title: Reprogramming urokinase into an antibody-recruiting anticancer agent.
abstract: Synthetic compounds for controlling or creating human immunity have the potential to revolutionize disease treatment. Motivated by challenges in this arena, we report herein a strategy to target metastatic cancer cells for immune-mediated destruction by targeting the urokinase-type plasminogen activator receptor (uPAR). Urokinase-type plasminogen activator (uPA) and uPAR are overexpressed on the surfaces of a wide range of invasive cancer cells and are believed to contribute substantially to the migratory propensities of these cells. The key component of our approach is an antibody-recruiting molecule that targets the urokinase receptor (ARM-U). This bifunctional construct is formed by selectively, covalently attaching an antibody-binding small molecule to the active site of the urokinase enzyme. We demonstrate that ARM-U is capable of directing antibodies to the surfaces of target cancer cells and mediating both antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) against multiple human cancer cell lines. We believe that the reported strategy has the potential to inform novel treatment options for a variety of deadly, invasive cancers.
authors.affiliation: Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Jakobsche
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: McEnaney
authors.forename: Andrew X
authors.initials: AX
authors.lastname: Zhang
authors.forename: David A
authors.initials: DA
authors.lastname: Spiegel
mesh_terms: D000906:Antibodies / Q000737:chemistry* / Q000276:immunology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000276:immunology / Q000627:therapeutic use*; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D010587:Phagocytosis / Q000187:drug effects; D055293:Receptors, Urokinase Plasminogen Activator / Q000276:immunology*; D014568:Urokinase-Type Plasminogen Activator / Q000737:chemistry* / Q000276:immunology / Q000627:therapeutic use*
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator
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