Targeting uPAR with an antibody-drug conjugate suppresses tumor growth and reshapes the immune landscape in pancreatic cancer models

• DOI: 10.1126/sciadv.adq0513
• Publication Date: 2025-01-17T18:58:55Z
• Authors: Virginia Metrangolo; Michaela Hansen B...; Ananya Dutta; Henrik Gårdsvoll; Oliver Krigslund; Kirstine Sandal N...; Henrik Jessen Jür...; Michael Ploug; Matthew J. Flick; Niels Behrendt; Lars H. Engelholm
• Keywords: Tumor; Animal; Carcinoma; Carcinoma, Pancreatic Ductal/drug therapy; Xenograft Model Antitumor Assays; Antibodies; Antibodies, Monoclonal/pharmacology; Tumor Microenvironment/drug effects; Cell Line; Monoclonal/pharmacology; Cell Proliferation/drug effects; Mice; Disease Models, Animal; Urokinase Plasminogen Activator/metabolism; Pancreatic Ductal/drug therapy; Immunoconjugates/pharmacology; Pancreatic Neoplasms/drug therapy; Cell Line, Tumor; Receptors; Disease Models; Humans; Animals; Biomedicine and Life Sciences; Receptors, Urokinase Plasminogen Activator/metabolism

Antibody-drug conjugates (ADCs) hold promise to advance targeted therapy of pancreatic ductal adenocarcinoma (PDAC), where the desmoplastic tumor stroma challenges effective treatment. Here, we explored the urokinase plasminogen activator receptor (uPAR) as a candidate ADC target in PDAC, harnessing its massive tumoral and stromal expression in this stroma-dense tumor. We generated a site-specific ADC offering high-affinity, cross-species reactivity, and efficient internalization of the anti-uPAR monoclonal antibody, FL1, carrying a potent anthracycline derivative (PNU-158692). In vitro, FL1-PNU exhibited potent and specific cytotoxicity against uPAR-expressing PDAC cell lines, stromal and immune cells, and bystander killing of uPAR-negative cells. In vivo, the ADC induced remission or sustained tumor regression and extended survival in xenograft models. In syngeneic orthotopic models, the antitumor effect promoted immunomodulation by enhancing infiltrating immune effectors and decreasing immunosuppressive cells. This study lays grounds for further exploring FL1-PNU as a putative clinical ADC candidate, potentially providing a promising therapeutic avenue for PDAC as a monotherapy or in combinatorial regimens.