Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
1999-03-03
2001-02-06
Housel, James C. (Department: 1641)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C530S387100, C530S388100, C435S007100, C435S007900, C435S007920, C435S971000, C424S130100, C424S134100, C424S139100, C424S141100, C424S156100
Reexamination Certificate
active
06184357
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to nucleic acid and amino acid sequences of a novel prostate-specific kallikrein and to the use of these sequences in the diagnosis, prevention, and treatment of disorders of the prostate, including cancer and benign hyperplasia.
BACKGROUND OF THE INVENTION
Prostate-specific antigen (PSA) is a 33 kD glycoprotein synthesized in the epithelial cells of the prostate gland. It is a secreted serine protease of the kallikrein family. PSA has been shown to digest the seminal vesicle protein, semenogelin, parathyroid hormone-related protein, and insulin-like growth factor-binding protein-3 (Henttu P. et al. (1994) Ann. Med. 26: 157-164; Cramer S. D. et al. (1996) J. Urol. 156: 526-531). PSA is likely to act in semen production, but may have additional functions.
Genes encoding the three human kallikreins, tissue kallikrein (KLK1), glandular kallikrein (KLK2), and APS are located in a cluster at chromosome map position 19q13.2-q13.4 (Riegmen P. H. (1992) Genomics 14: 6-11). PSA shares more extensive homology with KLK2 than with KLK1. Both PSA and KLK2 are produced by prostate epithelial cells and their expression is regulated by androgens. Three amino acid residues were found to be critical for serine protease activity, residues H
65
, D
120
, and S
213
in PSA (Bridon D. P. et al. (1995) Urology 45: 801-806). Substrate specificity, described as chymotrypsinogen-like (with KLK2) or trypsin-like (with PSA) is thought to be determined by S
207
in PSA and D
209
in KLK2 (Bridon et al., supra). KLK1 is chymotrypsinogen-like and expressed in the pancreas, urinary system, and sublingual gland. KLK1, like the other kallikreins, is made as a pre-pro-protein and is processed into an active form of 238 amino acids by cleavage of a 24 amino acid terminal signal sequence (Fukushima D. et al. (1985) Biochemistry 24: 8037-8043).
Adenocarcinoma of the prostate accounts for a significant number of malignancies in men over 50. There are over 122,000 new cases per year in the United States. Prostate-specific antigen (PSA) is the most sensitive marker available for monitoring cancer progression and response to therapy. Serum PSA is elevated in 25 to 92% of patients with prostatic carcinoma, depending upon tumor volume. Since PSA is also moderately elevated in patients with benign prostate hyperplasia, additional techniques are needed to distinguish between the two.
The discovery of polynucleotides encoding additional prostate specific molecules, and the molecules themselves, presents the opportunity to investigate disorders of the prostate, including benign hyperplasia and prostatic carcinoma. Discovery of molecules related to PSA satisfies a need in the art by providing new compositions useful in diagnosis, treatment, and prognosis of prostate cancer and hyperplasia.
SUMMARY OF THE INVENTION
The present invention features a novel prostate-specific kallikrein hereinafter designated HPSK and characterized as having chemical and structural similarity to KLK1.
Accordingly, the invention features a substantially purified HPSK which has the amino acid sequence shown in SEQ ID NO:1.
One aspect of the invention features isolated and substantially purified polynucleotides that encode HPSK. In a particular aspect, the polynucleotide is the nucleotide sequence of SEQ ID NO:2.
The invention also relates to a polynucleotide sequence comprising the complement of SEQ ID NO:2 or variants thereof. In addition, the invention features polynucleotide sequences which hybridize under stringent conditions to SEQ ID NO:2.
The invention additionally features nucleic acid sequences encluding polypeptides, oligonucleotides, peptide nucleic acids (PNA), fragments, portions or antisense molecules thereof, and expression vectors and host cells comprising polynucleotides that enclode HPSK. The present invention also features antibodies which bind specifically to HPSK, and pharmaceutical compositions comprising substantially purified HPSK. The invention also features the use of agonists and antagonists of HPSK.
REFERENCES:
patent: 5516639 (1996-05-01), Tindall et al.
patent: 5786148 (1998-07-01), Bandman et al.
patent: 5840871 (1998-11-01), Hillman et al.
patent: 5922321 (1999-07-01), Bandman et al.
Bridon, D.P. et al., “Structural Comparison of Prostate-Specific Antigen and Human Glandular Kallikrein Using Molecular Modeling”Urology45:801-806.
Christensson, A. et al., “Enzymatic activity of prostate-specific antigen and its reactions with extracelluar serine proteinase inhibitors”Eur. J. Biochem.194:755-763 (1990).
Cramer S.D. et al., “Prostate specific antigen cleaves parathyroid hormone-related protein in the PTH-like domain: inactivation of PTHrP-stimulated cAMP accumulation in mouse osteoblasts”J. Urol.156:526-531 (1996).
Evans B.A. et al., “Structure and chromosol localization of the human renal kallikrein gene”Biochemistry27:3124-3129 (1988) (Accession GI 186651).
Fukushima, D. et al., “Nucleotide sequence of cloned cDNA for human pancreatic kallikrein”Biochemistry24:8037-8043 (1985).
Henttu P. et al., “Prostate-specific antigen and human glandular kallikrein: two kallikreins of the human prostate”Ann. Med.26:157-164 (1994).
Lundwall, A. “Characterization of the gene for prostate-specific antigen, a human gladular kallikrein”Biochem Biophys Res Commun161:1151-1159 (1989) (Accession GI 190553).
Perelygina, et al., (Direct Submission), GenBank Sequence Database Accession GI 871814), National Center for Biotechnology Information, National Library of Medicine, Bethesda, Maryland 20894.
Riegman, P.H. et al., “Characterization of the human kallikrein locus”Genomics14:6-11 (1992).
Bandman Olga
Goli Surya K.
Devi S.
Housel James C.
Incyte Pharmaceuticals Inc.
Incyte Pharmaceuticals, Inc.
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