Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues
Reexamination Certificate
1997-04-24
2001-08-07
Mertz, Prema (Department: 1646)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
C435S069100, C435S070100, C435S071100, C435S071200, C435S252300, C435S254110, C435S320100, C435S325000, C435S471000
Reexamination Certificate
active
06271347
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to an eosinophil eotaxin receptor (“CC CKR3”), in particular, the human eosinophil eotaxin receptor and nucleic acids encoding this receptor. This invention further relates to assays which may be used to screen and identify compounds that bind to the eosinophil eotaxin receptor. Such compounds would be useful in the treatment and prevention of atopic conditions including allergic rhinitis, dermatitis, conjunctivitis, and particularly bronchial asthma.
BACKGROUND OF THE INVENTION
Eosinophils play prominant roles in a variety of atopic conditions including allergic rhinitis, dermatitis, conjunctivitis, and particularly bronchial asthma (for a reviews see e.g. Gleich, G. J., et al.,
Eosinophils.
J. I. Gallin, I. M. Goldstein, R. Snyderman, Eds., Inflammation: Basic Principles and Clinical Correlates (Raven Press, Ltd., New York, 1992) and Seminario, M. C., et al. (1994)
Current Opinion in Immunology
6, 860-864). A pivotal event in the process is the accumulation of eosinophils at the involved sites. While a number of the classical chemoattractants, including C5a, LTB4, and PAF, are known to attract eosinophils (Gleich, G. J., et al.,
Eosinophils.
J. I. Gallin, et al. Eds., Inflammation: Basic Principles and Clinical Correlates (Raven Press, Ltd., New York, 1992)), these mediators are promiscuous, acting on a variety of leukocytes including neutrophils, and are unlikely to be responsible for the selective accumulation of eosinophils. In contrast, the chemokines a family of 8-10 kDa proteins are more restricted in the leukocyte subtypes they target and are potential candidates for the recruitment of eosinophils in atopic diseases and asthma (Baggiolini, M., Dewald, B. and Moser, B. (1994)
Advances in Immunology
55, 97-179). Although there is a mounting body of evidence that eosinophils are recruited to sites of allergic inflammation by a number of &bgr;-chemokines, particularly eotaxin and RANTES, the receptor which mediates these actions has not been identified.
The chemokines contain four conserved cysteines, and are divided into two sub-families based on the arrangement of the first cysteine pair (Baggiolini, M., Dewald, B. and Moser, B. (1994)
Advances in Immunology
55, 97-179). In the &agr;-chemokine family, which includes IL-8, MGSA, NAP-2 and IP-10, these two cysteines are separated by a single amino acid, while in the &bgr;-chemokine family, which includes RANTES (“regulated on activation T expressed and secreted”), MCP-1 (“monocyte chemotactic protein”), MCP-2, MCP-3, MIP-1&agr; (“macrophage inflammatory protein”), MIP-1&bgr; and eotaxin, these two cysteines are adjacent. There is a functional correlate to this structural division. The &agr;-chemokines act primarily on neutrophils, and the &bgr;-chemokines on monocytes, lymphocytes, basophils and eosinophils (Baggiolini, M., Dewald, B. and Moser, B. (1994)
Advances in Immunology
55, 97-179). In particular, RANTES, MCP-2, MCP-3, and MIP-1&agr; have been shown to activate eosinophils in vitro (Dahinden, C. A., et al. (1994)
Journal of Experimental Medicine
179, 751-756; Ebisawa, M., et al. (1994)
Journal of Immunology
153, 2153-2160; Weber, M., et al. (1995)
Journal of Immunology
154, 4166-4172), and RANTES to selectively attract eosinophils in vivo (Meurer, R., et al. (1993)
Journal of Experimental Medicine
178, 1913-1921; Beck, L., et al. (1995)
FASEB Journal
9, A804). Similarly, eotaxin, a new member of the &bgr;-chemokine family, first described in guinea pigs (Griffiths-Johnson, D. A., et al. (1993)
Bichemical and Biophysical Research Communications
197, 1167-1172; Jose, P. J., et al. (1994)
Journal of Experimental Medicine
179, 881-887) and mice (Rothenberg, et al. (1995)
Proceedings of the National Academy of Sciences
92, 8960-8964) is also a potent attractant and activator of eosinophils both in vitro and in vivo. Moreover, eotaxin is generated during antigenic challenge in the guinea pig model of allergic airway inflammation (Jose, et al. (1994)
J. Exp. Med.,
179, 881-887; Rothenberg, et al. (1995)
J. Exp. Med.,
181, 1211-1216. The cloning of guinea pig eotaxin has been disclosed (PCT Patent Publication No. WO 95/07985; Mar. 23, 1995). The cloning of the human eosinophil chemoattractant eotaxin has recently been reported (Ponath, et al.,
J. Clin. Invest.
(1996) 97(3) 604-612) and eotaxin has been suggested to be a very important agent in the mechanism of allergic inflammation (Baggiolini, et al.,
J. Clin. Invest.
(1996) 97(3) 587).
