Development of a uPAR-Targeting Antibody-Drug Conjugate (ADC) for Pancreatic Adenocarcinoma

Abstract public domain (NIH RePORTER)

Project Summary Traverse Biotech is developing TB-UA-1, a first-in-class antibody-drug conjugate (ADC) targeting urokinase plasminogen activator receptor (uPAR) for the treatment of pancreatic ductal adenocarcinoma (PDAC). PDAC remains one of the deadliest malignancies, characterized by a dismal 5-year survival rate of 9-10% due to late- stage diagnosis, limited therapeutic efficacy, and profound resistance to existing treatments such as FOLFIRINOX and gemcitabine/nab-paclitaxel. PDAC is a highly fibrotic and immune-excluding tumor microenvironment where immunotherapies, such as checkpoint inhibitors, are unable to impact immune cells within the tumor and therefore offer little to no clinical outcome benefits. TB-UA-1 targets uPAR, a cell surface receptor overexpressed on the surface of PDAC tumor cells and associated stromal components, including tumor-associated macrophages and cancer-associated fibroblasts. Importantly, uPAR expression is negligible in normal pancreatic tissue, thus minimizing on-target toxicity risks. This dual expression of uPAR on both PDAC tumor cells and stromal components, positions uPAR as an ideal antigen for targeted ADC therapy. We have selected well-validated human anti-uPAR antibodies (3C6 and 2G10) with proven specificity, high affinity, and efficient receptor-mediated internalization into uPAR-expressing cancer cells. These antibodies will be coupled with our proprietary bioconjugation technology (InSideÒ), that enables stable and controlled attachment of cytotoxic payloads. This results in optimized ADC stability, drug-to-antibody ratio homogeneity, and ultimately therapeutic efficacy. In this Phase I, we will first construct and evaluate novel anti-uPAR ADC constructs built from well-characterized anti-uPAR antibodies with known binding and anti-cancer properties and using Inside technologyÒ. Leading uPAR-ADC constructs will be evaluated and rank-ordered based on efficacy against uPAR-expressing PDAC cell lines. The best performing uPAR-ADC, TB-UA-1, will be evaluated for efficacy in an industry-standard preclinical mouse xenograft model of PDAC. This comprehensive approach will result in human anti-uPAR-ADC product candidate that will be advanced into a future Phase II application and non-clinical studies with the ultimate goal of clinical entrance to address the significant unmet medical need in PDAC.

Public health relevance public domain (NIH RePORTER)

Project Narrative Traverse Biotech is developing a first-in-class antibody-drug conjugate (ADC) targeting urokinase plasminogen activator receptor (uPAR), a tumor-associated antigen highly expressed in pancreatic ductal adenocarcinoma (PDAC), a fibrotic cancer known for its poor prognosis and high mortality. Leveraging innovative bioconjugation technology, we will first produce stable, homogeneous uPAR-targeting ADC constructs that deliver potent cytotoxic payloads selectively to tumor cells and their surrounding stromal microenvironment and validate their therapeutic potential using industry-standard in vivo preclinical models. Successful completion of this study will advance a promising new targeted therapeutic approach that addresses the significant unmet need in pancreatic cancer.