Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving virus or bacteriophage
Reexamination Certificate
2001-07-13
2002-09-17
Salimi, Ali R. (Department: 1648)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving virus or bacteriophage
C435S007100, C435S007930, C435S007940, C435S345000, C424S141100
Reexamination Certificate
active
06451522
ABSTRACT:
BACKGROUND OF THE INVENTION
Over the past several years a growing family of leukocyte chemoattractant/activating factors, termed chemokines, has been described (Oppenheim, J. J. et al.,
Annu. Rev. Immunol.,
9:617-648 (1991); Schall and Bacon,
Curr. Opin. Immunol.,
6:865-873 (1994); Baggiolini, M., et al.,
Adv. Imunol.,
55:97-179 (1994)). Members of this family are produced and secreted by many cell types in response to early inflammatory mediators such as IL-1&bgr; or TNF&agr;. The chemokine superfamily comprises two main branches: the &agr;-chemokines (or CXC chemokines) and the &bgr;-chemokines (CC chemokines). The &agr;-chemokine branch includes proteins such as IL-8, neutrophil activating peptide-2 (NAP-2), melanoma growth stimulatory activity (MGSA/gro or GRO&agr;), and ENA-78, each of which have attracting and activating effects predominantly on neutrophils. The members of the &bgr;-chemokine branch affect other cell types such as monocytes, lymphocytes, basophils, and eosinophils (Oppenheim, J. J. et al.,
Annu. Rev. Immunol.,
9:617-648 (1991); Baggiolini, M., et al.,
Adv. Imunol.,
55:97-179 (1994); Miller and Krangel,
Crit. Rev. Immunol.,
12:17-46 (1992); Jose, P. J., et al.,
J. Exp. Med.,
179:881-118(1994); Ponath, P. D., et al.,
J. Clin. Invest.,
97:604-612 (1996)), and include proteins such as monocyte chemotactic proteins 1-4 (MCP-1, MCP-2, MCP-3, and MCP-4), RANTES, and macrophage inflammatory proteins (MIP-1&agr;, MIP-1&bgr;). Recently a new class of membrane-bound chemokines designated CX3C chemokines has been identified (Bazan, J. F., et al.,
Nature
385:640-644 (1997)). Chemokines can mediate a range of pro-inflammatory effects on leukocytes, such as triggering of chemotaxis, degranulation, synthesis of lipid mediators, and integrin activation (Oppenheim, J. J. et al.,
Annu. Rev. Immunol.,
9:617-648 (1991); Baggiolini, M., et al.,
Adv. Imunol.,
55:97-179 (1994); Miller, M. D. and Krangel, M. S.,
Crit. Rev. Immunol.,
12:17-46 (1992)). Lately, certain &bgr;-chemokines have been shown to suppress HIV-1 infection of human T cell lines in vitro (Cocchi, F., et al.,
Science
(Wash. D.C.), 270:1811-1815 (1995)).
Chemokines bind to 7 transmembrane spanning (7TMS) G protein-coupled receptors (Murphy, P. M.,
Annu. Rev. Immunol.,
12:593-633 (1994)). Some known receptors for the CC or &bgr; chemokines include CCR1, which binds MIP-1&agr; and RANTES (Neote, K., et al.,
Cell,
72:415-425 (1993); Gao, J. L.,
J. Exp. Med.,
177:1421-1427 (1993)); CCR2, which binds chemokines including MCP-1, MCP-2, MCP-3 and MCP-4 (Charo, I. F., et al.,
Proc. Natl. Acad. Sci. USA,
91:2752-2756 (1994); Myers, S. J., et al.,
J. Biol. Chem.,
270:5786-5792 (1995); Gong et al.,
J. Biol. Chem.
272:11682-11685 (1997); Garcia-Zepeda et al.,
J. Immunol.
157:5613-5626 (1996)); CCR3, which binds chemokines including eotaxin, RANTES and MCP-3 (Ponath, P. D., et al.,
J. Exp. Med.,
183:2437-2448 (1996)); CCR4, which has been found to signal in response to MCP-1, MIP-1&agr;, and RANTES (Power, C. A., et al., J. Biol. Chem., 270:19495-19500 (1995)); and CCR5, which has been shown to signal in response to MIP-1&agr;, MIP-1&bgr; and RANTES (Boring, L., et al.,
J. Biol. Chem.,
271 (13):7551-7558 (1996); Raport, C. J.,
J. Biol. Chem.,
271:17161-17166 (1996); and Samson, M. et al.,
Biochemistry,
35:3362-3367 (1996)).
