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

Storey, C. M.; Altai, M.; Lueckerath, K. M.; Zedan, W.; Zhu, H.; Trajkovic-Arsic, M.; Park, J. E.; Peekhaus, N.; Siveke, J.; Lilljebjorn, H.; Abou, D.; Marks, H. L.; Ulmert, E.; Lilja, H.; Ridley, A.; Safi, M.; Yuen, C.; Geres, S.; Mao, L.; Cheng, M.; Czernin, J.; Herrmann, K.; Bentolila, L.; Yang, X.; Fioretos, T.; Graeber, T.; Sjostrom, K.; Damoiseaux, R.; Thorek, D. L.; Ulmert, D.

doi:10.1101/2024.01.30.577289

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bioRxiv · 10.1101/2024.01.30.577289

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

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Abstract

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 (TGF{beta})-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. SIGNIFICANCEWe 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 TGF{beta}-driven treatment resistance. This approach offers a promising strategy for improving outcomes in aggressive cancers.

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Storey, C. M., Altai, M., Lueckerath, K. M., Zedan, W., Zhu, H., Trajkovic-Arsic, M., Park, J. E., Peekhaus, N., Siveke, J., Lilljebjorn, H., Abou, D., Marks, H. L., Ulmert, E., Lilja, H., Ridley, A., Safi, M., Yuen, C., Geres, S., Mao, L., Cheng, M., Czernin, J., Herrmann, K., Bentolila, L., Yang, X., Fioretos, T., Graeber, T., Sjostrom, K., Damoiseaux, R., Thorek, D. L., Ulmert, D.. 2024-02-02. Development of a LRRC15-Targeted Radio-Immunotheranostic Approach to Deplete Pro-tumorigenic Mechanisms and Immunotherapy Resistance. https://doi.org/10.1101/2024.01.30.577289

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