Development of a RadioImmunoTheranostic Agent Targeting LRRC15 - a TGFβ-driven Biomarker Specific to Mesenchymal Stem Cell Derived Cancer Cells and Tumor Stroma

The tumor stroma has a critical impact on disease progression, metastasis and treatment outcomes.

Leucine-rich repeat containing 15 (LRRC15) is highly expressed on cancer associated fibroblasts (CAFs) within the tumor stroma of a wide range of malignancies, as well as directly on cancer cells from a subset of mesenchymal tumors (e.g., sarcomas, GBM).

Compared to other mesenchymal associated markers, LRRC15 has a significantly lower baseline expression and a higher differential RNA expression between cancer and adjacent normal tissues, making LRRC15 an ideal target. Also, LRRC15 has been shown to promote metastatic spread in multiple cancers.

Importantly, analysis of tissues obtained from clinical trials show that LRRC15+ CAFs is associated with resistance to immune checkpoint blockade.

Based on the target avidity and cancer specificity, we hypothesize that LRRC15 targeted radiotheranostic compounds can provide substantive improvements for several currently untreatable malignancies.

To further explore this possibility we devised DUNP19, a humanized monoclonal antibody that is rapidly taken up and accumulates within LRCC15 expressing cells.

We set out to generate PET radiotracers based on DUNP19 to address the hypothesis that annotating LRRC15 expression clearly define aggressive and therapy resistant tumor phenotypes.

Further, we will utilize DUNP19 for intracellular high and low LET irradiation to effectively eradicate LRRC15+ tumor cells and/or stromal cells.