CCR2 is expressed on the surface of several leukocyte subsets, and appears to be expressed in two slightly different forms (CCR2a and CCR2b) due to alternative splicing of the mRNA encoding the carboxy-terminal region (Charo et al.,
Proc. Natl. Acad. Sci. USA
91:2752-2756 (1994)). MCP-1 acts upon monocytes, lymphocytes and basophils, inducing chemotaxis, granule release, respiratory burst and histamine and cytokine release. Studies have suggested that MCP-1 is implicated in the pathology of diseases such as rheumatoid arthritis, atherosclerosis, granulomatous diseases and multiple sclerosis (Koch,
J. Clin. Invest.
90:772-79 (1992); Hosaka et al.,
Clin. Exp. Immunol.
97:451-457 (1994); Schwartz et al.,
Am. J. Cardiol.
71(6):9B-14B (1993); Schimmer et al.,
J. Immunol.
160:1466-1471 (1998); Flory et al.,
Lab. Invest.
69:396-404 (1993); Gong et al.,
J. Exp. Med.
186:131-137 (1997)). Additionally, CCR2 can act as a co-receptor for HIV (Connor et al.,
J. Exp. Med.
185:621-628 (1997)). Thus, CCR2 receptor antagonists may represent a new class of important therapeutic agents.
SUMMARY OF THE INVENTION
The present invention relates to an antibody (immunoglobulin) or functional fragment thereof (e.g., an antigen-binding fragment) which binds to a mammalian CC-chemokine receptor 2 (also referred to as CCR2, CKR-2, MCP-1RA or MCP-1RB) or portion of the receptor (anti-CCR2). In one embodiment, the antibody of the present invention or fragment thereof has specificity for human or rhesus CCR2 or a portion thereof. In another embodiment, the antibody or fragment of the invention blocks binding of a ligand (e.g., MCP-1, MCP-2, MCP-3, MCP-4) to the receptor and inhibits function associated with binding of the ligand to the receptor (e.g., leukocyte trafficking). For example, as described herein, antibodies and fragments thereof of the present invention which bind human or rhesus CCR2 or a portion thereof, can block binding of a chemokine (e.g., MCP-1, MCP-2, MCP-3, MCP-4) to the receptor and inhibit function associated with binding of the chemokine to the receptor. In one embodiment, the antibody is monoclonal antibody (mAb) LS132.1D9 (1D9) or an antibody which can compete with 1D9 for binding to human CCR2 or a portion of human CCR2. Functional fragments of the foregoing antibodies are also envisioned.
In another embodiment, the antibody or functional fragment of the present invention binds human CCR2 or a portion thereof, and inhibits human immunodeficiency virus (HIV) binding to the receptor, thereby inhibiting function associated with binding of HIV to the receptor (e.g., HIV antigen release and infectivity). In one embodiment, the antibody is monoclonal antibody 1D9 or an antibody which can compete with 1D9 for binding to human CCR2 or a portion of human CCR2.
The present invention also relates to an antibody or functional fragment thereof (e.g., an antigen-binding fragment) which binds to a mammalian CCR2 or portion of the receptor and provides increased fluorescent staining intensity of CCR2 or compositions comprising CCR2 relative to other anti-CCR2 antibodies. In one embodiment, the antibody is monoclonal antibody 1D9 or LS 132.8G2 (8G2) or an antibody which can compete with 1D9 or 8G2 for binding to human CCR2 or a portion of human CCR2.
The present invention further relates to a method of inhibiting the interaction of a cell bearing mammalian (e.g., human, non-human primate or murine) CCR2 with a ligand thereof, comprising contacting the cell with an effective amount of an antibody or functional fragment thereof which binds to a mammalian CCR2 or a portion of CCR2. Suitable cells include granulocytes, leukocytes, such as monocytes, macrophages, basophils and eosinophils, mast cells, and lymphocytes including T cells (e.g., CD8+ cells, CD4+ cells, CD25+ cells, CD45RO+ cells), and other cells expressing CCR2 such as a recombinant cell expressing CCR2 (e.g., transfected cells). In a particular embodiment, the antibody is 1D9 or an antibody which can compete with 1D9 for binding to human CCR2 or a portion of human CCR2.
Another embodiment of the invention relates to a method of inhibiting the interaction of a cell bearing mammalian CCR2 with a chemokine, comprising contacting said cell with an effective amount of an antibody or functional fragment thereof which binds to CCR2 or a portion of said receptor. In one embodiment of the method, the antibody or functional fragment thereof is any one or more of 1D9, an antigen-binding fragment of 1D9 or an antibody or fragment thereof having an epitopic specificity which is the same as or similar to that of 1D9. Furthermore, the invention relates to a method of inhibiting a function associate
Hamilton Brook Smith & Reynolds P.C.
Millennium Pharmacueticals, Inc.
Salimi Ali R.
LandOfFree
Anti-CCR2 antibodies and methods of use therefor does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Anti-CCR2 antibodies and methods of use therefor, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Anti-CCR2 antibodies and methods of use therefor will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2867960