Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
1997-03-05
2001-10-09
Duffy, Patricia A. (Department: 1645)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S252300, C435S252330, C435S254110, C435S320100, C435S325000, C530S324000, C530S350000, C536S023500
Reexamination Certificate
active
06300093
ABSTRACT:
BACKGROUND OF THE INVENTION
Insulin-dependent diabetes mellitus (IDDM) is a disease resulting from the autoimmune destruction of the insulin-producing &bgr;-cells of the pancreas. Studies directed at identifying the autoantigen(s) responsible for &bgr;-cell destruction have generated several candidates, including poorly characterized islet cell antigens (ICA) (Bottazzo et al.,
Lancet
2: 1279-83, 1974), insulin (Palmer et al.,
Science
222: 1337-39, 1983), glutamic acid decarboxylase (GAD) (Baekkeskov et al.,
Nature
298: 167-69, 1982; Baekkeskov et al.,
Nature
347: 151-56, 1990), and a 64 kD islet cell antigen that is distinct from GAD and that which yields 37 kD and 40 kD fragments upon trypsin-digestion (Christie et al.,
Diabetes
41: 782-87, 1992).
Detection of specific autoantigens in prediabetic individuals has been used as a predictive marker to identify, before clinical onset and significant &bgr;-cell loss has occurred, those at greater risk of developing IDDM (Gorsuch et al.,
Lancet
2: 1363-65, 1981; Baekkeskov et al.,
J. Clin. Invest
. 79: 926-34, 1987; Johnstone et al.,
Diabetologia
32: 382-86, 1989; Ziegler et al.,
Diabetes
38: 1320-25, 1989; Baekkeskov et al.,
Nature
(Lond) 347: 151-56, 1990; Bonifacio et al.,
Lancet
335: 147-49, 1990; and Bingley et al.
Diabetes
43: 1304-10, 1994).
Antibodies to the 40 kD, and more particularly the 37 kD, ICA fragments are detected when clinical onset of IDDM is imminent and are found to be closely associated with IDDM development (Christie et al.,
Diabetes
41: 782-87, 1992). Diabetic sera containing antibodies specific to the 40 kD fragment were recently found to bind to the intracellular domain of the protein tyrosine phosphatase, IA-2/ICA512 (Lu et al.,
Biochem. Biophys. Res. Comm
. 204: 930-36, 1994; Lan et al.,
DNA Cell Biol
. 13: 505-14, 1994; Rabin et al.,
J. Immunol
. 152: 3183-88, 1994; Payton et al.,
J. Clinc. Invest
. 96: 1506-11, 1995; and Passini et al.,
Proc. Natl. Acad. Sci. USA
92: 9412-16, 1995). Antibodies specific to the 37 kD fragment are thought to bind either to a posttranslational in vivo modification of IA-2/ICA512 or a different, but probably related, protein precursor (Passini et al., ibid.).
ICA 512 was initially isolated as an autoantigen from an islet cell cDNA library, and was subsequently shown to be related to the receptor-linked protein tyrosine phosphatase family (Rabin et al., ibid.). ICA 512 was later found to be identical to a mouse and human protein tyrosine phosphatase, IA-2, isolated from brain and insulinoma cDNA libraries (Lu et al., ibid.; and Lan et al., ibid.).
Detection of diabetes-associated autoantigens, especially combinations of autoantigens, genotypes, such as HLA DR and HLA DQ, and loci, such as the polymorphic region in the 5′ flanking region of the insulin gene; in prediabetic individuals have been shown to be useful predictive markers of IDDM, see for example, Bell et al., (
Diabetes
33:176-83, 1984); Sheehy et al., (
J. Clin. Invest
. 83:830-35, 1989); and Bingley et al., (
Diabetes
43: 1304-10, 1994). There is therefore a need in the art for autoantigens that would serve to improve detection and diagnosis of IDDM. The present invention fulfills this need by providing novel autoantigens as well as related compositions and methods. The autoantigens of the present invention represent a new &bgr;-cell antigen. The present invention also provides other, related advantages.
