Islet cell antigen 1851
AssigneeZymoGenetics, Inc.
InventorsWayne Kindsvogel, Laura J. Jelinek, Paul O. Sheppard, William A. Hagopian, James M. LaGasse
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Abstract
A mammalian islet cell antigen polypeptide involved in the development of insulin-dependent diabetes mellitus (IDDM) is disclosed. This islet cell antigen polypeptide, 1851, was found to contain regions of homology to the protein tyrosine phosphatase family. Methods for diagnosis and treatment, including use in immunoprecipitation assays and the induction of immune tolerance using the recombinant mammalian polypeptides and antibodies specific to mammalian islet cell antigen 1851 polypeptides are presented.
Claims48
An isolated polynucleotide comprising a DNA segment encoding a mammalian islet cell antigen polypeptide comprising an amino acid sequence selected from the group consisting of:
- a) a polypeptide of SEQ ID NO:16 from Leu, amino acid residue 636 to Gln, amino acid residue 1012:
- b) a polypeptide of SEQ ID NO:22 from Leu, amino acid residue 442 to Gln, amino acid residue 818;
- and
- c) allelic variants of (a) or (b)
- wherein the polypeptide forms an immune complex with an autoantibody from a patient at risk of or predisposed to develop IDDM.
A DNA construct comprising a first DNA segment encoding a human islet cell antigen polypeptide operably linked to additional DNA segments required for the expression of said first DNA segment, wherein said first DNA segment encodes a human islet cell antigen polypeptide comprising an amino acid sequence selected from the group consisting of:
- a) SEQ ID NO:22 from Leu, amino acid residue 442 to Gln, amino acid residue 818;
- b) SEQ ID NO:22 from Phe, amino acid residue 418, to Gln, amino acid residue 818;
- c) a polypeptide of SEQ ID NO:22 from His, amino acid residue 1, to Gln, amino acid residue 818;
- and
- d) allelic variants of (a), (b) or (c)
- wherein said mammalian islet cell antigen polypeptide forms an immune complex with an autoantibody from a patient at risk of or predisposed to develop IDDM.
A host cell containing a DNA construct comprising a first DNA segment encoding a mammalian islet cell antigen polypeptide operably linked to additional DNA segments required for the expression of said first DNA segment, wherein said first DNA segment encodes a human islet cell antigen polypeptide comprising an amino acid sequence selected from the group consisting of:
- a) SEQ ID NO:22 from Leu, amino acid residue 442 to Gln, amino acid residue 818;
- b) SEQ ID NO:22 from Phe, amino acid residue 418, to Gln, amino acid residue 818;
- c) a polypeptide of SEQ ID NO:22 from His, amino acid residue 1, to Gln, amino acid residue 818;
- and
- d) allelic variants of (a), (b) or (c)
- wherein said mammalian islet cell antigen polypeptide forms an immune complex with an autoantibody from a patient at risk of or predisposed to develop IDDM.
An isolated mammalian islet cell antigen polypeptide comprising an amino acid sequence selected from the group consisting of:
- a) SEQ ID NO:22 from Leu, amino acid residue 442 to Gln, amino acid residue 818;
- b) SEQ ID NO:22 from Phe, amino acid residue 418, to Gln, amino acid residue 818;
- c) a polypeptide of SEQ ID NO:22 from His, amino acid residue 1, to Gln, amino acid residue 818;
- and
- d) allelic variants of (a), (b) or (c)
- wherein said mammalian islet cell antigen polypeptide forms an immune complex with an autoantibody from a patient at risk of or predisposed to develop IDDM.
A method for producing a mammalian islet cell antigen polypeptide comprising the steps of:
- culturing a host cell containing a DNA construct comprising a first DNA segment operably linked to additional DNA segments required for the expression of said first DNA segment, wherein said first DNA segment encodes a human islet cell antigen polypeptide comprising an amino acid sequence selected from the group consisting of:
- a) SEQ ID NO:22 from Leu, amino acid residue 442 to Gln, amino acid residue 818;
- b) SEQ ID NO:22 from Phe, amino acid residue 418, to Gln, amino acid residue 818;
- c) a polypeptide of SEQ ID NO:22 from His, amino acid residue 1, to Gln, amino acid residue 818;
- and
- d) allelic variants of (a), (b) or (c)
- wherein said mammalian islet cell antigen polypeptide forms an immune complex with an autoantibody from a patient at risk of or predisposed to develop IDDM;
- and
- isolating said mammalian islet cell antigen polypeptide.
A method for determining the presence of an autoantibody to a human islet cell antigen polypeptide in a biological sample comprising the steps of:
- contacting a biological sample with a human islet cell antigen polypeptide comprising an amino acid sequence selected from the group consisting of:
- a) SEQ ID NO:22 from Leu, amino acid residue 442 to Gln, amino acid residue 818;
- b) SEQ ID NO:22 from Phe, amino acid residue 418, to Gln, amino acid residue 818;
- c) a polypeptide of SEQ ID NO:22 from His, amino acid residue 1, to Gln, amino acid residue 818;
- and
- d) allelic variants of (a), (b) or (c),
- under conditions conducive to immune complex formation, and
- detecting the presence of immune complex formation between said human islet cell antigen polypeptide and said autoantibody to a human islet cell antigen, thereby determining the presence of an autoantibody to said human islet cell antigen in said biological sample.
