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

Reprogramming urokinase into an antibody-recruiting anticancer agent.

Author information

1
Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States.

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.

PMID:
22098560
PMCID:
PMC3288771
DOI:
10.1021/cb200374e
[Indexed for MEDLINE]
Free PMC Article

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