Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1999-01-14
2001-03-20
Huff, Sheela (Department: 1642)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S007230
Reexamination Certificate
active
06203999
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the field of cancer immunoassays. Specifically, provided is an immunoassay method for detection of the prostatic-specific antigen (PSA). The immunoassay of the present invention distinguishes between normal prostatic-specific antigen and abnormal prostatic-specific antigen, i.e., PSA that is related to the presence of a carcinoma of the prostate.
BACKGROUND OF THE INVENTION
Despite the widely accepted use of PSA as a marker for prostate cancer, this molecule has not yet been completely characterized. Past studies have established, however, using both amino acid and cDNA sequencing techniques, that PSA contains 237 amino acids, with a molecular mass of 26,079 Da for the peptide moiety of the molecule. The predominant PSA molecular species detected by ion spray mass spectrometry (ISMS) was at relative molecular mass of 28,430, indicating that PSA contains a carbohydrate residue having a molecular weight of 2,351 for a total weight percentage of carbohydrate of 8.3% (Belanger, A., et al.,
Prostate
, 27:187-197 (1995)). PSA is a kallikrein-like serine protease that is produced exclusively by the epithelial cells of all types of prostatic tissue, benign and malignant. Physiologically, it is present in the seminal fluid at high concentration and functions to cleave the high-molecular weight protein responsible for the seminal coagulum into smaller polypeptides. (Oesterling, J. E.,
J. Cell Biochem. Suppl
., 16H:31-43 (1992))
Prostate-specific antigen was first described by Wang, M.C., et al.,
Invest. Urol
., 17:159 (1979). It is a secretion of prostate epithelium and is also produced by prostate cancer cells. PSA was characterized as a glycoprotein monomer with protease activity. More recently, the amino acid sequence of the antigen has been reported (Watt, W. K., et al.,
PNAS USA
, 83:3166 (1986)) and the gene for PSA has been cloned (Lundwall, A.,
Biochem. Biophys. Res. Commun
., 161:1151 (1989)).
A variety of carbohydrate markers have been used to reveal the importance of carbohydrate information in the clinical characteristics of human carcinomas. Consequently, carbohydrate profiles of the primary tumor have been correlated with tumor grade, metastatic potential and prognosis, which are not mutually unrelated. Oncogenesis is usually associated with alterations in cell surface carbohydrate structure, and tumor-associated carbohydrate markers have been utilized in the diagnosis and followup of human cancers. (Hakomori, S. ,
Adv. Cancer Res
., 52:257-331 (1989).) Recently, it has been shown that carbohydrate structures on the tumor cell surface are associated with the metastatic potential of tumor cells.
The association of carbohydrate signals with metastatic potential was first revealed in experimental systems. Notably, &bgr;1→6 branching of asparagine-linked oligosaccharides, which are increased in a number of tumor cells (Yamashita, K., et al.,
J. Biol. Chem
., 259:10834-10840 (1984), and in metastases of murine melanomas and fibrosarcomas (Dennis, J. W., et al.,
Science
, 236:582-585 (1987)). N-linked glycosylation is initiated in mammalian cells, as in those of all higher eukaryotes, with the transfer of the precursor oligosaccharide to accepted asparagine residues of nascent or newly synthesized proteins. Subsequent modification of this oligosaccharide generates the extreme diversity of N-linked oligosaccharides found in mature glycoproteins. Steric accessibility to Golgi enzymes appears to determine whether the processing of a given N-linked glycan stops at the oligomannose stage or proceeds further (Hsieh, P., et al.,
J. Biol. Chem
., 258:2555-2561 (1983)). However, the regulation of the later stages of processing, in which a wide variety of bi, tri, and tetraantennary complex glycans are synthesized, is only poorly understood. This regulation is of special interest because it is altered in many differentiating (Feizi, T.,
Nature
, 314:53-57 (1985)) or oncogenically transformed (Warren, L., et al.,
Biochem. Biophys. Acta
., 516:97-127 (1978)) cells, resulting in a shift in an N-linked oligosaccharide composition. This is likely to have physiologically significant consequences, since altered protein glycosylation can affect processes such as adhesion, metastasis and immune recognition. (Hubbard, S. C.,
Journal of Biological Chemistry
, 262 (34):16403-16411 (1987).)
