An Fc domain protein-small molecule conjugate as an enhanced immunomodulator

Meng Jung Chiang, Marc A. Holbert, Jay H. Kalin, Young Hoon Ahn, John Giddens, Mohammed N. Amin, Martin S. Taylor, Samuel L. Collins, Yee Chan-Li, Adam Waickman, Po Yuan Hsiao, David Bolduc, Daniel J. Leahy, Maureen R. Horton, Lai Xi Wang, Jonathan D. Powell, Philip A. Cole

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Proteins as well as small molecules have demonstrated success as therapeutic agents, but their pharmacologic properties sometimes fall short against particular drug targets. Although the adenosine 2a receptor (A 2AR) has been identified as a promising target for immunotherapy, small molecule A2AR agonists have suffered from short pharmacokinetic half-lives and the potential for toxicity by modulating nonimmune pathways. To overcome these limitations, we have tethered the A2AR agonist CGS-21680 to the immunoglobulin Fc domain using expressed protein ligation with Sf9 cell secreted protein. The protein small molecule conjugate Fc-CGS retained potent Fc receptor and A2AR interactions and showed superior properties as a therapeutic for the treatment of a mouse model of autoimmune pneumonitis. This approach may provide a general strategy for optimizing small molecule therapeutics.

Original languageEnglish (US)
Pages (from-to)3370-3373
Number of pages4
JournalJournal of the American Chemical Society
Volume136
Issue number9
DOIs
StatePublished - Mar 5 2014

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry
  • Biochemistry
  • Colloid and Surface Chemistry

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