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Papers In Press, published online ahead of print July 5, 2002
Atheroclerosis and Endocrinolgy, Merck Research Laboratories, Rahway, NJ 07065
Corresponding Author: bruce_daugherty{at}merck.com
Eosinophils are major effector cells implicated in a number of chronic inflammatory diseases in humans, particularly bronchial asthma and allergic rhinitis. The
J. Biol. Chem, 10.1074/jbc.M205488200
Submitted on June 3, 2002
Revised on July 3, 2002
Accepted on July 3, 2002
Functional expression and characterization of macaque CCR3, and generation of potent antagonistic anti-macaque CCR3 monoclonal antibodies
-chemokine receptor CCR3 provides a mechanism for the selective recruitment of eosinophils into tissue, and thus, has recently become an attractive biological target for therapeutic intervention. In order to develop in vivo models of inflammatory diseases, it is essential to identify and characterize the homologues of human eotaxin (CCL11) and CCR3 from other species, such as non-human primates. Accordingly, we cloned the macaque eotaxin and CCR3 genes and revealed that they were 91% and 92% identical at the amino acid level to their human homologues, respectively. Macaque CCR3 expressed in the murine pre-B L1-2 cell line bound macaque eotaxin with high affinity (Kd = 0.1nM) and exhibited a robust eotaxin-induced Ca2+-flux and chemotaxis. Characterization of -chemokines on native macaque CCR3 on eosinophils was performed by means of eotaxin-induced shape change in whole blood using a novel signaling assay known as gated autofluorescence forward scatter. Additionally, mAbs were raised against macaque CCR3 using two different immunogens: a 30 amino acid synthetic peptide derived from the predicted NH2-terminus of macaque CCR3 and intact macaque CCR3-transfected cells. These anti-macaque CCR3 mAbs exhibited potent antagonist activity in receptor binding and functional assays. The characterization of the macaque eotaxin/CCR3 axis and development of antagonistic anti-macaque CCR3 mAbs will facilitate the development of CCR3 small molecule antagonists with the hope of ameliorating chronic inflammatory diseases in humans.
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