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Title:  Human thyroid protein ZSIG45

United States Patent:  6,500,925

Issued:  December 31, 2002

Inventors:  Deisher; Theresa A. (Seattle, WA); Sheppard; Paul O. (Redmond, WA)

Assignee:  ZymoGenetics, Inc. (Seattle, WA)

Appl. No.:  522980

Filed:  March 10, 2000

Abstract

The present invention relates to polynucleotide and polypeptide molecules for zsig45, a novel human protein expressed in thyroid. The polypeptides, and polynucleotides encoding them, may be used for detecting human disease states and chromosomal abnormalities, and as a therapeutic. The present invention also includes antibodies to the zsig45 polypeptides.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides, an isolated polynucleotide that encodes a polypeptide comprising a sequence of amino acid residues that is at least 90% identical to an amino acid sequence selected from the group consisting of: (a) the amino acid sequence as shown in SEQ ID NO:2 from amino acid number 47 (Lys) to amino acid number 114 (Asp) of SEQ ID NO:2; (b) the amino acid sequence as shown in SEQ ID NO:4 from amino acid number 1 (Met) to amino acid number 85 (Asp); (c) the amino acid sequence as shown in SEQ ID NO:3 from amino acid number 1 (Met) to amino acid number 89 (Asp); (d) the amino acid sequence as shown in SEQ ID NO:2 from amino acid residue number 1 (Met) to amino acid residue number 114 (Asp). In one embodiment, the present invention provides an isolated polynucleotide molecule selected from the group consisting of: (a) polynucleotide molecules comprising a nucleotide sequence as shown in SEQ ID NO:1 from nucleotide 219 to nucleotide 422; (b) polynucleotide molecules comprising a nucleotide sequence as shown in SEQ ID NO:1 from nucleotide 168 to nucleotide 422; (c) polynucleotide molecules comprising a nucleotide sequence as shown in SEQ ID NO:1 from nucleotide 156 to nucleotide 422; (d) polynucleotide molecules comprising a nucleotide sequence as shown in SEQ ID NO:1 from nucleotide 82 to nucleotide 422; and (e) polynucleotide molecules complementary to (a), (b), (c), or (d). In another embodiment, the polynucleotide disclosed above comprises nucleotide 1 to nucleotide 342 of SEQ ID. NO:15. In another embodiment, the polynucleotide disclosed above consists of a sequence of amino acid residues that is at least 90% identical the amino acid sequence as shown in SEQ ID NO:2 from amino acid number 47 (Lys) to amino acid number 114 (Asp) of SEQ ID NO:2. In another embodiment, the polynucleotide disclosed above consists of a sequence of amino acid residues that is as shown in SEQ ID NO:2 from amino acid number 47 (Lys) to amino acid number 114 (Asp) of SEQ ID NO:2. In another embodiment, the polynucleotide disclosed above encodes a polypeptide, wherein the polypeptide contains motifs 1 through 5.

In a second aspect, the present invention provides an expression vector comprising the following operably linked elements: a transcription promoter; a DNA segment encoding a zsig45 polypeptide that is 90% identical to and amino acid sequence as shown in SEQ ID NO:2 from amino acid number 47 (Lys) to amino acid number 114 (Asp) of SEQ ID NO:2; and a transcription terminator. In one embodiment, the expression vector disclosed above further comprises a secretory signal sequence operably linked to the DNA segment. In another embodiment, the expression vector disclosed above comprises a secretory signal sequence selected from the group consisting of: (a) amino acids 1 through 46 of SEQ ID NO:2; (b) amino acids 1 through 21 of SEQ ID NO:3; and (c) amino acids 1 through 17 of SEQ ID NO:4.

In a third aspect, the present invention provides a cultured cell into which has been introduced an expression vector as disclosed above, wherein the cell expresses a polypeptide encoded by the DNA segment.

In a fourth aspect, the present invention provides a DNA construct encoding a fusion protein, the DNA construct comprising: a first DNA segment encoding a polypeptide that is at least 90% identical to a sequence of amino acids selected from the group consisting of: (a) amino acids 1 through 46 of SEQ ID NO:2; (b) amino acids 1 through 21 of SEQ ID NO:3; and (c) amino acids 1 through 17 of SEQ ID NO:4;and a second DNA segment encoding an additional polypeptide, wherein the first and second DNA segments are connected in-frame; and encode the fusion protein.

