Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1999-03-11
2001-12-11
Saunders, David (Department: 1644)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C424S133100, C424S139100, C424S143100, C435S328000, C435S331000, C435S334000, C435S810000, C435S975000, C530S387300, C530S387900, C530S388220, C530S389100
Reexamination Certificate
active
06329159
ABSTRACT:
BACKGROUND OF THE INVENTION
Chemokines are a large and growing family of nearly forty 6-14 kD (non-glycosylated) heparin binding proteins that mediate a wide range of biological functions (Taub, D. D. and Openheim, J. J.,
Ther. Immunol
., 1:229-246 (1994)). The chemokines can be divided into families based on the position of four cysteine residues that form two disulfide bonds (Kelner, G. S., et al.,
Science
, 266:12395-1399 (1994); Bazan, J. F., et al.,
Nature
, 385:640-644 (1997); Pin, Y., et al.,
Nature
, 385:611-617 (1997)). Chemokine receptors can also be divided into families based on the type of chemokine they bind, although, no clear structural differences have been identified that distinguish the receptor sub-families (Mackay, C. R.,
J. Exp.Med
., 184:799-802 (1996)). In addition, there are a number of so called “orphan” chemokine receptors (e.g., GPR-9-6) which share sequence homology with well characterized chemokine receptors. However, the biological functions and specific agonists of orphan receptors remain unknown.
Chemokines play a vital role in leukocyte adhesion and extravasation. For example, in various in vitro assays, chemokines can induce the chemotaxis or transendothelial migration of leukocytes (Taub, D. D. and Openheim, J. J.,
Ther. Immunol
., 1:229-246 (1994)), while in vivo injection (Taub, D. D., et al.,
J. Clin. Invest
., 97:1931-1941 (1996)) or over-expression of chemokines (Fuentes, M. E., et al.,
J. Immunol
., 155:5769-5776 (1995)) can result in leukocyte accumulation at the site of chemokine injection or expression. Antagonists of chemokines can prevent leukocyte trafficking (Bargatze, R. F. and Butcher, E. C.,
J. Exp. Med
., 178:367-372 (1993)) and may have beneficial effects in several models of acute and chronic inflammation (Sekido, N., et al.,
Nature
, 365:654-657 (1993); Karpus, W. J., et al.,
J. Immunol
., 155:5003-5010 (1995)). Chemokines have also been reported to modulate angiogenesis (Gupta, S. K., et al.,
Proc. Natl. Acad. Sci. USA
, 92:7799-7803 (1995)), hematopoiesis (Taub, D. D. and Openheim, J. J.,
Ther. Immunol
., 1:229-246 (1994)) as well as T lymphocyte activation (Zhou, Z., et al.,
J. Immunol
. 151:4333-4341 (1993); Taub, D. D., et al.,
J. Immunol
., 156:2095-2103 (1996)). In addition, several chemokine receptors act as co-receptors, along with CD4, for entry of M tropic and T tropic HIV-1 (Choe, H., et al.,
Cell
, 85:1135-1148 (1996); Feng, Y., et al.,
Science
, 272:872-877 (1996)).
Several subsets of CD4 lymphocytes can be defined based on their expression of various adhesion molecules that are known to effect trafficking to different physiologic sites (Mackay, C. R.,
Curr. Opin. Immunol
., 5:423-427 (1993)). For example, CLA
+ve
memory CD4 lymphocytes traffic to the skin (Berg, E. L., et al.,
Nature
, 174(6): 1461-1466 (1991)), while CLA
−ve
&agr;4&bgr;7
+ve
memory CD4 lymphocytes traffic to mucosal sites (Hamman, A., et al.,
J. Immunol
., 152:3282-3292 (1994)). Leukocyte adhesion to endothelium is thought to involve several overlapping steps including rolling, activation and arrest. Rolling leukocytes are exposed to factors expressed at the adhesion site resulting in activation of the leukocyte and up-regulation of integrin-mediated adhesion. As a consequence of such integrin-mediated interactions, leukocytes arrest on the endothelium (Bargatze, R. F. and Butcher, E. C.,
J. Exp. Med
., 178:367-372 (1993); Bargatze, R. F., et al.,
Immunity
, 3:99-108 (1995)). Leukocyte activation and up-regulation of integrin molecules occurs via a pertussis toxin sensitive mechanism that is thought to involve chemokine receptors (Bargatze, R. F. and Butcher, E. C.,
J. Exp. Med
., 178:367-372 (1993); Campbell, J. J., et al.,
Science
, 279:381-383 (1998)).
