Abstract 5597: Efficacy of novel urokinase plasminogen activator receptor-associated protein targeted antibody-drug conjugates in patient-derived xenografts of soft tissue sarcoma

Abstract Objective: Soft tissue sarcoma is a heterogeneous group of rare malignant tumors with a high unmet medical need. We evaluated the efficacy of two novel antibody-drug conjugates (ADC), ADCE-017 and ADCE-202, each consisting of three components: (1) an antibody targeting urokinase plasminogen activator receptor-associated protein (uPARAP), a collagen receptor highly expressed on mesenchymal tumor cells, (2) a linker, (3) and deruxtecan, a topoisomerase I inhibitor payload. The efficacy of ADCE-017 and ADCE-202 was assessed in 4 in vivo experiments using three different patient-derived xenograft (PDX) models with high uPARAP expression. Methods: A total of 164 NMRI nu/nu mice were transplanted with PDX models of dedifferentiated liposarcoma (models UZLX-STS5, -STS200) or myxofibrosarcoma (-STS45). Mice were randomized for the following treatments: (1) vehicle control, (2) doxorubicin, (3) targeted antibody (“naked” antibody without payload), (4) ADC-isotype control (deruxtecan linked to a non-specific antibody), (5) uPARAP-targeted ADC. Treatments were given as tail vein injection on days 1, 8 and 15. Tumor volume, bodyweight and general well-being of animals were monitored until day 100 or until reaching the humane endpoint. Statistical analysis was performed with Wilcoxon test and Mann-Whitney U-test, with p< 0.05 defined as statistically significant. Results: Treatment with ADCE-017 and ADCE-202 resulted in significant tumor growth delay in two experiments with STS200, compared to vehicle control and doxorubicin, and tumor volume shrinkage compared to baseline (day 1). Similar results were obtained with STS45, however, in this experiment the ADC-isotype control showed superior tumor volume shrinkage compared to ADCE-017. In STS5, tumor growth delay was observed with ADCE-017 as compared to the vehicle control and ADC-isotype control, with effects being similar to doxorubicin. Based on bodyweight assessment and necropsy of the mice, no severe toxicity was observed. Conclusion: In general, the novel uPARAP-targeted ADCs ADCE-017 and ADCE-202 showed superior anti-tumor effect in all three soft tissue sarcoma models as compared to vehicle control without any treatment-related side effects. These results warrant further preclinical studies in other types of sarcoma and a clinical evaluation of the ADCs as a potential new treatment option for soft tissue sarcoma. Citation Format: Chao-Chi Wang, Agnieszka Wozniak, Luna De Sutter, Lore De Cock, Karo Wyns, Ulla Vanleeuw, Sander Van Putten, Carmel Lynch, Patrick Schöffski. Efficacy of novel urokinase plasminogen activator receptor-associated protein targeted antibody-drug conjugates in patient-derived xenografts of soft tissue sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr XX.