s41392-025-02410-9
- language
- English
- LU publication?
- yes
- id
- 121c7296-e9c5-42eb-aff7-8eb3010d9213
- date added to LUP
- 2025-11-21 14:45:10
- date last changed
- 2025-11-22 03:00:04
@article{121c7296-e9c5-42eb-aff7-8eb3010d9213,
abstract = {{<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>}},
author = {{Storey, Claire M. and Altai, Mohamed and Lückerath, Katharina and Zedan, Wahed and Zhu, Henan and Breuer, Lara and Trajkovic-Arsic, Marija and Park, Julie and Hasson, Abbie and Siveke, Jens and Abou, Diane and Marks, Haley and Ulmert, Enna and Ridley, Alexander and Safi, Marcella and Lamminmäki, Urpo and Yuen, Constance and Geres, Susanne and Mao, Liqun and Cheng, Michael and Subudhi, Sumit K. and Siddiqui, Bilal A. and Federman, Noah and Czernin, Johannes and Herrmann, Ken and Bentolila, Laurent and Yang, Xia and Graeber, Thomas G. and Damoiseaux, Robert and Thorek, Daniel and Ulmert, David}},
issn = {{2095-9907}},
language = {{eng}},
number = {{1}},
publisher = {{Springer Nature}},
series = {{Signal Transduction and Targeted Therapy}},
title = {{Development of a leucine-rich repeat-containing protein 15-targeted radio-immunotheranostic approach to deplete pro-tumorigenic mechanisms and immunotherapy resistance}},
url = {{http://dx.doi.org/10.1038/s41392-025-02410-9}},
doi = {{10.1038/s41392-025-02410-9}},
volume = {{10}},
year = {{2025}},
}