揭示跨癌种双靶向uPAR定向ADC的泛癌潜力

Antibody-drug conjugates (ADCs) are revolutionizing cancer therapy; yet, their impact in solid tumors remains limited, partly because most approved ADCs primarily target tumor-associated antigens on malignant cells. This tumor-centric approach is often insufficient in highly desmoplastic cancers such as pancreatic ductal adenocarcinoma (PDAC), where the dense, immunosuppressive stroma promotes tumor progression, restricts drug penetration, and contributes to therapeutic resistance. Targeting both malignant and stromal compartments is therefore a critical unmet need to enhance ADCs' efficacy in these refractory tumors. To address this gap, PanTarg is advancing a novel ADC that targets both the cancer and the surrounding stromal compartment. The ADC specifically targets the urokinase plasminogen activator receptor (uPAR), which is broadly overexpressed across tumor and stromal populations in aggressive cancers, particularly PDAC, while minimally expressed in normal tissues. This dual-targeting strategy aims to overcome stromal barriers and support a broader, potentially Pan-Cancer therapeutic approach. PanTarg's ADC leverages a proprietary uPAR antibody with optimal biophysical and ADC properties. In preclinical models of PDAC and other uPAR-positive tumors, PanTarg ADCs demonstrated potent anti-tumor activity across multiple payload classes. Mechanistic studies revealed stromal targeting, bystander killing of uPAR-negative cancer cells, and immune-modulatory effects promoting a more permissive tumor microenvironment. Moreover, the ADCs showed favorable tolerability consistent with uPAR's restricted expression profile. Overall, these findings validate uPAR as a clinically relevant dual-compartment ADC target and position PanTarg as a promising next-generation therapeutic candidate for PDAC and, more broadly, aggressive uPAR-positive cancers.