In another aspect, the present invention provides an isolated polypeptide comprising a sequence of amino acid residues that is at least 90% identical to an amino acid sequence selected from the group consisting of: (a) the amino acid sequence as shown in SEQ ID NO:2 from amino acid number 47 (Lys) to amino acid number 114 (Asp) of SEQ ID NO:2; (b) the amino acid sequence as shown in SEQ ID NO:4 from amino acid number 1 (Met) to amino acid number 85 (Asp); (c) the amino acid sequence as shown in SEQ ID NO:3 from amino acid number 1 (Met) to amino acid number 89 (Asp); (d) the amino acid sequence as shown in SEQ ID NO:2 from amino acid residue number 1 (Met) to amino acid residue number 114 (Asp). In one embodiment, the isolated polypeptide disclosed above consists of a sequence of amino acid residues that is at least 90% identical to an amino acid sequence as shown in SEQ ID NO:2 from amino acid number 47 (Lys) to amino acid number 114 (Asp). In another embodiment, the isolated polypeptide disclosed above is as shown in SEQ ID NO:2 from amino acid number 47 (Lys) to amino acid number 114 (Asp). In another embodiment, the isolated polypeptide disclosed above contains motifs 1 through 5.

In another aspect, the present invention provides, a method of producing a zsig45 polypeptide comprising: culturing a cell into which has been introduced an expression vector as disclosed above; and isolating the zsig45 polypeptide produced by the cell.

In another aspect, the present invention provides, a method of producing an antibody to zsig45 polypeptide comprising: inoculating an animal with a polypeptide selected from the group consisting of: (a) a polypeptide consisting of 9 to 67 amino acids, wherein the polypeptide is at least 90% identical to a contiguous sequence of amino acids in SEQ ID NO:2 from amino acid number 47 (Lys) to amino acid number 114 (Asp); and (b) a polypeptide consisting of the amino acid sequence of SEQ ID NO:2 from amino acid number 47 (Lys) to amino acid number 114 (Asp); and wherein the polypeptide elicits an immune response in the animal to produce the antibody; and isolating the antibody from the animal.

In another aspect, the present invention provides, an antibody produced by the method disclosed above, which binds to a zsig45 polypeptide. In one embodiment, the antibody disclosed above is a monoclonal antibody. In another aspect, the present invention provides, an antibody which binds to a polypeptide disclosed above.

In another aspect, the present invention provides, a method of detecting, in a test sample, the presence of an antagonist of zsig45 protein activity, comprising: transfecting a zsig45-responsive cell, with a reporter gene construct that is responsive to a zsig45-stimulated cellular pathway; and producing a zsig45 polypeptide by the method disclosed above; and adding the zsig45 polypeptide to the cell, in the presence and absence of a test sample; and comparing levels of response to the zsig45 polypeptide, in the presence and absence of the test sample, by a biological or biochemical assay; and determining from the comparison, the presence of the antagonist of zsig45 activity in the test sample.

In another aspect, the present invention provides, a method of detecting, in a test sample, the presence of an agonist of zsig45 protein activity, comprising: transfecting a zsig45-responsive cell, with a reporter gene construct that is responsive to a zsig45-stimulated cellular pathway; and adding a test sample; and comparing levels of response in the presence and absence of the test sample, by a biological or biochemical assay; and determining from the comparison, the presence of the agonist of zsig45 activity in the test sample.

Claim 1 of 12 Claims

What is claimed is:

1. An isolated polypeptide comprising a sequence of amino acid residues selected from the group consisting of:

(a) the amino acid sequence as shown in SEQ ID NO:2 from amino acid number 47 (Lys) to amino acid number 114 (Asp) of SEQ ID NO:2;

(b) the amino acid sequence as shown in SEQ ID NO:4 from amino acid number 1 (Met) to amino acid number 85 (Asp);

(c) the amino acid sequence as shown in SEQ ID NO:3 from amino acid number 1 (Met) to amino acid number 89 (Asp); and

(d) the amino acid sequence as shown in SEQ ID NO:2 from amino acid residue number 1 (Met) to amino acid residue number 114 (Asp).
 


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