Journal Article

DKFZ-2025-01993

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Development of a leucine-rich repeat-containing protein 15-targeted radio-immunotheranostic approach to deplete pro-tumorigenic mechanisms and immunotherapy resistance.

Storey, C. M. ; Altai, M. ; Lückerath, K.DKFZ* ; Zedan, W. ; Zhu, H. ; Breuer, L.DKFZ* ; Trajkovic-Arsic, M.DKFZ* ; Park, J. ; Hasson, A. ; Siveke, J.DKFZ* ; Abou, D. ; Marks, H. ; Ulmert, E. ; Ridley, A. ; Safi, M. ; Lamminmäki, U. ; Yuen, C. ; Geres, S. ; Mao, L. ; Cheng, M. ; Subudhi, S. K. ; Siddiqui, B. A. ; Federman, N. ; Czernin, J. ; Herrmann, K.DKFZ* ; Bentolila, L. ; Yang, X. ; Graeber, T. G. ; Damoiseaux, R. ; Thorek, D. ; Ulmert, D.

2025
Macmillan Publishers, part of Springer Nature London

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Please use a persistent id in citations: doi:10.1038/s41392-025-02410-9

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 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.

Keyword(s): Animals (MeSH) ; Mice (MeSH) ; Humans (MeSH) ; Immunotherapy (MeSH) ; Cell Line, Tumor (MeSH) ; Lutetium (MeSH) ; Xenograft Model Antitumor Assays (MeSH) ; Neoplasms: genetics (MeSH) ; Neoplasms: immunology (MeSH) ; Neoplasms: pathology (MeSH) ; Neoplasms: therapy (MeSH) ; Membrane Proteins: genetics (MeSH) ; Membrane Proteins: immunology (MeSH) ; Membrane Proteins: antagonists & inhibitors (MeSH) ; Antibodies, Monoclonal, Humanized: pharmacology (MeSH) ; Drug Resistance, Neoplasm: genetics (MeSH) ; Neoplasm Proteins: genetics (MeSH) ; Neoplasm Proteins: immunology (MeSH) ; Neoplasm Proteins: antagonists & inhibitors (MeSH) ; Transforming Growth Factor beta: genetics (MeSH) ; Transforming Growth Factor beta: immunology (MeSH) ; Radioisotopes (MeSH) ; Lutetium ; Membrane Proteins ; Antibodies, Monoclonal, Humanized ; Lutetium-177 ; Neoplasm Proteins ; Transforming Growth Factor beta ; Radioisotopes

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Essen/Düsseldorf (ED01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2025

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