This study developed a radioimmunotherapy platform targeting LRRC15, DUNP19, which utilizes radioactive isotopes for non-invasive imaging and efficient therapy. It effectively suppresses multiple solid tumor progressions and enhances immune checkpoint inhibitor efficacy, demonstrating broad clinical translation potential.
Literature Overview
This article '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's potential as a cancer therapeutic target and DUNP19 antibody 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 to radioactive isotopes for non-invasive tumor imaging and radioimmunotherapy. It evaluated therapeutic effects across multiple xenograft and syngeneic tumor models and demonstrated transcriptomic clearance of TGFβ-driven drug resistance pathways through cross-fire effects, providing theoretical basis for subsequent combination therapies with immune checkpoint inhibitors.
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. Current immune checkpoint inhibitors (ICIs) show limited efficacy in solid tumors with immune-excluded microenvironments, where LRRC15+ CAFs correlate with immune exclusion, treatment resistance, and disease aggressiveness. Targeting LRRC15 may therefore reshape tumor microenvironments, 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 radioimmunotherapy (RIT) vehicle. When 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, RIT treatment significantly reduces TGFβ-driven drug resistance signals in tumor transcriptomes and achieves durable complete remission when combined with ICIs, offering a novel solution to immunotherapy resistance.
Research Methods and Experiments
Researchers developed a high-affinity, internalizing anti-LRRC15 monoclonal antibody DUNP19 conjugated with 64Cu or 177Lu for positron emission tomography (PET) imaging and radioimmunotherapy (RIT), respectively. They evaluated DUNP19's targeting specificity, biodistribution, therapeutic efficacy, and impact on tumor microenvironments across multiple xenograft and syngeneic tumor models. Transcriptomic analysis examined gene expression changes post-RIT treatment, focusing on TGFβ signaling, immune exclusion, and immune checkpoint blockade resistance pathways. Synergistic effects between DUNP19-RIT and anti-CTLA4/anti-PD1 antibodies were also assessed in syngeneic tumor models.
Key Conclusions and Perspectives
Research Significance and Prospects
This study establishes a novel radioimmunotherapy platform targeting LRRC15 with integrated diagnostic and therapeutic functions, enabling personalized tumor treatment and dose optimization. The approach particularly benefits tumors with immune-excluded microenvironments and drug resistance. Future research should explore its clinical translation potential across multiple solid tumors and synergistic effects with diverse immunotherapy strategies.
Conclusion
This study successfully developed and validated a novel radioimmunotherapy platform, DUNP19, targeting LRRC15+ tumor and stromal cells. Conjugated with 177Lu, the antibody not only effectively inhibits tumor growth but also remodels the tumor microenvironment by suppressing TGFβ signaling and immune exclusion gene expression, thereby enhancing immune checkpoint inhibitor efficacy. The platform demonstrated favorable biodistribution and therapeutic outcomes across multiple tumor models with manageable toxicity. Future applications may extend to preclinical studies for various cancer types and provide innovative strategies for overcoming drug-resistant tumors.
