Drug – bio-affecting and body treating compositions – Lymphokine
Reexamination Certificate
2000-08-11
2002-11-26
Mertz, Prema (Department: 1646)
Drug, bio-affecting and body treating compositions
Lymphokine
C514S002600, C514S008100, C514S012200, C435S069500, C435S071100, C435S071200, C435S471000, C435S325000, C435S320100, C435S252300
Reexamination Certificate
active
06485719
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel chemokine polypeptides and encoding nucleic acids. More specifically, therapeutic compositions and methods are provided using isolated nucleic acid molecules encoding a human chemokine beta-11 (Ck beta-11) polypeptide; and a human leukocyte adhesion inhibitor (LAI-1) polypeptide (previously termed chemokine &agr;1(CK&agr;1 or cka-1)), as well as Ck beta-11 and/or LAI-1 polypeptides themselves, as are vectors, host cells and recombinant methods for producing the same.
2. Related Art
Chemokines, also referred to as intercrine cytokines, are a subfamily of structurally and functionally related 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-8 (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 can 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.
SUMMARY OF THE INVENTION
In accordance with one aspect of the present invention, there are provided novel full length or mature polypeptides which are LAI-1 and/or Ck beta-11, as well as biologically active, diagnostically useful or therapeutically useful fragments, analogs and derivatives thereof. LAI-1 and/or Ck beta-11 polypeptides or encoding nucleic acids of the present invention are preferably of animal origin, and more preferably of human origin.
In accordance with another aspect of the present invention there are provided nucleic acid probes comprising nucleic acid molecules of sufficient length to specifically hybridize to Ck&bgr;-11 and LAI-2 sequences.
In accordance with another aspect of the present invention, there are provided polynucleotides (DNA or RNA) which encode such polypeptides and isolated nucleic acid molecules encoding such polypeptides, including mRNAs, DNAs, cDNAs, genomic DNA as well as biologically active and diagnostically or therapeutically useful fragments, analogs and derivatives thereof.
Ck beta-11 Polynucleotides. The present invention also provides isolated nucleic acid molecules comprising a polynucleotide encoding the Ck beta-11 polypeptide having the amino acid sequence shown in
FIG. 1
(SEQ ID NO:2) or the amino acid sequence encoded by the cDNA clone deposited in a bacterial host as ATCC Deposit Number 75948 on Nov. 11, 1994. The nucleotide sequence determined by sequencing the deposited Ck beta-11 clone, which is shown in
FIG. 1
(SEQ ID NO: 1), contains an open reading frame encoding a polypeptide of 98 amino acid residues, with a leader sequence of about 17 amino acid residues, and a predicted molecular weight for the mature protein of about 10 kDa in non-glycosylated form, and about 10-14 kDa in glycosylated form, depending on the extent of glycoslyation. The amino acid sequence of the mature Ck beta-11 protein is shown in
FIG. 1
, as amino acid residues 18-98 of SEQ ID NO:2.
Thus, one aspect of the invention provides an isolated nucleic acid molecule comprising a polynucleotide having a nucleotide sequence selected from the group consisting of: (1)(a) a nucleotide sequence encoding an Ck beta-11 polypeptide having the complete amino acid sequence in
FIG. 1
(SEQ ID NO:2); (1)(b) a nucleotide sequence encoding the mature Ck beta-11 polypeptide having the amino acid sequence at positions 18-98 in
FIG. 1
(SEQ ID NO:2); (1)(c) a nucleotide sequence encoding the Ck beta-11 polypeptide having the complete amino acid sequence encoded by the cDNA clone contained in ATCC Deposit No. 75948; (1)(d) a nucleotide sequence encoding the mature Ck beta-11 polypeptide having the amino acid sequence encoded by the cDNA clone contained in ATCC Deposit No. 75948; and (1)(e) a nucleotide sequence complementary to any of the nucleotide sequences in (1)-(a), (b), (c) or (d) above.
LAI-1 Polynucleotides. In one aspect, the present invention provides isolated nucleic acid molecules comprising a polynucleotide encoding the LAI-1 polypeptide having the amino acid sequence shown in
FIG. 2
(SEQ ID NO:4) or the amino acid sequence encoded by the cDNA clone deposited in a bacterial host as ATCC Deposit Number 75947 on Nov. 11, 1994. The nucleotide sequence determined by sequencing the deposited LAI-1 clone, which is shown in
FIG. 2
(SEQ ID NO:3), contains an open reading frame encoding a polypeptide of 109 amino acid residues, with a leader sequence of about 22 amino acid residues, and a predicted molecular weight of about 110 kDa in non-glycosylated form, and about 11-14 kDa in glycosylated form, depending on the extent of glycoslyation. The amino acid sequence of the mature LAI-1 protein is shown in
FIG. 2
, as amino acid residues 23-109 of SEQ ID NO:4.
Thus, one aspect of the invention provides an isolated nucleic acid molecule comprising a polynucleotide having a nucleotide sequence selected from the group consisting of: (2)(a) a nucleotide sequence encoding the LAI-1 polypeptide having the complete amino acid sequence in
FIG. 2
(SEQ ID NO:4); (2)(b) a nucleotide sequence encoding the mature LAI-1 polypeptide having the amino acid sequence at positions 23-109 in
FIG. 2
(SEQ ID NO:4); (2)(c) a nucleotide sequence encoding the LAI-1 polypeptide having the complete amino acid sequence encoded by the cDNA clone contained in ATCC Deposit No. 75947; (2)(d) a nucleotide sequence encoding the mature LAI-1 polypeptide having the amino acid sequence encoded by the cDNA clone contained in ATCC Deposit No.75947; a
Kreider Brent L.
Li Haodong
Human Genome Sciences Inc.
Mertz Prema
Sterne Kessler Goldstein & Fox P.L.L.C.
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