Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Reexamination Certificate
1999-01-15
2002-12-03
Ulm, John (Department: 1646)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
C530S388200
Reexamination Certificate
active
06488930
ABSTRACT:
BACKGROUND OF THE INVENTION
Over the last decade chemokines have emerged as key mediators of inflammation as a result of their numerous proinflammatory activities which affect virtually every leukocyte type. More recently, chemokines have been recognized as a critical component of basal leukocyte trafficking essential for normal immune surveillance and response, as well as for several other functions in hematopoiesis, angiogenesis, control of viral infection, and T cell differentiation (Baggiolini et al.,
Ann. Rev. Immunol.
15:675 (1997); Zou et al.,
Nature
393:595 (1998); Tachibana et al.,
Nature
393:591 (1998)). This diverse array of biological activities, including mediation of a range of pro-inflammatory effects on leukocytes, such as triggering of chemotaxis, degranulation, synthesis of lipid mediators, and integrin activation, together with their critical role in the initiation and maintenance inflammatory diseases, and the recent identification of certain chemokine receptors as co-receptors for HIV-1 entry, have made chemokines and chemokine receptors an attractive new set of therapeutic targets.
Members of the chemokine 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) which are characterized by a single amino acid separating the first 2 cysteines, and the &bgr;-chemokines (CC chemokines), which contain two adjacent cysteines. 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, macrophage inflammatory proteins (MIP-1&agr;, MIP-1&bgr;), thymus and activation-regulated chemokine (TARC; Imai et al.,
J. Biol. Chem.
271:21514-21521 (1996)) and macrophage-derived chemokine (MDC; Godiska et al.,
J. Exp. Med.
185:1595-1604 (1997)).
Chemokines bind to 7 transmembrane spanning G protein-coupled receptors (Murphy, P. M.,
Annu. Rev. Immunol.,
12:593-633 (1994)). A number of &bgr; chemokine receptors (CCR1-CCR10) have been identified to date, and the search for additional chemokine receptors is the subject of active research (Baggiolini,
Nature
392:565-568 (1998)). Chemokine receptor CCR4 was identified by Power et al. (
J. Biol. Chem.
270:19495-19500 (1995); Genbank accession number X85740) and Meyer et al. (
J. Biol. Chem.
271(24):14445-14451 (1996); Genbank accession number X94151). A murine homolog of human CCR4 has also been identified (Youn et al.,
Blood
89(12):4448-4460 (1997)). CCR4 was originally found to signal in response to MCP-1, MIP-1&agr;, and RANTES but more recently has been shown to be specific for the chemokines TARC and MDC (Imai et al.,
J. Biol. Chem.
272(23):15036-15042 (1997); Imai et al.,
J. Biol. Chem.
273:1764-1768 (1998)).
The selective recruitment of leukocyte subsets to sites of inflammation and the ordered trafficking of leukocytes through the circulation, tissues, lymphatic system and secondary lymphoid organs is controlled in part by the differential expression of chemokine receptors on subsets of cells. Such expression patterns would seem to ensure that a functionally related group of leukocytes can coordinately respond to a specific set of chemokines induced by a given stimulus. 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 express particular receptors 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. However, most leukocytes express several chemokine receptors, many with complex and promiscuous ligand interactions. This makes elucidating the normal immune function for a specific receptor on a given cell type and determining the relevance to initiation and progression of disease difficult, especially since specific antibodies are not available for many chemokine receptors.
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 4 (also referred to as CCR4, CKR-4, TARC-receptor and MDC receptor) or portion of the receptor (anti-CCR4). In one embodiment, the antibody of the present invention or fragment thereof has specificity for human CCR4 or a portion thereof. In another embodiment, the antibody or fragment of the invention blocks binding of a ligand (e.g., TARC, MDC, MCP-1, MIP-1&agr;, RANTES) to the receptor and inhibits function associated with binding of the ligand to the receptor (e.g., leukocyte trafficking). In a preferred embodiment, the ligand is TARC and/or MDC. For example, as described herein, antibodies and fragments thereof of the present invention which bind human CCR4 or a portion thereof, can block binding of a chemokine (e.g., TARC, MDC, MCP-1, MIP-1&agr;, RANTES) to the receptor and inhibit function associated with binding of the chemokine to the receptor. In a preferred embodiment, the chemokine is TARC and/or MDC. In one embodiment, the antibody is monoclonal antibody (mAb) LS141-1G1 (1G1) or an antibody which can compete with 1G1 for binding to human CCR4 or a portion of human CCR4. In another embodiment, the antibody is monoclonal antibody (mAb) LS185-2B10 (2B10) or an antibody which can compete with 2B10 for binding to human CCR4 or a portion of human CCR4. Functional fragments of the foregoing antibodies are also envisioned.
The present invention also relates to an antibody or functional fragment thereof (e.g., an antigen-binding fragment) which binds to a mammalian CCR4 or portion of the receptor and provides increased fluorescent staining intensity of CCR4 or compositions comprising CCR4 relative to other anti-CCR4 antibodies. In one embodiment, the antibody is monoclonal antibody 1G1 or 2B10 or an antibody which can compete with 1G1 or 2B10 for binding to human CCR4 or a portion of human CCR4.
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) CCR4 with a ligand thereof, comprising contacting the cell with an effective amount of an antibody or functional fragment thereof which binds to a mammalian CCR4 or a portion of CCR4. 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) such as Th1 and Th2 cells, and other cells expressing CCR4, such as a recombinant cell expressing CCR4 or portion thereof (e.g., transfected cells). In a particular embodiment, the antibody is 1G1 or 2B10 or an antibody which can compete with 1G1 or 2B10 for binding to human CCR4 or a portion of human CCR4.
Another embodiment of the invention relates to a method of inhibiting the interaction of a cell bearing mammalian CCR4 with a chemokine, comprising contacting said cell with an effective amount of an antibody or functional fragment thereof which binds to CCR4 or a portion of said receptor. In one embodiment of the method, the antibody or functional fragment thereof is any one or more of
Andrew David
Ruffing Nancy
Wu Lijun
Hamilton Brook Smith & Reynolds P.C.
Millennium Pharmaceuticals Inc.
Ulm John
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