Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1999-03-24
2001-05-15
Ulm, John (Department: 1646)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C436S501000, C435S007200
Reexamination Certificate
active
06232084
ABSTRACT:
This invention relates to the identification of the ligand for an orphan 7TM receptor and its use as a screening tool to identify antagonists and agonists of the receptor, to the antagonists and agonists so identified and their use in therapy.
Chemokines are structurally and functionally related 8 to 10 kD polypeptides, involved in the recruitment of white blood cell into areas of inflammation and their subsequent activation (Miller, M. D. and Krangel, M. S. (1992)
Crit. Rev. Immunol.
12, 17-46; Baggiolini, M., Dewald, B. and Moser, B.(1994)
Adv. Immunol.
55, 97-179). In addition, some chemokines are able to regulate the proliferative potential of hematopoietic progenitor cells, endothelial cells and certain types of transformed cells (Oppenheimer, J. J., Zachariae, C. O. C., Mukaida, N., and Matsushima, K. (1991)
Ann. Rev. Immunol.
9, 617-648; Schall, T. J. (1991)
Cytokine
3, 165-183). Based on whether the first two cysteine moieties are separated by one amino acid residue or are adjacent, chemokines belong to the &agr;- or CXC chemokine family (e.g interleukin (IL)-8) or the &bgr;- or CC chemokine family (e.g. RANTES and MCP-1). CXC chemokines play a key role in the accumulation of various cell types, including neutrophils, monocytes, T-lymphocytes, basophils and fibroblasts at sites of inflammation. These chemokines are implicated in both acute and chronic inflammatory disease states, including rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, asthma, leprosy, psoriasis, various respiratory syndromes, and also contribute towards modulation of angiogenesis and fibroplasia.
Chemokines express their biological responses through interaction with chemokine receptors (Horuk, R. and Peiper, S. C. (1995)
Exp. Opin. Ther. Patents
5, 1185-1200).
Several chemokine receptors have already been cloned, for instance, the following human CXC chemokine receptors:
the receptors for IL8 (CXCR1) and IL8/ELR chemokines, (CXCR2, Holmes, W. E., Lee, J., Kuang, W. J., Rice, G. C. and Wood, W. I. (1991)
Science
253, 1278-1280; Murphy, P. M. and Tiffany, H. L. (1991)
Science
253, 1280-1283);
a receptor for IP10/Mig (CXCR3, Loetscher, M., Gerber, B., Loetscher, P., Jones, S. A., Piali, L., Clark-Lewis, I., Baggiolini, M., and Moser, B. (1996) J. Exp. Med. 184, 963-969.);
a receptor for SDF-1 (CXCR4 or LESTR, Bleul, C. C., Farzan, M., Choe, H., Parolin, C., Clark-Lewis, I., Sodroski, J., Springer, T. A. (1996) Nature, 382, 829-836.)
In addition, the following human CC chemokine receptors:
MIP-1&agr;/RANTES receptor (CCR-1, Neote, K., Digregorio, D., Mak, J. K., Horuk, R. and Schall, T. J. (1993)
Cell
72, 415-425; Gao, B. J-L., Kuhns, D. B., Tiffany, H. L., McDermott, D., Li, X., Francke, U. and Murphy, P. M. (1993)
J. Exp. Med.
177, 1421-1427);
MCP-1A and B receptors (CCR-2A and B, Charo, I. F., Myers, S. J., Herman, A., Franci, C., Connolly, A. J. and Coughlin, S. R. (1994)
Proc. Natl. Acad. Sci. USA
91, 2752-2756; Yamagami, S., Tokuda, Y., Ishii, K., Tanaka, T. and Endo, N. (1994)
Biochem. Biophys. Res. Commun.
202, 1156-1162);
the eotaxin/RANTES receptor (CCR-3, Combadiere, C., Ahuja, S. K. and Murphy, P. M. (1995)
J. Biol. Chem.
270, 16491-16494; Daugherry, D. L., Siciliano, S. J., DeMartino, J. A., Malkowitz, L., Sirotina, A. and Springer, M. S. (1996)
J.Exp.Med.
183, 2349-2354; Kitaura, M., Nakajima, T., Imai, T., Harada, S., Combadiere, C., Tiffany, H. L., Murphy, P. M. and Yoshie, O. (1996)
J. Biol Chem.
271, 7725-7730),
the promiscuous receptor on basophils (CCR-4, Power, C. A., Meyer, A., Nemeth, K., Bacon, K. B., Hoogewerf, A. J., Proudfoot, A. E. I. and Wells, T. N. C. (1995)
J. Biol. Chem.
270, 19495-19500);
a new MIP-1&agr;/MIP-1&bgr;/RANTES receptor (CCR-5, Samson, M., Labbe, O., Mollereau, C., Vassart, G. and Parmentier, M. (1996)
Biochemistry
35, 3362-3367.)
