Treatment and diagnosis of prostate cancer

Abstract

The present invention is directed to the use of antibodies or binding portions thereof or probes which recognize an antigen of normal, benign, hyperplastic, and cancerous prostate epithelial cells or portions thereof. These antibodies or binding portions thereof or probes can be labeled and used for detection of such cells. They also can be used alone or bound to a substance effective to ablate or kill such cells as a therapy for prostate cancer. Also disclosed is a hybridoma cell line which produces a monoclonal antibody recognizing antigens of normal, benign, hyperplastic, and cancerous prostate epithelial cells or portions thereof.

Description

[0001] This application is a divisional of U.S. Ser. No. 09 / 929,543, filed Aug. 13, 2001, which is a continuation of U.S. Ser. No. 09 / 039,826, filed Mar. 16, 1998, now abandoned, which is a divisional of U.S. Ser. No. 08 / 463,500, filed Jun. 5, 1995, now U.S. Pat. No. 5,773,292, issued Jun. 30, 1998, the contents of which are incorporated herein by reference.[0002] The present invention relates to the treatment and diagnosis of prostate cancer with antibodies or binding portions thereof.[0003] Prostate cancer is the most common cancer in men with an estimated 244,000 cases in 1995 in the United States. It is the second leading cause of death among men who die from neoplasia with an estimated 44,000 deaths per year. Prompt detection and treatment is needed to limit mortality caused by prostate cancer.[0004] Detection of Prostate Cancer[0005] When it metastasizes, prostatic cancer has a distinct predilection for bone and lymph nodes. Saitoh, H., et al., "Metastatic Patterns of Prostati...

AI Technical Summary

Benefits of technology

[0039] Fusion with mammalian myeloma cells or other fusion partners capable of replicating indefinitely in cell culture is effected by standard and well-known techniques, for example, by using polyethylene glycol (PEG) or other fusing agents (See Milstein and Kohler, Eur. J. Immunol. 6:511 (1976), which is hereby incorporated by reference). This immortal cell line, which is preferably murine, but may also be derived from cells of other mammalian species, including but not limited to rats and humans, is selected to be deficient in enzymes necessary for the utilization of certain nutrients, to be capable of rapid growth and to have good fusion capability. Many such cell lines are known to those skilled in the art, and others are regularly described.

[0065] Also encompassed by the present invention is a method of killing or ablating which involves using the antibodies, binding portions thereof, or probes for prophylaxis. For example, these materials can be used to prevent or delay development or progression of prostate cancer.

[0066] Use of the prostate cancer therapy of the present invention has a number of benefits. Since the is antibodies or binding portions thereof or probes according to the present invention only target prostate epithelial cells, other tissue is spared. As a result, treatment with such antibodies or binding portions thereof or probes is safer, particularly for elderly patients. Treatment according to the present invention is expected to be particularly effective, because it directs high levels of antibodies or binding portions thereof or probes to the bone marrow and lymph nodes where prostate cancer metastases predominate. Moreover, tumor sites for prostate cancer tend to be small in size and, therefore, easily destroyed by cytotoxic agents. Treatment in accordance with the present invention can be effectively monitored with clinical parameters such as serum prostate specific antigen and / or pathological features of a patient's cancer, including stage, Gleason score, extracapsular, seminal, vesicle or perineural invasion, positive margins, involved lymph nodes, etc.

Problems solved by technology

Accurate clinical evaluation of nodal involvement has proven to be difficult.

Therefore, by definition, these imaging modalities are inherently insensitive in the detection of small volume (<1 cm) disease as well as non-specific in the detection of larger volume adenopathy.

Prior art attempts to develop a specific test for prostatic acid phosphatase have met with only limited success, because techniques which rely on enzyme activity on a so-called "specific." substrate cannot take into account other biochemical and immunochemical differences among the many acid phosphatases which are unrelated to enzyme activity of prostate origin.

In addition to the aforementioned problems of non-specificity which appear to be inherent in many of the prior art reagents employed for the detection of prostate acid phosphatase, there have been reports of elevated serum acid phosphatase associated with other diseases, which further complicates the problem of obtaining an accurate clinical diagnosis of prostatic cancer.

However, the previously reported immunochemical methods have drawbacks of their own which have precluded their widespread acceptance.

However, this method has the disadvantages of limited sensitivity, even with the large amounts of antigen employed, and of employing antisera which may cross-react with other, antigenically unrelated serum protein components present in prostatic fluid.

However, practical problems are posed by the need for a source of cancerous prostate tissue from which the diagnostically relevant prostatic acid phosphatase isoenzyme patterns associated with prostatic cancer are extracted for the preparation of antibodies thereto.

Historically, the drawback of this procedure is that most cancers had spread beyond the bounds of the operation by the time they were detected.

Patients with bulky, high-grade tumors are less likely to be successfully treated by radical prostatectomy.

Diethylstilbestrol from estrogen is another useful hormonal therapy which has a disadvantage of causing cardiovascular toxicity.

As a result, it blocks the effect of testosterone, increasing serum testosterone concentrations and allows patients to remain potent--a significant problem after radical prostatectomy and radiation treatments.

Cytotoxic chemotherapy is largely ineffective in treating prostate cancer.

Its toxicity makes such therapy unsuitable for elderly patients.

While many mAbs have previously been prepared against prostate related antigens, none of these mAbs were specifically generated with an imaging objective in mind.

However, the antigens detected by these monoclonal antibodies are present in the blood and, therefore, compete with antigens at tumor sites for the monoclonal antibodies.

This causes background noise which makes the use of such antibodies inappropriate for in vivo imaging.

In therapy, such antibodies, if bound to a cytotoxic agent, could be harmful to other organs.

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