Development of a LRRC15-Targeted Radio-Immunotheranostic Approach to Deplete Pro-tumorigenic Mechanisms and Immunotherapy Resistance

Leucine-rich repeat containing 15 (LRRC15) has emerged as an attractive biomarker and target for cancer therapy. We have developed a humanized monoclonal antibody (mAb), DUNP19, that specifically binds to a phylogenetically conserved LRRC15 epitope and is internalized by target-expressing cancer and stromal cells. In xenograft mouse models, Lutetium-177 labeled DUNP19 ([177Lu]-DUNP19) enables non-invasive imaging and precise radiotherapy to LRRC15-expressing cancer cells and murine cancer-associated fibroblasts (CAFs), halting tumor progression and prolonging survival with minimal toxicity. Transcriptomic analyses of [177Lu]-DUNP19-treated tumors reveal a loss of pro-tumorigenic mechanisms, including a transforming growth factor beta (TGFβ)-driven and LRRC15+ signature associated with immunotherapy resistance. 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 aggressive disease. SIGNIFICANCE We introduce a pioneering LRRC15-guided radio-theranostic approach integrating clinical imaging and radioimmunotherapy. Our strategy utilizes a mAb, DUNP19, to target LRRC15-expressing cancer cells and fibroblasts, demonstrating significant tumor reduction, prolonged survival, and reversal of TGFβ-driven treatment resistance. This approach offers a promising strategy for improving outcomes in aggressive cancers. ### Competing Interest Statement DU, RD, LM, NP and CMS are inventors on a patent application submitted by UCLA that covers radiotheranostic applications of DUNP19. KH and DU serve as board members on Radiopharm Theranostics Scientific Advisory board, which has licensed DUNP19 for radiotheranostic use. DU reports grants from Radiopharm Theranostics, and grants from Janssen Pharmaceuticals outside the submitted work; in addition, DU has a patent for EP2771688A4 issued and a patent for EP3297669A1 issued; and DU reports grants from Prostate Cancer Foundation and Department of Defense during the conduct of the study. Consultant to Diaprost AB and has stock in Diaprost AB; and received a speakers honorarium from Janssen R&D LLC. KL reports personal fees from Sofie Biosciences outside the submitted work. RD reports personal fees from Amgen, Panorama Medicine, and Epirium Bio outside the submitted work. DT reports non-financial support and other support from Diaprost during the conduct of the study; in addition, DT has a patent for WO2020180756A1 issued and has several research project awards from the NIH, and a research project funded by Janssen Pharmaceuticals. HL is named on patents for assays to measure intact PSA and on a statistical method to detect prostate cancer licensed to Arctic Partners, sublicensed to and commercialized by OPKO Health at the 4Kscore test. HL receives royalties for sales of this test and has shares in Arctic Partners and OPKO. HL is also named on a patent on free PSA antibodies as in vivo diagnostics and therapeutics for prostate cancer licensed to Diaprost AB and have rights to receive licensing income from this relationship. HL has shares Diaprost AB, Acousort AB, and is on SAB with Fujirebio Diagnostics Inc. No disclosures were reported by the other authors.