Endogenous retrovirus polypeptides linked to oncogenic transformation

• US 20070037147A1
• Filed: 12/09/2002
• Published: 02/15/2007
• Est. Priority Date: 12/07/2001
• Status: Abandoned Application

• Current Assignee: Chiron Ocrporation
• Original Assignee: Chiron Ocrporation
• Inventors: Escobedo, Jaime, Garcia, Pablo, Hardy, Stephen, Williams, Lewis
• Application Number:
  US10/497,786
• Publication Number:
  US 20070037147A1
• Time in Patent Office: Days
• US Class Current: 435/6
• CPC Class Codes: A61K 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 14/005 from viruses
• CPC Class Codes: C12N 2740/10021 Viruses as such, e.g. new isolates, mutants or their genomic sequences
• CPC Class Codes: C12N 2740/10022 New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
• CPC Class Codes: C12N 7/00 Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00
• CPC Class Codes: C12Q 1/6886 for cancer immunoassay for cancer G01N33/574
• CPC Class Codes: C12Q 1/702 for retroviruses
• CPC Class Codes: C12Q 2600/136 Screening for pharmacological compounds
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: G01N 2333/15 Retroviridae, e.g. bovine leukaemia virus, feline leukaemia virus, feline leukaemia virus, human T-cell leukaemia-lymphoma virus
• CPC Class Codes: G01N 33/57434 of prostate

Abstract

HERV-K human endogenous retroviruses show up-regulated expression in tumors. In particular, splicing events in the env region generate a series of transcripts which utilise the +2 reading frame, relative to the env reading frame. The proteins show activity typical of transcriptional regulators, and they also have oncogenic potential. Two related proteins, PCAP2 and PCAP3, are strongly associated with breast cancer and prostate cancer, respectively. PCAP4 stimulates cell division. These proteins can be used in cancer diagnosis and therapy, and are also drug target e.g. for adjuvant therapy. The identification of these splice products is remarkable because full sequence information has been available for HERV-K viruses since 1986.

Claims

1. A method for diagnosing prostate cancer, the method comprising the step of detecting the presence or absence of a HML-2 expression product in a patient sample, wherein the expression product is produced by a splicing event in which the 5′

region and start codon of the env coding region are joined to a downstream coding region in the reading frame +2 relative to that of env.

2. The method of claim 1, wherein the patient sample is a prostate tissue sample, a breast tissue sample, or a blood sample.

3. The method of any preceding claim, wherein the expression product is a mRNA transcript or a polypeptide.

4. The method of any preceding claim, wherein the mRNA transcript comprises a sequence which has at least 50% sequence identity to one or more of SEQ IDs 19, 20, 21, 24, 25, 26, 38, 40, and/or 42.

5. The method of any preceding claim, wherein the mRNA transcript encodes a polypeptide having at least 50% sequence identity to one or more of SEQ IDs 7, 8, 9, 10, 11, 12, 28, 29, 30, 31, 34, 35, 36, 39, 41 43, 67, 68 and 69.

6. The method of any preceding claim, wherein the method comprises the step of extracting RNA from the patient sample.

7. The method of any preceding claim, wherein the expression product is detected by hybridization.

8. An isolated polynucleotide comprising:

(a) the nucleotide sequence of SEQ IDs 19, 20, 21, 24, 25, 26, 38, 40, 42, 51, 52, and 278 to 477 and/or 42;

(b) a fragment of at least 7 nucleotides of (a);

(c) a nucleotide sequence having at least 50% identity to (a);

or (d) the complement of (a), (b) or (c).

9. An isolated polypeptide encoded by a transcript produced by a splicing event in which the 5′

region and start codon of a HERV-K env coding region are joined to a downstream coding region in the reading frame +2 relative to that of env in the HERV-K genome.

10. The polypeptide of claim 9, comprising:

(a) an amino acid sequence selected from the group consisting of SEQ IDs 7, 8, 9, 10, 11, 12, 28, 29, 30, 31, 34, 35, 36, 39, 41, 43, 66, 67, 68 and 78 to 277;

(b) a fragment of at least 5 amino acids of (a);

or (c) a polypeptide sequence having at least 50% identity to (a).

11. The polypeptide of claim 10, wherein (b) the fragment comprises a T cell or a B cell epitope of one or more of SEQ IDs 7, 8, 9, 10, 11, 12, 28, 29, 30, 31, 34, 35, 36, 39, 41, 43, 66, 67, 68 and 78 to 277.

12. An isolated polynucleotide which encodes the polypeptide of claim 9, claim 10 or claim 11.

13. An antibody that binds to the polypeptide of claim 9, claim 10 or claim 11.

14. The antibody of claim 13, wherein the antibody is a monoclonal antibody.

16. The polynucleotide, polypeptide or antibody of any one of claims 8 to 15, for use as a pharmaceutical.

17. The use of polynucleotide, polypeptide or antibody of any one of claims 8 to 15, in the manufacture of a medicament for preventing or treating prostate cancer, breast cancer, testicular cancer, multiple sclerosis and/or insulin-dependent diabetes mellitus.

18. An immunogenic composition comprising the polypeptide of claim 9 or claim 10 or claim 11, and a pharmaceutically acceptable carrier.

19. The composition of claim 18, further comprising an adjuvant.

15. An isolated polypeptide which can bind to a protein comprising the amino acid sequence SEQ ID 7, 8 and/or 9 and which can prevent said protein acting as a transcriptional activator.