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A Novel Recombinant Fusion Protein Encoding a 20-Amino Acid Residue of the Third Extracellular (E3) Domain of CCR2 Neutralizes the Biological Activity of CCL2¹

Liat Izhak^*, Gizi Wildbaum^*, Yaniv Zohar^*, Rachel Anunu^*, Leah Klapper, Adi Elkeles, Jane Seagal^*, Eitan Yefenof, Michal Ayalon-Soffer and Nathan Karin^2,*

^* Department of Immunology, Rappaport Family Institute for Research in the Medical Sciences, Haifa, BioLine Innovations Jerusalem, Jerusalem, and Lautenberg Center for General and Tumor Immunology, The Hebrew University Hadassah Medical Center, Jerusalem, Israel

CCL2 is a key CC chemokine that has been implicated in a variety of inflammatory autoimmune diseases and in tumor progression and it is therefore an important target for therapeutic intervention in these diseases. Soluble receptor-based therapy is a known approach for neutralizing the in vivo functions of soluble mediators. Owing to the complexity of seven-transmembrane G protein-coupled receptors, efforts to generate neutralizing soluble chemokine receptors have so far failed. We developed a strategy that is based on the generation of short recombinant proteins encoding different segments of a G protein-coupled receptor, and tested the ability of each of them to bind and neutralize its target chemokine. We show that a fusion protein comprised of as few as 20 aa of the third extracellular (E3) domain of the CCL2 receptor, stabilized by the IgG H chain Fc domain (E3-IgG or BL-2030), selectively binds CCL2 and CCL16 and effectively neutralizes their biological activities. More importantly, E3-IgG (BL-2030) could effectively suppress the in vivo biological activity of CCL2, attenuating ongoing experimental autoimmune encephalomyelitis, as well as the development of human prostate tumor in SCID mice.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by grants from the Israel Science Foundation, the Israel Ministry of Health Chief Scientist, and a sponsored research grant from the Israel Ministry of Industry, together with BiolineRx.

² Address correspondence and reprint requests to Dr. Nathan Karin, Bruce Rappaport Faculty of Medicine, Technion, Rappaport Family Institute for Research in the Medical Sciences, PO Box 9697, Haifa 31096, Israel. E-mail address: nkarin{at}tx.technion.ac.il

³ Abbreviations used in this paper: MS, multiple sclerosis; EAE, experimental autoimmune encephalomyelitis.