Reprogramming urokinase into an antibody-recruiting anticancer agent

ACS Chem Biol. 2012 Feb 17;7(2):316-21. doi: 10.1021/cb200374e. Epub 2011 Nov 18.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies / chemistry*
  • Antibodies / immunology
  • Antibodies / therapeutic use*
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / immunology
  • Antineoplastic Agents / therapeutic use*
  • Catalytic Domain
  • Cell Line, Tumor
  • Humans
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Neoplasms / immunology
  • Phagocytosis / drug effects
  • Receptors, Urokinase Plasminogen Activator / immunology*
  • Urokinase-Type Plasminogen Activator / chemistry*
  • Urokinase-Type Plasminogen Activator / immunology
  • Urokinase-Type Plasminogen Activator / therapeutic use*

Substances

  • Antibodies
  • Antineoplastic Agents
  • Receptors, Urokinase Plasminogen Activator
  • Urokinase-Type Plasminogen Activator