SUMMARY OF THE INVENTION
The present invention provides an isolated polynucleotide which forms an immune complex with an autoantibody from a patient at risk of or predisposed to develop IDDM, comprising a DNA segment encoding a mammalian islet cell antigen polypeptide of SEQ ID NO:16 from Leu, amino acid residue 636 to Gln, amino acid residue 1012. The invention also provides a mammalian islet cell antigen polypeptide of SEQ ID NO:22 from Leu, amino acid residue 442 to Gln, amino acid residue 818. The invention also provides allelic variants of these polypeptides. Within one aspect of the invention, the isolated polynucleotide encodes a mammalian islet cell antigen polypeptide of SEQ ID NO:22 from Phe, amino acid residue 418, to Gln, amino acid residue 818. Within another aspect of the invention, the isolated polynucleotide encodes a mammalian islet cell antigen polypeptide of SEQ ID NO:16 from Phe, amino acid residue 612, to Gln, amino acid residue 1012. The invention further provides allelic variants of these polypeptides. Within another aspect, the isolated polynucleotide encoding a polypeptide of SEQ ID NO:16 from Ala, amino acid residue 1, to Gln, amino acid residue 1012. Within another aspect, the isolated polynucleotide encoding a polypeptide of SEQ ID NO:22 from His, amino acid residue 1, to Gln, amino acid residue 818. The invention further provides allelic variants of these polypeptides. Within another aspect, the isolated polynucleotide is a DNA molecule comprising a coding sequence corresponding to SEQ ID NO:21 from nucleotide 1325 to nucleotide 2455. In still another aspect, the DNA molecule comprises a coding sequence corresponding to SEQ ID NO:15 from nucleotide 1909 to nucleotide 3039. The invention also provides allelic variants of these molecules. The invention further provides complements of polynucleotide molecules which specifically hybridize to these molecules. In yet another aspect, the isolated polynucleotide is a DNA molecule comprising a coding sequence corresponding to SEQ ID NO:21 from nucleotide 1253 to nucleotide 2455. Within another aspect, the isolated polynucleotide is a DNA molecule comprising a coding sequence corresponding to SEQ ID NO:15 from nucleotide 1837 to nucleotide 3039. The invention also provides allelic variants of these molecules. The invention further provides complements of polynucleotide molecules which specifically hybridize to these molecules. In still another aspect, the DNA molecule comprises a coding sequence corresponding to SEQ ID NO:15 from nucleotide 4 to nucleotide 3039. In still another aspect, the DNA molecule comprises a coding sequence corresponding to SEQ ID NO:21 from nucleotide 2 to nucleotide 2455. The invention also provides allelic variants of these molecules. The invention further provides complements of polynucleotide molecules which specifically hybridize to these molecules. The invention also provides an isolated polynucleotide molecule which encodes a complete coding sequence of a mammalian islet cell antigen polypeptide comprising the sequence of SEQ ID NO:22 from Leu, amino acid residue 442 to Arg, amino acid residue 738. The invention also provides mammalian islet cell antigens that are primate islet cell antigens.
The invention also provides DNA constructs comprising a first DNA segment encoding a human islet cell antigen polypeptide operably linked to additional DNA segments required for the expression of the first DNA segment. The invention further provides a first DNA segment that is an isolated polynucleotide molecule encoding a human islet cell antigen polypeptide comprising the amino acid sequence of SEQ ID NO:22 from Leu, amino acid residue 442 to Gln, amino acid residue 818. The invention also provides a first DNA segment that is an isolated polynucleotide molecule encoding a human islet cell antigen polypeptide comprising the amino acid sequence of SEQ ID NO:22 from Leu, amino acid residue 442 to Gln, amino acid residu 818. Within another aspect, the invention provides a first DNA segment that is an isolated polynucleotide molecule encoding a human islet cell antigen polypeptide comprising the amino acid sequence of SEQ ID NO:22 from His, amino acid residue 1, to Gln, amino acid residue 818. The invention further provides host cells containing such DNA constructs, as well as methods for producing human islet cell antigen polypeptides comprising the steps of culturing such host cell and isolating the human islet cell antigen polypeptide.
The invention further provides isolated mammalian islet cell antigen polypeptides, wherein said isolated mammalian islet cell antigen polypeptide forms
Hagopian William A.
Jelinek Laura J.
Kindsvogel Wayne
LaGasse James M.
Sheppard Paul O.
Duffy Patricia A.
Lingenfelter Susan E.
ZymoGenetics Inc.
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