Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1999-11-24
2001-11-20
Gambel, Phillip (Department: 1644)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S007210, C435S007240, C530S350000, C530S387300, C530S395000
Reexamination Certificate
active
06319675
ABSTRACT:
BACKGROUND OF THE INVENTION
Chemokines are a large and growing family of 6-14 kD (non-glycosylated) 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., Bonzo) which share sequence homology with well-characterized chemokine receptors, but for which the biological functions and specific receptor agonists 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 Oppenheim, 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) and 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)).
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 antibodies (immunoglobulins) and antigen-binding fragments thereof which bind mammalian Bonzo or portion of the receptor. In one embodiment, the antibody or antigen-binding fragment thereof binds human Bonzo. In another embodiment, the antibody or antigen-binding fragment thereof can inhibit the binding of ligand (e.g., SExCkine (Spleen Extracted Chemokine) also referred to as chemokine alpha-5 (WO 99/27078)) to a mammalian Bonzo. In a preferred embodiment, the antibody or antibody-binding fragment can bind human Bonzo and inhibit the binding of SExCkine to the receptor. In another embodiment, the antibody or antigen-binding fragment can bind Bonzo expressed on the membrane of a cell and inhibit a cellular response to binding of ligand to Bonzo.
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 4A11, mAb 7A2, mAb 7F3, mAb 9G2 or an antigen-binding fragment of any of the foregoing. In another embodiment, the binding of the antibody or antigen-binding fragment of the invention to human Bonzo can be inhibited by mAb 4A11, mAb 7A2 or mAb 7F3. In another embodiment, the antibody is mAb 4A11, mAb 7A2, mAb 7F3, mAb 9G2 or an antigen-binding fragment of any of the foregoing.
The invention also relates to an isolated cell that produces tan antibody or antigen-binding fragment of the present invention, including those which bind to mammalian Bonzo and inhibit the binding of a ligand to the receptor. In one embodiment, the isolated cell is murine hybridoma 4A11 (also referred to as murine hybridoma LS212-4A11-30-8) deposited imdcr ATCC Accession No. PTA-991. In another embodiment, the isolated cell is murine hybridoma 7A2 (also referred to as murine hybridoma LS212-7A2-32-1) deposited under ATCC Accession No. PTA-992. In another embodiment, the isolated cell is murine hybridoma 7F3 (also referred to as murine hybridoma LS212-7F3-8-7) deposited under ATCC Accession No. PTA-990, In another embodiment, the isolated cell is murine lybridoma 9G2 (also referred to as murine hybridoma LS212-9G2-7-2).
The invention also relates to antibodies (immunoglobulin) and antigen-binding fragments thereof (e.g., an antigen-binding fragment) which bind mammalian SExCkine. In one embodiment, the antibody or antigen-binding fragment thereof binds human SExCkine. In another embodiment, the antibody or antigen-binding fragment thereof can inhibit the binding of SExCkine to receptor. In a preferred embodiment, the antibody or antibody-binding fragment can bind human SExCkine and inhibit the binding of SExCkine to Bonzo.
The invention also relates to a method of detecting or identifying an agent (i.e., molecule or compound) which binds to mammalian Bonzo. In one embodiment, an agent which can bind to mammalian Bonzo and inhibit (reduce or prevent) the binding of a ligand (e.g., SExCkine) to Bonzo 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 Bonzo function, such as ligands or other s
Briskin Michael J.
Murphy Kristine E.
Wilbanks Alyson M.
Wu Lijun
Gambel Phillip
Hamilton Brook Smith & Reynolds P.C.
Millennium Pharmaceuticals Inc.
Roark Jessica H.
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