Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1998-03-06
2001-04-17
Schwartzman, Robert A. (Department: 1635)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S024300, C536S024330
Reexamination Certificate
active
06218523
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides polynucleotides encoding a prostate cancer-specific cDNA, proteins encoded by the polynucleotides, and methods of using these materials.
BACKGROUND OF THE INVENTION
The prostate is almost invariably the site of benign and malignant proliferative changes in aging males. Benign prostatic hypertrophy (BPH) is the most common non-malignant proliferative abnormality of internal organs. A high percentage of these age-related growth disorders develop into malignancies. As a result of this, adenocarcinoma of the prostate represents the most common malignancy in American males and is the second leading cause of cancer deaths in men.
A useful method in the diagnosis of prostate cancer is determining the level of prostate specific antigen (PSA) in the blood. PSA is a glycoprotein secreted by the prostate gland. However, the PSA test has limitations of sensitivity and selectivity: In general, levels above 4 ng/ml are suggestive of cancer and levels above 10 ng/ml are highly suggestive. However, many individuals with elevated levels do not have prostate cancer, but exhibit benign prostatic hypertrophy. Conversely, many persons with prostate cancer have normal PSA levels at the time of diagnosis. Therefore, prostate cancer markers with greater sensitivity and selectivity for prostate cancer would be usefull for, among other things, the diagnosis of prostate cancer.
SUMMARY OF THE INVENTION
A cDNA encoding a prostate cancer-specific marker, called Repro-PC-1.0, has been cloned and its nucleotide sequence determined. The nucleotide sequence of the cDNA and deduced amino acid sequence of Repro-PC-1.0 are presented as SEQ ID NO:1 and SEQ ID NO:2, respectively. Repro-PC-1.0 is expressed in prostate cancer cells and is useful as a marker in the detection of prostate cancer. Inhibition of Repro-PC-1.0 expression is useful in the prophylactic and therapeutic treatment of prostate cancer.
It also has been found that Repro-PC-1.0 expression is dependent on environment—cells from the prostate adenocarcinoma cell line, LNCaP, over-expresses Repro-PC-1.0 when propagated in male nude mice, but not when propagated in female nude mice. Repro-PC-1.0 has a significant level of amino acid sequence identity with the synaptotagmins. Therefore, it is believed that Repro-PC-1.0 functions in membrane fusion and membrane budding reactions.
Accordingly, the invention provides recombinant polynucleotide molecules comprising a nucleotide sequence encoding Repro-PC-1.0 polypeptide or Repro-PC-1.0. Repro-PC-1.0 peptides include native Repro-PC-1.0 (SEQ ID NO:2) and allelic variants of it. Repro-PC-1.0 analogs include active analogs, which have the biological activity of Repro-PC-1.0, inactive analogs, useful as decoys, and immunogenic analogs, that, when used as an immunogen, elicit an immune response against Repro-PC-1.0 or cells expressing it. In one embodiment, the recombinant polynucleotide molecule comprises a nucleotide sequence encoding at least 5 consecutive amino acids of Repro-PC-1.0 polypeptide (SEQ ID NO:1). In another embodiment the nucleotide sequence is substantially identical or identical to the nucleotide sequence of Repro-PC-1.0 (SEQ ID NO:1).
In one aspect this invention provides expression vectors comprising expression control sequences operatively linked to a nucleotide sequence encoding a Repro-PC-1.0 protein or an Repro-PC-1.0 analog.
In another aspect, this invention provides polynucleotide probes and primers of at least 7 nucleotides that specifically hybridize to a sequence selected from Repro-PC-1.0 cDNA (SEQ ID NO:1) or its complement.
In another aspect, this invention provides an inhibitory polynucleotide comprising an antisense sequence of at least 7 nucleotides that specifically hybridizes to a nucleotide sequence selected from Repro-PC-1.0 cDNA (SEQ ID NO:1) and that inhibits expression of Repro-PC-1.0 in cells.
