Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
2001-04-23
2004-02-24
Helms, Larry R. (Department: 1642)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C530S387100, C530S387300, C424S130100, C424S133100, C424S156100
Reexamination Certificate
active
06696550
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 GROA), 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 LS132.8G2 (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 also relates to a humanized immunoglobulin or antigen-binding fragment thereof having binding specificity for CCR2, said immunoglobulin comprising an antigen binding region of nonhuman origin (e.g., rodent) and at least a portion of an immunoglobulin of human origin (e.g., a human framework region, a human constant region of the gamma type). In one embodiment, the humanized immunoglobulin or fragment thereof described herein can compete with 1D9 for binding to CCR2. In a preferred embodiment, the antigen binding region of the humanized immunoglobulin is derived from monoclonal antibody 1D9 (e.g., an immunoglobulin comprising the variable regions of the light and heavy chains as shown in
FIG. 7
(SEQ ID NO: 9) and
FIG. 8
(SEQ ID NO: 10), respectively).
For example, the humanized immunoglobulin or antigen-binding fragment thereof can comprise an antigen binding region comprising at least one complementarity determining region (CDR) of nonhuman origin, and a framework region (FR) derived from a human framework region. In one aspect, the humanized immunoglobulin having binding specificity for CCR2 comprises a light chain comprising at least one CDR derived from an antibody of nonhuman origin which binds CCR2 and a FR derived from a light chain of human origin (e.g., from HF-21/28), and a heavy chain comprising a CDR derived from an antibody of nonhuman origin which binds CCR2 and a FR derived from
Horvath Christopher
Jones S. Tarran
LaRosa Gregory J.
Newman Walter
O'Brien Siobhan H.
Hamilton Brook Smith & Reynolds P.C.
Helms Larry R.
Millennium Pharmaceuticals Inc.
LandOfFree
Humanized 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 Humanized 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 Humanized anti-CCR2 antibodies and methods of use therefor will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3293337