{"doi":"10.1038/s41392-025-02410-9","title":"Development of a leucine-rich repeat-containing protein 15-targeted radio-immunotheranostic approach to deplete pro-tumorigenic mechanisms and immunotherapy resistance","abstract":"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 ([ 177 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 [ 177 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 [ 177 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.","journal":"Signal Transduction and Targeted Therapy","year":2025,"id":532967,"datarank":0.26876392038420827,"base_score":1.791759469228055,"endowment":1.791759469228055,"self_citation_contribution":0.26876392038420827,"citation_network_contribution":0.0,"self_endowment_contribution":0.26876392038420827,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9613,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":567776,"name":"Mohamed Altai","orcid":"0000-0002-7624-0313","position":1,"is_corresponding":false},{"id":568215,"name":"Katharina Lückerath","orcid":null,"position":2,"is_corresponding":false},{"id":1004470,"name":"Wahed Zedan","orcid":"0000-0002-0287-5367","position":3,"is_corresponding":false},{"id":250854,"name":"Henan Zhu","orcid":"0000-0003-1617-0146","position":4,"is_corresponding":false},{"id":1414481,"name":"Lars Breuer","orcid":"0000-0002-7797-9662","position":5,"is_corresponding":false},{"id":95426,"name":"Marija Trajkovic-Arsic","orcid":null,"position":6,"is_corresponding":false},{"id":1004469,"name":"Julie E. 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