Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Lymphokines – e.g. – interferons – interlukins – etc.
Reexamination Certificate
1999-01-27
2002-11-12
Eyler, Yvonne (Department: 1646)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Lymphokines, e.g., interferons, interlukins, etc.
C530S300000, C530S350000, C530S324000, C530S326000, C530S388220, C424S811000, C514S008100, C514S012200, C536S023500, C435S006120, C435S007210, C435S069100, C435S069500, C435S252300, C435S320100
Reexamination Certificate
active
06479633
ABSTRACT:
FIELD OF THE INVENTION
This invention relates, in part, to newly identified polynucleotides and polypeptides; variants and derivatives of the polynucleotides and polypeptides; processes for making the polynucleotides and the polypeptides, and their variants and derivatives; agonists and antagonists of the polypeptides; and uses of the polynucleotides, polypeptides, variants, derivatives, agonists and antagonists. In particular, in these and in other regards, the invention relates to polynucleotides and polypeptides of human chemokine alpha-2, hereinafter referred to as “CK&agr;-2”.
BACKGROUND OF THE INVENTION
The ability to control the migration and “trafficking” of various cell types is controlled by a subset of factors, or proteins, among which chemokines are an example.
Chemokines, also referred to as intercrine cytokines, are a subfamily of structurally and functionally related chemotactic cytokines. These molecules are 8-10 kd in size. In general, chemokines exhibit 20% to 75% homology at the amino acid level and are characterized by four conserved cysteine residues that form two disulfide bonds. Based on the arrangement of the first two cysteine residues, chemokines have been classified into two subfamilies, alpha and beta. In the alpha subfamily, the first two cysteines are separated by one amino acid and hence are referred to as the “C—X—C” subfamily. In the beta subfamily, the two cysteines are in an adjacent position and are, therefore, referred to as the “C—C” subfamily. Thus far, at least eight different members of this family have been identified in humans.
The intercrine cytokines exhibit a wide variety of functions. A hallmark feature is their ability to elicit chemotactic migration of distinct cell types, including monocytes, neutrophils, T lymphocytes, basophils and fibroblasts. Many chemokines have proinflammatory activity and are involved in multiple steps during an inflammatory reaction. These activities include stimulation of histamine release, lysosomal enzyme and leukotriene release, increased adherence of target immune cells to endothelial cells, enhanced binding of complement proteins, induced expression of granulocyte adhesion molecules and complement receptors, and respiratory burst. In addition to their involvement in inflammation, certain chemokines have been shown to exhibit other activities. For example, macrophage inflammatory protein 1 (MIP-1) is able to suppress hematopoietic stem cell proliferation, platelet factor-4 (PF-4) is a potent inhibitor of endothelial cell growth, interleukin-3 (IL-8) promotes proliferation of keratinocytes, and GRO is an autocrine growth factor for melanoma cells.
In light of the diverse biological activities, it is not surprising that chemokines have been implicated in a number of physiological and disease conditions, including lymphocyte trafficking, wound healing, hematopoietic regulation and immunological disorders such as allergy, asthma and arthritis.
Members of the “C—C” branch exert their effects on the following cells: eosinophils which destroy parasites to lessen parasitic infection and cause chronic inflammation in the airways of the respiratory system; macrophages which suppress tumor formation in vertebrates; and basophils which release histamine which plays a role in allergic inflammation. However, members of one branch may exert an effect on cells which are normally responsive to the other branch of chemokines and, therefore, no precise role can be attached to the members of the branches.
While members of the C—C branch act predominantly on mononuclear cells and members of the C—X—C branch act predominantly on neutrophils a distinct chemoattractant property cannot be assigned to a chemokine based on this guideline. Some chemokines from one family show characteristics of the other.
The polypeptide of the present invention has the conserved cysteine residues of the “C—X—C” region, and have amino acid sequence homology to known chemokines.
Clearly, there is a need for factors that regulate the migration of distinct cell types and their roles in dysfunction and disease. There is a need, therefore, for identification and characterization of such factors that regulate the migration of cells, particularly cells of the immune system, and which can play a role in preventing, ameliorating or correcting dysfinctions or diseases.
Summary of the Invention
Toward these ends, and others, it is an object of the present invention to provide polypeptides, inter alia, that have been identified as novel CK&agr;-2 by homology between the amino acid sequence set out in both
FIG. 1
(SEQ ID NO:2) and
FIG. 2
(SEQ ID NO:3) and known amino acid sequences of other proteins such as Chinese hamster GRO protein set out in
FIGS. 3 and 4
(SEQ ID NO:4).
It is a further object of the invention, moreover, to provide polynucleotides that encode CK&agr;-2, particularly polynucleotides that encode the polypeptides herein designated CK&agr;-2.
In a particularly preferred embodiment of this aspect of the invention the polynucleotide comprise the regions encoding the human CK&agr;-2 polypeptides in the sequences set out in
FIGS. 1 and 2
(SEQ ID NO:1).
In accordance with this aspect of the present invention there is provided an isolated nucleic acid molecule encoding mature polypeptides expressed by the human cDNA contained in ATCC Deposit No. 97400 deposited on Jan. 2, 1996.
In accordance with this aspect of the invention there are provided isolated nucleic acid molecules encoding human CK&agr;-2 polypeptides, including mRNAs, cDNAs, genomic DNAs and, in further embodiments of this aspect of the invention, biologically, diagnostically, clinically or therapeutically useful variants, analogs or derivatives thereof, or fragments thereof, including fragments of the variants, analogs and derivatives.
Among the particularly preferred embodiments of this aspect of the invention are naturally occurring allelic variants of human CK&agr;-2.
It also is an object of the invention to provide CK&agr;-2 polypeptides, particularly human CK&agr;-2 polypeptides, that may be employed for therapeutic purposes, for example, to treat and/or prevent tumors, chronic infections, leukemia, T-cell mediated auto-immune diseases, parasitic infections, psoriasis, asthma, allergy, to regulate hematopoiesis, to stimulate growth factor activity, to inhibit angiogenesis and to promote wound healing.
In accordance with this aspect of the invention there are provided novel polypeptides of human origin referred to herein as CK&agr;-2 as well as biologically, diagnostically or therapeutically useful fragments, variants and derivatives thereof, variants and derivatives of the fragments, and analogs of the foregoing.
Among the particularly preferred embodiments of this aspect of the invention are variants of human CK&agr;-2 encoded by naturally occurring alleles of the human CK&agr;-2 gene.
It is another object of the invention to provide a process for producing the aforementioned polypeptides, polypeptide fragments, variants and derivatives, fragments of the variants and derivatives, and analogs of the foregoing. In a preferred embodiment of this aspect ofthe invention there are provided methods for producing the aforementioned CK&agr;-2 polypeptides comprising culturing host cells having expressibly incorporated therein an exogenously-derived human CK&agr;-2-encoding polynucleotide under conditions for expression of a human CK&agr;-2 polypeptide in the host and then recovering the expressed polypeptide.
In accordance with another object the invention there are provided products, compositions, processes and methods that utilize the aforementioned polypeptides and polynucleotides for research, biological, clinical and therapeutic purposes, inter alia.
In accordance with certain preferred embodiments of this aspect of the invention, there are provided products, compositions and methods, inter alia, for, among other things: assessing CK&agr;-2 expression in cells by determining CK&agr;-2 polypeptides or CK&agr;-2-encoding mRNA; assaying genetic variation and aberrations, suc
Gentz Reiner L.
Li Haodong
Ni Jian
Su Jeffrey Y.
Brannock Michael
Eyler Yvonne
Human Genome Sciences Inc.
Human Genome Sciences Inc.
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