Re-engineering the Immune Response to Metastatic Cancer: Antibody-Recruiting Small Molecules Targeting the Urokinase Receptor

Developing selective strategies to treat metastatic cancers remains a significant challenge. Herein, we report the first antibody‐recruiting small molecule (ARM) that is capable of recognizing the urokinase‐type plasminogen activator receptor (uPAR), a uniquely overexpressed cancer cell‐surface marker, and facilitating the immune‐mediated destruction of cancer cells. A co‐crystal structure of the ARM‐U2/uPAR complex was obtained, representing the first crystal structure of uPAR complexed with a non‐peptide ligand. Finally, we demonstrated that ARM‐U2 substantially suppresses tumor growth in vivo with no evidence of weight loss, unlike the standard‐of‐care agent doxorubicin. This work underscores the promise of antibody‐recruiting molecules as immunotherapeutics for treating cancer. Ein immuntherapeutischer Ansatz mit kleinen Molekülen basiert auf der selektiven Markierung von Krebszellen zur Erkennung durch Immunzellen und gezielten Zerstörung. Diese Herangehensweise ist äußerst vielversprechend für die Behandlung von hoch aggressivem metastatischem Krebs, möglicherweise sogar mit nur geringen Nebenwirkungen.