This study developed a targeted LRRC15 radio-immunotherapy platform, DUNP19, which combines radioactive isotopes to enable non-invasive imaging and efficient therapy. It effectively suppresses progression of multiple solid tumors and enhances the efficacy of immune checkpoint inhibitors, demonstrating significant clinical translational potential.
Literature Overview
This article titled 'Development of a leucine-rich repeat-containing protein 15-targeted radio-immunotheranostic approach to deplete pro-tumorigenic mechanisms and immunotherapy resistance', published in Signal Transduction and Targeted Therapy, reviews LRRC15 as a cancer therapeutic target and evaluates the DUNP19 antibody's applications in tumor targeting, imaging, and therapy. Leveraging LRRC15's high expression in TGFβ-driven tumor-associated fibroblasts and cancer cells with minimal presence in healthy tissues, the study developed a high-affinity, internalizing antibody conjugated with radioactive isotopes for non-invasive tumor imaging and radio-immunotherapy. Treatment efficacy was evaluated across multiple xenograft and syngeneic tumor models, with transcriptomic analysis revealing its clearance of TGFβ-driven drug resistance signaling pathways, providing theoretical foundations for subsequent combination with immune checkpoint blockade therapies.
Background Knowledge
LRRC15 (Leucine-Rich Repeat-Containing Protein 15) is a transmembrane protein induced by TGFβ, predominantly expressed in mesenchymal stem cell-derived cancer cells and cancer-associated fibroblasts (CAFs), but minimally in normal tissues, making it an ideal cancer target. Currently, immune checkpoint inhibitors (ICIs) demonstrate limited efficacy against solid tumors, particularly those with immune-excluded microenvironments. LRRC15+ CAFs are associated with immune exclusion, treatment resistance, and disease aggressiveness. Therefore, targeting LRRC15 may reshape the tumor microenvironment, enhance immune cell infiltration, and improve ICI efficacy. DUNP19, a fully human IgG1 monoclonal antibody with high affinity and rapid internalization properties, serves as an optimal radio-immunotherapy (RIT) vehicle. Conjugated with Lutetium-177, it effectively targets and eliminates LRRC15+ tumor and stromal cells while inducing DNA damage through cross-fire effects to kill surrounding antigen-negative cells. Additionally, the study demonstrates that RIT significantly reduces TGFβ-driven resistance signaling in tumor transcriptomes and achieves durable complete remission when combined with ICIs, offering novel solutions for cancer immunotherapy resistance.
Research Methods and Experiments
Researchers developed a high-affinity, internalizing anti-LRRC15 monoclonal antibody, DUNP19, labeled with 64Cu or 177Lu for positron emission tomography (PET) imaging and radio-immunotherapy (RIT), respectively. DUNP19's targeting specificity, biodistribution, therapeutic efficacy, and impact on tumor microenvironment were evaluated in multiple murine xenograft models. Transcriptomic analysis investigated gene expression changes post-RIT, focusing on TGFβ signaling, immune exclusion, and immune checkpoint blockade resistance. Synergistic effects of DUNP19-RIT with anti-CTLA4 and anti-PD1 antibodies were further assessed in syngeneic tumor models.
Key Conclusions and Perspectives
Research Significance and Prospects
This study establishes a novel LRRC15-targeted cancer therapeutics platform integrating diagnostic and therapeutic dual functions, enabling personalized tumor treatment and dose planning. The approach specifically addresses immune-excluded and drug-resistant tumors, warranting further exploration of its clinical translational potential across diverse solid tumors and synergistic effects with various immunotherapy strategies.
Conclusion
This study successfully developed and validated a novel radio-immunotherapy platform, DUNP19, targeting LRRC15+ tumor and stromal cells. Conjugation with 177Lu enables effective tumor suppression while reshaping the tumor microenvironment by reducing TGFβ signaling and immune exclusion gene expression, thereby enhancing immune checkpoint inhibitor efficacy. The platform demonstrates favorable biodistribution and therapeutic outcomes with manageable toxicity across tumor models. Future applications may expand to preclinical studies in broader cancer types, providing innovative strategies for drug-resistant tumor management.
