An Fc Domain Protein鈥揝mall Molecule Conjugate as an Enhanced Immunomodulator

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• 作者：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
• 刊名：Journal of the American Chemical Society
• 出版年：2014
• 出版时间：March 5, 2014
• 年：2014
• 卷：136
• 期：9
• 页码：3370-3373
• 全文大小：304K
• 年卷期：v.136,no.9(March 5, 2014)
• ISSN：1520-5126

文摘

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 A_2AR 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 A_2AR 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 A_2AR 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.