Severin, India C. and Souza, Adriano L. S. and Davis, Jonathan H. and Musolino, Najia and Mack, Matthias and Power, Christine A. and Proudfoot, Amanda E. I. (2012) Properties of 7NDCCL2 are modulated upon fusion to Fc. PROTEIN ENGINEERING DESIGN & SELECTION, 25 (5). pp. 213-222. ISSN 1741-0126,
Full text not available from this repository. (Request a copy)Abstract
7ND, a truncated version of the chemokine MCP-1/CCL2 lacking amino acids 28, is a potent antagonist of CCR2. In contrast to CCL2, 7ND is an obligate monomer. Similar to other chemokines, the in vivo half-life of 7ND is very short and its use as an antagonist in disease models is thus limited. We therefore constructed a 7ND-Fc fusion protein to extend the half-life of 7ND and overcome its limitations as a potential therapeutic antagonist. When we tested the properties of the fusion molecule in vitro, we found to our surprise that 7ND-Fc, in contrast to 7ND, produced a distinct, albeit small, chemotactic response in THP-1 cells, and a robust chemotactic response in L1.2 cells stably transfected with CCR2. To test whether this unexpected observation might be due to the bivalency of 7ND-Fc stemming from the dimeric nature of Fc fusions, we produced a heterodimeric Fc fusion which displays only one 7ND moiety, using a technology called strand exchange of engineered CH3 domains (SEED). The monovalent construct had properties equivalent to the parent 7ND. Furthermore, partial agonist activity appears to depend on receptor density as well as the signaling pathway examined. However, we were able to show that 7ND-Fc, but not 7ND alone, has antagonistic activity in experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | MONOCYTE CHEMOATTRACTANT PROTEIN-1; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; MACROPHAGE INFLAMMATORY PROTEIN-1-ALPHA; MULTIPLE-SCLEROSIS LESIONS; CHEMOKINE RECEPTORS; CC-CHEMOKINE; NERVOUS-SYSTEM; IN-VIVO; EXPRESSION; MCP-1; anti-inflammatory; chemokine receptor antagonist; Fc fusion protein |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 15 May 2020 06:06 |
| Last Modified: | 15 May 2020 06:06 |
| URI: | https://pred.uni-regensburg.de/id/eprint/18823 |
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