The urokinase plasminogen activator receptor-associated protein (uPARAP) is an attractive target for the development of antibody-drug conjugates (ADCs) for treatment of mesenchymal malignancies

Abstract Background: Soft tissue sarcoma (STS) is a complex family of rare malignancies with high unmet medical need. uPARAP is an endocytic receptor expressed at low levels on selected mesenchymal cell types, which internalizes fragments of collagen and transfers them to the lysosome for degradation. Besides its physiological role, uPARAP is considered a critical modulator of the tumor microenvironment. Here, for the first time, we explored the molecular epidemiology of uPARAP in sarcoma tissue to validate this receptor as target for the development of ADCs in this indication. Methods: uPARAP expression was assessed in STS-specific tissue microarrays by immunohistochemistry in tissue samples from more than three hundred individual donors. Stainings were assessed by histopathologic scoring and grouped into high, medium and low expressing subgroups. Results: uPARAP was found to be strongly over-expressed in a high percentage of cases of common STS, with variations in terms of incidence and level of expression between histological subtypes. High uPARAP expression was found in fibro- (86% of cases), synovial (84%), dedifferentiated lipo- (68%), pleomorphic lipo- (65%), myxofibro- (59%), leiomyo- (49%), and myxoid liposarcoma (24%). Work is ongoing in additional sarcoma subtypes. Conclusions: Based on protein expression uPARAP is an attractive emerging therapeutic target for the development of uPARAP-binding ADCs in a broad range of mesenchymal malignancies. In addition, expression of uPARAP in STS may serve as a potential marker for patient selection in early clinical studies with uPARAP-targeting ADCs. Citation Format: Pernille Barkholt, Agnieszka Wozniak, Chao-Chi Wang, Che-Jui Lee, Lore De Kock, Lars H. Engelholm, Carmel Lynch, Dominik Mumberg, Patrick Schöffski. The urokinase plasminogen activator receptor-associated protein (uPARAP) is an attractive target for the development of antibody-drug conjugates (ADCs) for treatment of mesenchymal malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1547.