(P 331) EFFICACY OF NOVEL UROKINASE PLASMINOGEN ACTIVATOR RECEPTOR-ASSOCIATED PROTEIN TARGETED ANTIBODY-DRUG CONJUGATES IN PATIENT-DERIVED XENOGRAFTS OF SOFT TISSUE SARCOMA

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), which is a collagen receptor highly expressed on tumor cells, (2) a linker, (3) and deruxtecan, a topoisomerase I inhibitor as payload. The efficacy of ADCE-017 and ADCE-202 was assessed in four in vivo experiments with three different patient-derived xenograft (PDX) models.

Methods: A total of 164 NMRI nu/nu mice were transplanted with PDX models of dedifferentiated liposarcoma (models UZLX-STS5, UZLX-STS200) or myxofibrosarcoma (UZLX-STS45). Mice were randomized for the following treatments: (1) vehicle control, (2) doxorubicin (5 mg/kg), (3) targeted antibody (“naked” antibody without payload, 3 or 10 mg/kg), (4) ADC-control (deruxtecan linked to a non-specific antibody, 3 or 10 mg/kg), (5) uPARAP-targeted ADC (3, 10 or 20 mg/kg). Treatments were given intravenously as tail vein injection on days 1, 8 and 15. Tumor volume, bodyweight and general well-being of the animals were monitored until day 100 or until reaching the humane endpoint. At the end of the experiment mice were sacrificed, and tumors were collected for hematoxylin & eosin staining and immunohistochemistry to assess proliferation and apoptotic activity. 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 volume shrinkage in two experiments with UZLX-STS200, compared to vehicle control, doxorubicin and ADC-control. Similar results were also obtained with UZLX-STS45, however, in this experiment the ADC-control showed superior tumor volume shrinkage compared to the ADCE-017. In UZLX-STS5, significant tumor growth delay was observed with ADCE-017 as compared to the vehicle control and ADC-control with effects being similar to doxorubicin. Based on bodyweight assessments and necropsy of the mice, no severe toxicity was observed with any of the experimental treatments. Mode of action studies on proliferation and apoptosis yielded mixed results, likely due to late sample collection and differences in the time points of tissue collection.

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 sarcomas and evaluation of the ADCs as a potential new treatment option for soft tissue sarcoma.