Memory CD4
+
lymphocytes can be grouped based upon the expression of certain chemokine receptors. For example, CXCR3, CCR2 and CCR5 (Qin, S., et al.,
Eur. J. Immunol
., 26:640-647 (1996); Qin, S., et al.,
J. Clin. Invest
., 101:746-754 (1998); Liao, F., et al.,
J. Immunol
., 162:186-194 (1999)) are all expressed on subsets of memory CD4 lymphocytes, and certain chemokines act selectively on naive T cells (Adema, G. J., et al.,
Nature
, 387:713-717 (1997)). Furthermore, several chemokines which are ligands for such receptors have been shown to be expressed in inflammatory sites (Gonzalo, J. A., et al.,
J. Clin. Invest
., 98:2332-2345 (1996)) and in some cases in lymph nodes draining a challenged site (Tedla, N., et al.,
J. Immunol
., 161:5663-5672 (1998)). In vitro derived T
H
1/T
H
2 lymphocyte lines have also been shown to differentially express chemokine receptors. Specifically, T
H
1 lymphocytes have been shown to selectively express CXCR3 and CCR5, while T
H
2 lymphocytes selectively express CCR4, CCR8 and CCR3 (Bonecchi, R. G., et al.,
J.Exp. Med
., 187:129-134 (1998); Sallusto, F. D., et al.,
J. Exp. Med
., 187:875-883 (1998); Sallusto, F.,
Science
, 277:2005-2007 (1997); Andrew, D. P., et al.,
J. Immunol
161:5027-5038 (1998); Zingoni, A., et al.,
J. Immunol
., 161:547-555 (1998)). Interestingly, in some cases the chemokines for these respective chemokine receptors, such as MDC for CCR4 and IP-10 for CXCR3, are induced by cytokines associated with a T
H
1/T
H
2 environment (Andrew, D. P., et al.,
J. Immunol
161:5027-5038(1998); Luster, A. D., et al.,
Nature
, 315:672-676 (1985)).
SUMMARY OF THE INVENTION
The invention relates to an antibody (immunoglobulin) or functional fragment thereof (e.g., an antigen-binding fragment) which binds to a mammalian GPR-9-6 or portion of the receptor. In one embodiment, the antibody or antigen-binding fragment thereof binds to human GPR-9-6. In another embodiment, the antibody or antigen-binding fragment thereof can inhibit the binding of a ligand to a mammalian GPR-9-6. In a preferred embodiment, the antibody or antibody-binding fragment can bind to human GPR-9-6 and inhibit the binding of TECK to the receptor.
In another embodiment, the antibody or antigen-binding fragment of the invention binds to an epitope which is the same as or is similar to the epitope recognized by mAb 3C3 or an antigen-binding fragment thereof. For example, the binding of the antibody or antigen-binding fragment of the invention to human GPR-9-6 can be inhibited a peptide that consists of the amino acid sequence of SEQ ID NO:3. In another embodiment, the binding of the antibody or antigen-binding fragment of the invention to human GPR-9-6 can be inhibited by mAb 3C3. In a preferred embodiment, the antibody is mAb 3C3 or antigen-binding fragment thereof.
The invention also relates to an isolated cell that produces an antibody or antigen-binding fragment of the present invention, including those which bind to mammalian GPR-9-6 and inhibit the binding of a ligand to the receptor. In a particular embodiment, the isolated cell is murine hybridoma 3C3 (also referred to as murine hybridoma LS129-3C3-E3-1) deposited under ATCC Accession No. HB-12653.
The invention also relates to a method of detecting or identifying an agent (i.e., molecule or compound) which binds to a mammalian GPR-9-6. In one embodiment, an agent which can bind to mammalian GPR-9-6 and inhibit (reduce or prevent) the binding of a ligand (e.g., TECK) to GPR-9-6 is identified in a competitive binding assay. In other embodiments, agents for use in therapy are identified in a direct binding assay. Thus, the invention encompasses methods of identifying agents which modulate GPR-9-6 function, such as, ligands or other substances which bind a mammalian GPR-9-6, including inhibitors (e.g., antagonists) or promoters (e.g., agonists) of receptor function. A suitable source of a mammalian GPR-9-6 or a ligand-binding variant thereof can be used to identify a GPR-9-6 binding agent in accordance with the method of the invention. In one embodiment, a cell (e.g., cell line, recombinant cell) that expresses a mammalian GPR-9-6 or a ligand binding variant thereof is used. In another embodiment, a membrane preparation of a cell that expresses a mammalian GPR-9-6 or
Andrew David P.
Ponath Paul D.
Zabel Brian A.
Hamilton Brook Smith & Reynolds P.C.
Millennium Pharmaceuticals Inc.
Saunders David
Tung Mary Beth
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