The proposed carbohydrate structure of PSA is a diantennary N-linked oligosaccharide of the N-acetyllactosamine type, with a sialic acid group at the end of each of the two branches. Approximately 70% of the PSA molecules contain a fucose group in the core chitobiose moiety. PSA contains only one N-linked chain, which is linked to asparagine
45
(Watt, et al.,
Proc. Nat. Acad. Sci
., Vol. 83, pgs. 3166-3170 (1986); Schaller, et al.,
Eur. J. Biochem
., Vol. 170, pgs. 111-120 (1987); Riegman, et al.,
Biochem. Biophys. Res. Commun
., Vol. 155, pgs. 181-188 (1988); Van Halbeek,
Methods in Molecular Biology
, Jones, et al., eds., Totowa, N. J., Humana Press, pgs. 115-148 (1993); Lundwall, et al.,
FEBS Lett
., Vol. 214, pgs. 317-322 (1987)). Van Halbeek, et al. suggest that this protein is composed of several isoforms whose structure may differ in their carbohydrate composition.
The proposed carbohydrate structure of PSA confirms that only one glycosylation site in the protein is occupied. This glycosylation site is readily identified based on the amino acid sequence of the protein; the only consensus ASN-X-SER/THR sequence in PSA is found at residue 45-46-47 (ASN-LYS-SER). (Belanger, et al.). The complete characterization in the structure of the carbohydrate side-chain of PSA has been determined by Belanger, et al.
Carcinoma of the prostate has long been regarded as an unpredictable disorder which makes sound therapeutic decisions in evaluating the results of different types of treatment very difficult. Prostate cancer is unique among the potentially lethal human malignancies in that there is a wide discrepancy between the high prevalence of histologic changes recognizable as cancer and the much lower prevalence of clinical disease.
The concept that adenocarcinoma of the prostate exists in a latent and a clinical form is supported by epidemiologic, pathologic and clinical evidence. Although these divergent manifestations of prostate cancer have come in architectural and cytologic features, they can be distinguished from each other to some degree by differences in certain pathologic features, such as the volume, grade, and invasiveness of the lesion.
Prostate cancer has become the most common cancer among American men, and only lung cancer is responsible for more cancer deaths (Boring, C. C., Cancer Statistics, 41:19-36 (1991)) The age specific mortality rate has slowly increased over the past 50 years and in black American men is nearly double the rate found in white men (Carter, H. B., Prostate, 16:39-48 (1990)). Prostate cancer is responsible for nearly three percent of all deaths in men over the age of 55 years (Seidman, H., et al., Probabilities of Eventually Developing or Dying of Cancer-United States, 35:36-56 (1985)). Since the incidence of prostate cancer increases more rapidly with age than any other cancer, and the average age of American men is rising, the number of patients with prostate cancer is expected to increase dramatically over the next decade.
Approximately 30% of men with prostate cancer have distant metastases at the time of diagnosis (Schmidt, J. D., et al., J. Urol., 136:416-421 (1986)). Despite the impressive symptomatic response of metastases to hormonal manipulation (androgen deprivation), the survival rate for these patients is dismal: the median duration of survival is less than three years (Eyar, D. P., Urologic Pathology: The Prostate, Philadelphia, Pa., Lea and Febiger, 241-267 (1977)). By five years, over 75% and by ten years, more than 90% of these patients die of their cancer rather than with it (Silverberg, E., Cancer, 60:692-717 (1987) (Suppl.)).
The problem with prostate cancer is that many forms of pros
Prakash Sadhana
Robbins Phillips W.
Huff Sheela
Lillie Raymond J.
Millennium Pharmaceuticals Inc.
Olstein Elliot M.
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