a new receptor for LARC (CCR6, Baba, M., Imai, T., Nishimura, M., Kakizaki, M., Takagi, S., Hieshima, Nomiyuki, H., and Yashie, O. (1997) J. Biol Chem. 272, 14893-14898.)
a new receptor for ELC/exodus3 (CCR7, Yoshida, R., Imai, T., Hieshima, K., Kusuda, J., Baba, M., Kitaura, M., Nishimura, M., Kakizaki, M., Nomiyama, H., and Yoshie, O. (1997) J. Biol. Chem. 272, 13803-13809.)
a new receptor for I-309 (CCR8, Samson, M., Stordeur, P., Labbe, O., Soularue, P., Vassart, G., and Parmentier, M. (1997) Eur. J. Immunol. 26, 3021-3028; Tiffany, H L, Lautens, L L, Gao,J-L, Pease, J., Locati, M., Combadiere, C., Modi, W., Bonner, T. I. and Murphy, P. M. (1997)
J Exp. Med.
186, 165-170; Stuber-Roos, R., Loetscher, M., Legner, D. F., Clark-Lewis, I., Baggiolini, M. and Moser, B. (1997) J. Biol. Che. 272, 17251-17254)
Recently the receptor for the newly described CX3C chemokine fractalkine
eurotacin has also been identified (Imai, T., Hieshima, K., Haskell, C., Baba, M., Nagira, M., Nishimura, M., Kakizaki, M., Takagi, S., Nomiyama, H., Schall, T. J., Yoshie, O. (1997) Cell 91, 521-530.).
Chemokine receptors belong to the group of 7 transmembrane (7TM) spanning receptors and their signal transduction pathway involves pertussus toxin-sensitive G-protein and a rise in [Ca
2+
]
i
. Although details about the molecular events are still incomplete, a complex array of intracellular signals ultimately lead to leucocyte activation and chemotaxis (Premack, B. A. and Schall, T. J. (1996) Nature medicine 2, 1174-1178).
Chemokine receptors, like chemokines, are divided into at least three sub-families, the CXC chemokine receptors (CXCR), the CC chemokine receptors (CCR) and the CX3CR, based on their selectivity for either CXC, CC, CX3C chemokines. Ligand cross-selectively, that is CXCRs that bind CC chemokines or vice versa, is not observed. Chemokine receptors consist of 350-368 amino acids and the sequence identity amongst members of the receptor sub-families is wide (36-77%). Most chemokine receptors recognise more than one chemokine and many chemokines, including IL-8, RANTES, MIP-1&agr; and the MCPs, bind to more than one receptor (Roos et al, J Biol Chem, 1997, 272 (28), 17521).
Current research suggests a pathophysiological role for chemokines in wide range of inflammatory states and infectious diseases. These disease states include, but are not limited to various viral, bacterial and parasital infection, rheumatoid arthritis, atherosclerosis and restenosis, psoriasis, asthma, chronic contact dermatitis, inflammatory bowel disease, multiple sclerosis, stroke, sarcoidosis, idiopathic pulmanory fibrosis as well as organ transplant rejection. Chemokines and their receptors have been recognised as targets for therapeutic agents.
The orphan 7TM receptor, HBMBU14, has been identified using EST (Expressed Sequence Tag) sequencing technology (Adams, M. D., et al.
Science
(1991) 252:1651-1656; Adams, M. D. et al.,
Nature,
(1992) 355:632-634; Adams, M. D., et al.,
Nature
(1995) 377 Supp:3-174) and the full-sequence length cDNA isolated (EP application no. 97307428.9; SmithKline Beecham Corp.). The sequence alignment of HBMBU 14 shows 100% identity with the published 7TM receptors TYMSTR (T-lymphocyte expressed seven transmembrane domain receptor) (Loetscher, M., et al, 1997 Current Biology 17, vol 9, 652-660), STRL-33, (Liao, F., et al, 1997, J. Exp. Med, 185, no.11, 2015-2023), and BONZO (Deng, H., et al, 1997, Nature, 388, 296-300).
TYMSTR is reported to be expressed in activated T-lymphocytes but not in freshly isolated lymphocytes and leucocytes. It has been identified as a co-receptor for human immunodeficiency virus-1 (HIV-1). Similarly, STRL33, has been reported to act as a co-receptor for both M-tropic and T-tropic HIV-1 (Liao, F., et al 1997, J. Exp Med 185, 11, 2015-23), and also as a co-receptor for SIV (Nature 1997 388, 238). STRL33 has also been found to be a co-receptor for SIV as well as HIV-1 (Deng et al, Nature 1997, 388, 296-300). BONZO mRNA has been detected in monocytes (Farzan, M., et al, 1997, J.Exp. Med 186, no3, 405-411). It has also been reported that human peripheral blood mononuclear cells express an SIV co-receptor(s) that is distinct from CCR5 (Nature 238,
Berkhout Theodorus Antonius
MacPhee Colin Houston
Moores Kitty
Han William T.
King William T.
Ratner & Prestia
SmithKline Beecham Plc
Ulm John
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