In another aspect, this invention provides expression vectors comprising expression control sequences operably linked to a nucleotide sequence encoding Repro-PC-1.0 polypeptide, a Repro-PC-1.0 analog or a probe, primer or inhibitory polynucleotide of this invention.
In another aspect this invention provides recombinant cells into which have been introduced an expression vector comprising expression control sequences operatively linked to a nucleotide sequence encoding a Repro-PC-1.0 polypeptide or a Repro-PC-1.0 analog.
In another aspect, this invention provides a method for expressing Repro-PC-1.0 mRNA in a cell that has a nucleotide sequence encoding Repro-PC-1.0 comprising operably linking an expression control sequence to the nucleotide sequence. The nucleotide sequence can be, for example, a sequence within the animal's genomic DNA.
In another aspect, this invention provides methods for producing a Repro-PC-1.0 polypeptide or a Repro-PC-1.0 analog comprising culturing a recombinant cell that comprises a recombinant polynucleotide that comprises expression control sequences operably linked to a nucleotide sequence encoding the Repro-PC-1.0 polypeptide or Repro-PC-1.0 analog.
In another aspect, this invention provides methods for detecting a Repro-PC-1.0 polynucleotide in a sample, comprising the steps of (a) contacting the sample with a polynucleotide probe or primer comprising a sequence of at least 7 nucleotides that specifically hybridizes to a nucleotide sequence selected from Repro-PC-1.0 and (b) detecting whether the polynucleotide has specifically hybridized to the Repro-PC-1.0 polynucleotide. Specific hybridization provides a detection of Repro-PC-1.0 in the sample.
In another aspect this invention provides methods for inhibiting Repro-PC-1.0 expression in a cell comprising providing the cell with an inhibitory polynucleotide of the invention or with a polynucleotide that encodes an inactive decoy Repro-PC-1.0 analog.
In another aspect this invention provides purified, recombinant Repro-PC-1.0 protein, e.g. a protein whose amino acid sequence is identical to the sequence of SEQ ID NO:2 and allelic variants of it. The invention also provides Repro-PC-1.0 analogs whose amino acid sequence is not naturally occurring and is substantially identical to the amino acid sequence of Repro-PC-1.0 (SEQ ID NO:2). Such analogs include active analogs having the biological activity of Repro-PC-1.0, as well as immunogenic analogs, capable of eliciting the production of antibodies that recognize Repro-PC-1.0.
In another aspect, this invention provides antibodies that specifically bind to Repro-PC-1.0 polypeptide.
In another aspect, this invention provides methods for detecting a Repro-PC-1.0 polypeptide in a sample, comprising the steps of (a) contacting the sample with an antibody that specifically binds to the Repro-PC-1.0 polypeptide and (b) detecting specific binding between the antibody and Repro-PC-1.0 polypeptide. Specific binding provides a detection of Repro-PC-1.0 in the sample.
In another aspect, this invention provides methods for diagnosing, monitoring or making a prognosis for prostate cancer in a subject. The methods involve detecting Repro-PC-1.0 mRNA or polypeptide in a sample from the subject. In the diagnostic method, a diagnostic amount of Repro-PC-1.0 mRNA or Repro-PC-1.0 polypeptide in a sample from the subject is determined and the diagnostic amount is compared with a normal range of Repro-PC-1.0 mRNA or Repro-PC-1.0 polypeptide in a non-cancerous control sample. A diagnostic amount above the normal range provides a positive indication in the diagnosis of prostate cancer. The detection of an amount of Repro-PC-1.0 mRNA or polypeptide at a particular prognostic level provides a prognosis for the subject. Methods for monitoring the progress of prostate cancer involve detecting the amount of Repro-PC-1.0 mRNA or Repro-PC-1.0 polypeptide in the subject at a first and a second time, and comparing the amounts. A change in the amount indicates a change in the course of the disease, with a decreasing amount indicating remission of prostate cancer and increase indicating progression of the prostate cancer. One emb
French Cynthia K.
Schneider Patrick A.
Yamamoto Karen K.
Diagnostic Products Corporation
Mueth Joseph E.
Schmidt Mary M.
Schwartzman Robert A.
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