A method for predicting the clinical course of IDDM in a patient comprising:
- testing a biological sample from a patient for the presence of human islet cell antigen polypeptide comprising an amino acid sequence selected from the group consisting of:
- a) SEQ ID NO:22 from Leu, amino acid residue 442 to Gln, amino acid residue 818;
- b) SEQ ID NO:22 from Phe, amino acid residue 418, to Gln, amino acid residue 818;
- c) a polypeptide of SEQ ID NO:22 from His, amino acid residue 1, to Gln, amino acid residue 818;
- and
- d) allelic variants of (a), (b) or (c), wherein said polypeptide forms an immune complex with an autoantibody from a patient at risk of or predisposed to develop IDDM and
- classifying said patient for clinical course of diabetes based on the presence or absence of mammalian islet cell antigen polypeptides in said sample.
A method of treating a patient to prevent an autoimmune response to a human islet cell antigen polypeptide, the method comprising inducing immunological tolerance in said patient by administering a human islet cell antigen polypeptide comprising an amino acid sequence selected from the group consisting of:
- a) SEQ ID NO:22 from Leu, amino acid residue 442 to Gln, amino acid residue 818;
- b) SEQ ID NO:22 from Phe, amino acid residue 418, to Gln, amino acid residue 818;
- c) a polypeptide of SEQ ID NO:22 from His, amino acid residue 1, to Gln, amino acid residue 818;
- and
- d) allelic variants of (a), (b) or (c),
- that specifically binds a human islet cell antigen receptor on immature or mature T or B lymphocytes.
A probe which comprises an oligonucleotide of at least about 16 nucleotides, wherein said oligonucleotide is at least 85% identical to a sequence of the human islet cell antigen DNA sequence of SEQ ID NOs:
- 15 or 21.
An isolated antibody which specifically binds to a human islet cell antigen polypeptide, wherein said human islet cell antigen polypeptide comprising an amino acid sequence selected from the group consisting of:
- a) SEQ ID NO:22 from Leu, amino acid residue 442 to Gln, amino acid residue 818;
- b) SEQ ID NO:22 from Phe, amino acid residue 418, to Gln, amino acid residue 818;
- c) a polypeptide of SEQ ID NO:22 from His, amino acid residue 1, to Gln, amino acid residue 818;
- and
- d) allelic variants of (a), (b) or (c).
A hybridoma which produces a monoclonal antibody which specifically binds to a human islet cell antigen polypeptide, wherein said human islet cell antigen polypeptide comprises an amino acid sequence selected from the group consisting of:
- a) SEQ ID NO:22 from Leu, amino acid residue 442 to Gln, amino acid residue 818;
- b) SEQ ID NO:22 from Phe, amino acid residue 418, to Gln, amino acid residue 818;
- c) a polypeptide of SEQ ID NO:22 from His, amino acid residue 1, to Gln, amino acid residue 818;
- and
- d) allelic variants of (a), (b) or (c).
A diagnostic kit for use in detecting an autoantibody to pancreatic β-islet cells, comprising a container containing a human islet cell antigen polypeptide wherein said human islet cell antigen polypeptide comprises an amino acid sequence selected from the group consisting of:
- a) SEQ ID NO:22 from Leu, amino acid residue 442 to Gln, amino acid residue 818;
- b) SEQ ID NO:22 from Phe, amino acid residue 418, to Gln, amino acid residue 818;
- c) a polypeptide of SEQ ID NO:22 from His, amino acid residue 1, to Gln, amino acid residue 818;
- and
- d) allelic variants of (a), (b) or (c),
- wherein said polypeptide forms an immune complex with an autoantibody from a patient at risk of or predisposed to develop IDDM, and one or more containers containing additional reagents.
A pharmaceutical composition which comprises a human islet cell antigen polypeptide, wherein said human islet cell antigen polypeptide comprises an amino acid sequence selected from the group consisting of:
- a) SEQ ID NO:22 from Leu, amino acid residue 442 to Gln, amino acid residue 818;
- b) SEQ ID NO:22 from Phe, amino acid residue 418, to Gln, amino acid residue 818;
- c) a polypeptide of SEQ ID NO:22 from His, amino acid residue 1, to Gln, amino acid residue 818;
- and
- d) allelic variants of (a), (b) or (c), wherein said polypeptide forms an immune complex with an autoantibody from a patient at risk of or predisposed to develop IDDM in combination with a pharmaceutically acceptable carrier or vehicle.
A method for monitoring the disease state in a patient comprising:
- testing a biological sample from a patient for the presence of mammalian islet cell antigen post-translationally modified polypeptides;
- determining the concentration of said polypeptides;
- and
- correlating levels of said polypeptides in said sample with the disease state in a patient.
A method for monitoring the disease state in a patient comprising:
- exposing T cells to islet cell antigen 1851 peptides;
- detecting T cell reactivity;
- and
- correlating T cell reactivity with disease state.
Dependencies are inferred from the claim text.