EACR26-1623

Preclinical Evaluation of the FAP-Targeted Immunoconjugate OMTX705 Reveals Stromal-Mediated Bystander Activity in Sarcoma Patient-Derived Xenografts

P. Gilabert Prieto1,2, J. Fernández Juarez1, M. Perez3, M. Jordán Pérez1,2, M. Fabre4, Á. González4, L. Simon4, C. Castilla5, E. De Álava Casado6,2
1Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocío University Hospital/CSIC/University of Sevilla, Sevilla, Spain
2CIBERONC, Madrid, Spain
3Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocío University Hospital/CSIC/University of Sevilla, Department of Normal and Pathological Cytology and Histology, Sevilla, Spain
4Oncomatryx, Bilbao, Spain
5Virgen del Rocío University Hospital, Node Biobank, Virgen del Rocío University Hospital – Institute of Biomedicine of Seville, Sevilla, Spain
6Virgen del Rocío University Hospital, Department of Normal and Pathological Cytology and Histology, Sevilla, Spain
Introduction:

Fibroblast Activation Protein (FAP) is a protease highly expressed in Cancer-Associated Fibroblasts (CAFs)—a key component of the tumor microenvironment (TME)—and in certain sarcoma subtypes. OMTX705 is a novel immunoconjugate designed to selectively deliver a cytotoxic payload to FAP+ cells, facilitating targeted tumor cell elimination. Here, we evaluate the antitumor activity of OMTX705 across a panel of sarcoma Patient-Derived Xenografts (PDXs) and dissect the relative contribution of tumor cell versus stromal targeting.

Material and method:

FAP expression was quantified by H-score in a Tissue Microarray (TMA) panel covering multiple sarcoma histologies. Based on expression profiles, PDX models were stratified into FAP-High and FAP-Low/Negative phenotypes. Immunodeficient mice bearing these established PDX tumors received intravenous OMTX705 (once weekly for 4 weeks). Tumor volume was monitored by caliper measurements, and ex vivo histological analyses (IHC for FAP and apoptosis markers) to correlate stromal architecture with therapeutic response.

Result and discussion:

FAP expression was heterogeneous across sarcoma histologies. In preclinical studies, OMTX705 induced tumor regression in FAP-High sarcoma models, including Leiomyosarcoma (LMS), Undifferentiated Pleomorphic Sarcoma (UPS) and Rhabdomyosarcoma (RMS). Notably, RMS models with FAP (-) tumor cells also exhibited comparable regression. Histological analysis linked this response to the presence of FAP-positive stromal septa and perivascular cells. This dissociation between tumor cell FAP expression and therapeutic response supports a stromalmediated bystander effect, whereby the lipophilic payload released from FAP-positive stromal compartments diffuses to eliminate adjacent RMS tumor cells. This stromal-mediated efficacy was consistent across different RMS PDXs. OMTX705 was well tolerated, with no evidence of liver toxicity in any treated cohort.

Conclusion:

Our findings demonstrate that OMTX705 exerts robust antitumor activity in sarcoma PDX models through both direct tumor cell targeting and stromal-mediated bystander mechanisms. Importantly, therapeutic efficacy in RMS with FAP (-) tumor cells highlights the relevance of stromal FAP expression as a predictive biomarker. These results support a patient selection strategy integrating both tumoral and stromal FAP assessment and provide a strong rationale for clinical development of OMTX705 in sarcoma.

Acknowledgement:

This study, CPP2022-009791, was supported by Spanish Ministerio de Ciencia, Innovación y Universidades and funded by the European Union (NextGenerationEU). We thank the patients and Node Biobank, Virgen del Rocío University Hospital for providing the biological samples used in this study.