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 mark...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2016-03, Vol.55 (11), p.3642-3646
Main Authors: Rullo, Anthony F., Fitzgerald, Kelly J., Muthusamy, Viswanathan, Liu, Min, Yuan, Cai, Huang, Mingdong, Kim, Minsup, Cho, Art E., Spiegel, David A.
Format: Article
Language:English
Subjects:
Antibodies - immunology
antitumor agents
Cancer
cell recognition
Cell surface
Crystal structure
Crystallography, X-Ray
Destruction
Doxorubicin
drug design
Engineering
Humans
Immune response
Immune system
immunology
medicinal chemistry
Metastases
Metastasis
Neoplasm Metastasis - immunology
Neoplasms - pathology
Reengineering
Surface markers
U-Plasminogen activator
Urokinase
Urokinase-Type Plasminogen Activator - metabolism
Weight loss
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Summary: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. Marked for death: A small‐molecule immunotherapeutic strategy involves the selective tagging of cancer cells for immune‐cell recognition and targeted destruction. This approach holds tremendous promise in guiding the development of selective treatments against highly aggressive metastatic cancers with potentially few side effects.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201510866