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
1997-07-11
2003-03-04
Gambel, Phillip (Department: 1644)
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, C530S388100, C530S388200, C530S388700, C530S388730, C530S388750, C530S389100, C530S389200, C530S389600, C530S866000, C435S326000, C435S328000, C435S332000, C435S334000, C435S346000, C435S810000, C435S070200, C435S070210, C424S130100, C424S133100, C424S136100, C424S141100, C424S143100, C424S152100, C424S153100, C424S154100
Reexamination Certificate
active
06528625
ABSTRACT:
BACKGROUND
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 chemokine having a CX
3
C motif 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 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. DC), 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)). The principal human CXC chemokine receptors characterized to date include: CXCR1 (IL-8 Receptor type A (IL-8 RA)), which binds IL-8; CXCR2 (IL-8 RB), which binds a number of CXC chemokines including IL-8 and GRO&agr; (Murphy, P. M. and Tiffany, H. L.,
Science
(Wash. DC), 253:1280-3 (1991); Beckmann, M. P., et al.,
Biochem. Biophys. Res. Commun.,
179:784-789 (1991); Holmes, W. E., et al.,
Science
(Wash. DC), 253:1278-1280 (1991)); an IP-10/Mig receptor designated CXCR3 (Loetscher et al.,
J. Exp. Med.
184:963-969 (1996)); and CXCR4 (also referred to as “LESTR” or “fusin”), which binds SDF-1 (Nagasawa et al.,
Proc. Natl. Acad. Sci. USA
93:14726-14729 (1996)). The 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 MCP-1 and MCP-3 (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)); 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, MTP-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)).
The precise expression of many of the chemokine receptors is not yet known, because specific mAbs are not available. For T cells, PCR or Northern blotting indicates that the known receptors for CC chemokines are expressed on subsets of T cells. Delineating exactly which subsets is an area of intense study, because chemokine receptor expression may explain the localization or migration of various cell types, such as TH1 or TH2 T cells or tissue homing subsets. It may also determine which T cells are infected with different strains of HIV-1. Despite the development of over 130 CD-defined specificities on leukocytes by the 5
th
International Leukocyte Workshop in 1993 (Schlossman, S. F., et al.,
Leukocyte Typing V,
Oxford University Press, 1995), none of these are specific for chemokine receptors, pointing to the difficulty in making antibodies to these cell surface receptors.
SUMMARY OF THE INVENTION
The present invention relates to an antibody (immunoglobulin) or functional portion thereof (e.g., antigen binding fragment) which binds to a mammalian chemokine receptor 5 protein (also referred to as CKR-5 or CCR5) or portion of the receptor (anti-CCR5). In one embodiment, the antibody of the present invention has specificity for human CCR5 or portion thereof, wherein the antibody blocks binding of a ligand (e.g., RANTES, MIP-1&agr;, MIP-1&bgr;, human immunodeficiency virus (HIV)) 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 of the present invention having specificity for human CCR5 or a portion thereof, can block binding of a chemokine (e.g., RANTES, MIP-1&agr;, MIP-1&bgr;) to the receptor and inhibit function associated with binding of the chemokine to the receptor. In one embodiment, the antibody is monoclonal antibody 5C7 or a monoclonal antibody (mAb) which can compete with 5C7 for binding to human CCR5 or portion of human CCR5. In another embodiment, the antibody is monoclonal antibody 2D7 or a mAb which can compete with 2D7 for binding to human CCR5 or portion of human CCR5.
The present invention further relates to a method of inhibiting the interaction of a cell (e.g., leukocytes, T cells such as CD8+ cells, CD4+ cells and CD45RO+ cells, monocytes and transfected cells) bearing mammalian (e.g., human, non-human primate or murine) CCR5 with a ligand thereof, comprising contacting the cell with an effective amount of an antibody or functional portion thereof which binds to a mammalian CCR5 or portion of CCR5.
Another embodiment of the invention relates to a method of inhibiting the interaction of a cell bearing mammalian chemokine receptor 5 protein with a chemokine, comprising contacting said cell with an effective amount of an antibody or functional portion thereof which binds to a mammalian chemokine receptor 5 protein or portion of said receptor. In one embodiment of the method, the antibody or functional portion thereof is any one or more of 2D7, an antigen binding fragment of 2D7 or an antibody having an epitopic specificity which is the same as or similar to that of 2D7. Furthermore, the invention relates to a method of inhibiting a function associated with binding of a chemokine to the chemokine 5 receptor protein, comprising administering an effective amount of an antibody or functional portion thereof which binds to a mammalian chemokine receptor 5 protein or portion of said receptor. In one aspect of the method, the antibody or functional portion thereof is any one or more of 2D7, an antigen binding fragment of 2D7 or an antibody having an epitopic specificity which is the same as or similar to that of 2D7.
Another aspect of the invention is a method of identifying expression of a mammalian CCR5 or portion of the receptor by a cell. According to the method, a composition comprising a cell or fraction thereof (e.g., a membrane fraction) is contacted with an antibody or functional portion thereof (e.g., 5C7 or 2D7) which binds to a mammalian CCR5 or portion of the receptor under conditions appropriate for binding of the antibody thereto, and the formation of a complex between said antibody and said protein or portion thereof
Mackay Charles R.
Wu Lijun
Gambel Phillip
Hamilton Brook Smith & Reynolds P.C.
Millennium Pharmaceuticals Inc.
Roark Jessica H.
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