Eosinophils are attracted by a number of &bgr;-chemokines, the most potent of which are eotaxin (Griffiths-Johnson, D. A., et al. (1993)
Bichemical and Biophysical Research Communications
197, 1167-1172; Jose, P. J., et al. (1994)
Journal of Experimental Medicine
179, 881-887; Rothenberg, et al. (1995)
Proceedings of the National Academy of Sciences
92, 8960-8964) and RANTES (Dahinden, C. A., et al. (1994)
Journal of Experimental Medicine
179, 751-756; Ebisawa, M., et al. (1994)
Journal of Immunology
153, 2153-2160; Weber, M., et al. (1995)
Journal of Immunology
154, 4166-4172; Meurer, R., et al. (1993)
Journal of Experimental Medicine
178, 1913-1921; Beck, L., et al. (1995)
FASEB Journal
9, A804). Although several human &bgr;-chemokine receptors have been characterized in detail, none have the appropriate selectivity to account for the observed responses.
While elucidation of the actions of &bgr;-chemokines on eosinophils has contributed greatly to the understanding of eosinophil biology, information regarding the cell surface receptors which mediate these effects remain sparse. Furthermore, there are no reports describing binding studies of any of the &bgr;-chemokines to primary eosinophils. The known &bgr;-chemokine receptors are members of the G protein-coupled receptor superfarnily. Two of these receptors, CC CKR1 (12, 13) and CC CKR2 (MCP-1R) (Charo, I. F., et al. (1994)
Proceecing of the National Academy of Sciences
91, 2752-2756; Myers, S. J., et al. (1995)
Journal of Biological Chemistry
270, 5786-5792; Franci, C., et al. (1995)
Journal of Immunology
154, 6511-6517) found on monocytes, have been extensively studied and their selectivity for the different chemokines defined. However, neither of these receptors has the necessary ligand selectivity or the appropriate expression patterns required to mediate the effects of the &bgr;-chemokines on eosinophils. For example, CC CKR1 binds RANTES with high affinity, but binds eotaxin poorly, and while the effects of eotaxin on CC CKR2 have not been studied this receptor has no avidity for RANTES (Myers, S. J., et al. (1995)
Journal of Biological Chemistry
270, 5786-5792).
A review of the role of chemokines in allergic inflammation is provided by Kita, H., et al.,
J. Exp. Med.
183, 2421-2426 (June 1996). In particular, this review discusses the role which the receptor CKR-3 plays in the process of allergic inflammation. The cloning, expression and characterization of the human eosinophil eotaxin receptor has been reported by Daugherty, B. J., et al.,
J. Exp. Med.
183, 2349-2354 (May 1996). This publication discloses the cloning and functional expression of the chemokine receptor CC CKR3, as well as its characterization.
The cloning and expression of a human eosinophil receptor was allegedly achieved by Combadiere, C., et al.,
J. Biological Chem.
270 (27), 16491-16494 (Jul. 14, 1995). However, in a subsequent retraction (
J. Biological Chem.
270, 30235 (1995)) they confirmed that the receptor which was actually cloned and expressed was not CC CKR3, but was another CC chemokine receptor CC CKR5. This receptor was subsequently characterized by Kitaura, M., et al.,
J. Biological Chem.
271 (13), 7725-7730 (Mar. 29, 1996).
A human eotaxin receptor has been reported by Ponath, P. D., et al.
J. Exp. Med.
183, 2437-2448 (June 1996) and Gerard, C. J., et al., PCT Publication No. WO 96/22371 (Jul. 25, 1996). However, the sequence disclosed in this publication possesses an error in the assignment of threonine rather than serine at posi
Daugherty Bruce L.
Demartino Julie A.
Siciliano Salvatore J.
Springer Martin S.
Merck & Co. , Inc.
Mertz Prema
Rose David L.
Thies J. Eric
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