1. Field of the Invention
The present invention relates generally to the fields of immunological compositions and detection methods. More particularly, it concerns compositions and methods for detecting benign prostate hyperplasia (BPH) and for differentiating BPH from normal prostate and prostate cancer. Disclosed are antibodies, including a monoclonal antibody, directed against a highly restricted biological marker of BPH, methods for making and using BPH-specific antibodies and antigens, and methods for the detection and diagnosis of BPH.
2. Description of the Related Art
Benign prostate hyperplasia (BPH) is the most common non-malignant proliferative abnormality found in any internal organ and the major cause of morbidity in the adult male. The initial development of BPH begins as early as 30 to 40 years of age and the prevalence is approximately 10% for that age group (Berry et al., 1984). With advancing age, the prevalence of BPH increases progressively. BPH occurs in over 75% of men over 50 years of age, reaching 88% prevalence by the ninth decade, often resulting in symptoms of outlet obstruction that can lead to bladder wall hypertrophy, increased risk of urinary infection, and chronic renal disease.
The currently accepted treatment for BPH is surgical resection of the prostate. The probability of requiring surgical intervention for BPH is approximately 25% if a man lives to 80 years of age. In the U.S. approximately 400,000 prostatectomies are performed annually to relieve urinary obstruction caused by this disease, making this the most common surgical procedure performed in U.S. males (Vital and Health Statistics, 1986; Carter & Coffey, 1990). The morbidity and mortality for transurethral resection of the prostate is 17% and 0.2-1.0%, respectively, including all age groups (Mebust et al., 1989). Surgical, hospitalization and other treatment for BPH are estimated to cost over a billion dollars per year. Although the statistics cited are for U.S. males, BPH has and continues to be a major health problem worldwide and will become even more significant as the aged male population increases.
The natural history of BPH is composed of two phases, a pathological phase and a clinical phase. Although almost every man who lives long enough will develop microscopic BPH, only about 50% will go on to develop macroscopic BPH, and only about 50% of the patients who develop macroscopic BPH will actually develop the clinical syndrome (Issacs, 1990). Thus, not all prostate growth requires clinical treatment. While prostate enlargement is a necessary condition of clinical BPH, size alone is usually not sufficient of itself to cause BPH to progress from the pathological to the clinical symptomatic phase. The clinician is thus faced with the problem of not being able to distinguish between pathological and clinical BPH.
Although evidently two separate diseases, recent observations have suggested a link between BPH and prostate cancer (CAP). For example, when BPH is found associated with small anterior CaPs, it has been reported that the cancer has generally originated within the hyperplastic nodules (McNeal et al., 1988). The early events for progression from either normal to BPH or normal to CaP have also been proposed to be similar (Partin et al., 1993). Nevertheless, the wide range of epithelial transformations that occur in both BPH and CaP, suggests that each end of this spectrum represents different disease processes that are not interrelated.
Due to the morbidity and mortality associated with BPH, the problem of overtreating, and the recent evidence that at least some BPH may be precursors of malignant changes in the prostate, it is evident that effective means for detecting BPH are urgently needed. Unfortunately, although a number of different molecules have been investigated in an attempt to find a specific or highly restricted marker for BPH, such a marker has yet to be identified.
Various markers allowing differentiation of the malignant phenotype from normal tissues have been identified, including prostate specific antigen (PSA), prostatic acid phosphatase (PAP) and prostate secretory protein (PSP). However, none of these substances have proven to be useful in the differentiation of BPH from CaP. Also, in contrast to BPH, monoclonal antibodies (MAbs) specific for CaP have been identified, including PD41 that recognizes a novel mucin (prostate mucin antigen, PMA) (Beckett et al., 1991); TURP-27, that recognizes a complex of 6-8 glycoproteins (Wright et al., 1991) and 7E11-C5 (Horoszewics et al., 1987) that recognizes a highly unstable complex of 3 glycoproteins.
It has been reported that the levels of certain growth factors, such as bFGF, EGF, PDGF or TGF-.beta., differ between BPH and CaP. Unfortunately, quantitative differences in the tissue concentrations of a particular molecule, unlike qualitative differences, would be unlikely to be specific enough to diagnose BPH or to differentiate BPH from CaP. Other studies have reported that BPH can be differentiated from CaP by the expression of basal cell cytokeratin (Verhagen et al., 1992; Sherwood et al., 1991; Brawer et al., 1985), however, a recent conflicting report showed that basal cell cytokeratin is also expressed by some prostate cancers (Verhagen et al., 1992). Furthermore, attempts to use cytokeratins to detect other cancers have been disappointing, such as the bladder cancer study that resulted in an unacceptably high frequency (55%) of false positives (AL-Hilaly et al., 1991). Another group proposed that the loss of HLA-DR may be a useful indicator of BPH progression to cancer (Theyer et al., 1992), but the variable expression of HLA-DR on benign ducts and epithelial cells will likely invalidate its use as a biomarker of BPH.
One- (1-D) and two-dimensional (2-D) gel electrophoresis has also been used in attempts to identify specific differences in the protein content of prostate tissue extracts and biological fluids from normal males and patients with prostate disease (Tsai et al., 1984; Johnson et al., 1985; Anderson et al., 1985; Carter et al., 1985; Wada et al., 1985; Gerhardt et al., 1985; Lee et al., 1986). These studies have yielded conflicting results, for example, one reported the presence of 5 protein spots unique to BPH (Anderson et al., 1985), whereas another showed no BPH-specific differences (Tsai et al., 1984). Furthermore, one proposed 40 kDa protein marker for prostate cancer identified by 2-D electrophoresis (Edwards et al., 1982), was later shown to be actin (Tsai et al., 1984).
It is thus evident that, despite intensive efforts in this area, the search for a unique or very specific marker for BPH has proven unsuccessful. The identification of a biological marker that allows BPH to be distinguished from normal or malignant tissues would represent a significant development, especially if such a marker could be readily detected using immunological techniques.
USPTO Backgrounds
USPTO Backgrounds