Targeting uPARAP with an antibody-drug conjugate exhibits efficacy against mesothelioma and synergizes with cisplatin

Abstract uPARAP is a collagen-internalizing receptor with emerging relevance as a therapeutic target. The involvement of uPARAP in extracellular matrix turnover and stromal remodeling within the tumor microenvironment (TME) makes it an especially promising target in tumors with a high stromal component. Mesothelioma, characterized by its unique complex TME, is a highly refractory cancer type for which no effective targeted therapy exists. uPARAP has been shown to be expressed across all subtypes of mesothelioma, especially in the sarcomatoid and biphasic subtypes, suggesting that a uPARAP-targeted therapy may benefit a specific patient population. Here, we utilized an antibody-drug conjugate (ADC) comprising an anti-uPARAP monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a protease-sensitive linker for preclinical studies on mesothelioma treatment. Employing mouse xenograft models with a human mesothelioma cell line or a patient-derived mesothelioma cell isolate, we demonstrated a strong anti-cancer effect following treatment with the uPARAP-targeting ADC. Immunohistochemical studies revealed this to be the case, even in tumors exhibiting a heterogeneous expression of uPARAP, suggesting that uPARAP-expressing cancer-associated fibroblasts also play a role in the anti-cancer effect through a bystander mechanism. Furthermore, we show that combination-treatment with cisplatin, commonly used in first-line mesothelioma therapy, leads to a strongly enhanced anti-cancer effect relative to treatment with either drug alone. Our study demonstrates the potential utility of a uPARAP-targeted ADC as a therapeutic option for mesothelioma, alone or in combination with chemotherapeutics. This perspective is particularly emphasized by a recently initiated clinical trial with a humanized anti-uPARAP-ADC for the treatment of other malignancies.