Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1998-07-17
2002-03-05
Ungar, Susan (Department: 1642)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C530S387100, C435S007100, C435S007930, C435S007940, C435S007950, C435S962000
Reexamination Certificate
active
06352834
ABSTRACT:
BACKGROUND OF THE INVENTION
In 1995, an estimated 41,000 deaths from metastatic prostate cancer occurred, despite some promising treatments. Some of these deaths would have been prevented had prostate specific antigen diagnostic tests been more reliable. The present invention improves the specificity of PSA screening tests, and will increase survival rates via early detection and early treatment.
Great strides have been made in detection of prostate malignancies since the identification of prostate specific antigen (PSA) by Wang et al. in 17
Invest Urol
159 (1979), the subject matter of which was claimed in U.S. Pat. No. 4,446,122 (reissued as Reissue No. 33,405 in 1990). Distinctions can now be made between patients whose PSA levels are elevated due to prostate cancer and those whose PSA levels are elevated due to benign prostate hypertrophy. For example, U.S. Pat. No. 5,614,372 and U.S. Pat. No. 5,599,677 describe some of the strategies used to distinguish the two forms. These three patents (U.S. Pat. No. 4,446,122, including Re. 33,405, U.S. Pat. No. 5,614,372 and U.S. Pat. No. 5,599,677) are hereby incorporated by reference in their entirety into this application. In particular, U.S. Pat. No. 5,599,677 at column 2, lines 1-13 discusses PCT patent application WO 92/01936. WO 92/01936 is incorporated by reference into U.S. Pat. No. 5,599,677 (see, colunmn 15, lines 51-54). Table 2a, found at page 12 of WO 92/01936 presents the results of the testing of patient samples for free, complexed and total PSA. In the table, BPH indicates benign prostatic hyperplasia, CAP indicates prostate cancer, G indicates the differentiation grade, and T indicates the grade. Table 2a is reproduced below:
TABLE 2a
Correlation
Ratio
coefficient
mean
BPH (n = 144)
A. PSA c/PSA tot
0.932
0.970
B. PSA f/PSA tot
0.853
0.302
CAP (n = 122)
A.
0.994
1.219
B.
0.784
0.191
CAP, G1 (n = 31)
A.
0.994
1.628
B.
0.922
0.190
CAP, G2 (n = 47)
A.
0.972
1.141
B.
0.956
0.169
CAP, G3 (n = 43)
A.
0.996
1.014
B.
0.818
0.218
CAP T1-2 (n = 56)
A.
0.985
1.044
B.
0.868
0.178
CAP T3-4 (n = 65)
A.
0.993
1.372
B.
0.770
0.204
CAP T4 (n = 25)
A.
0.997
1.174
(not treated)
B.
0.825
0.188
BPH (n = 84) PSA ≦ 5
A.
0.879
1.059
B.
0.850
0.301
BPH (n = 60) PSA > 5
A.
0.888
0.846
B.
0.735
0.303
CAP (n = 26) PSA ≦ 5
A.
0.913
1.773
B.
0.826
0.202
CAP (n = 94) PSA >5
A.
0.993
1.065
B.
0.778
0.188
CAP (n = 25)
A.
0.919
1.025
PSA > 5 ≦ 20
B.
0.502
0.187
CAP (n = 69)
A.
0.993
1.080
PSA > 20
B.
0.770
0.184
Commercially-available PSA assays are commonly sold as kits, and the assays performed in regional or local laboratories. For example, PSA diagnostic kits are sold under the names of: PROS-CHECK PSA, from Yang Laboratories, Inc. Bellevue, Wash.; Hybritech Tandem-E and Hybritech Tandem-R, from Hybritech, Inc., La Jolla, Calif.; Abbott Imx PSA Assay, from Abbott Laboratories, Abbott Park, Ill.; and ACS PSA Assay, from Ciba-Corning Diagnostics Corporation, East Walpole, Mass.
These kits (and other assays, for example, those mentioned in U.S. Pat. Ser. No. 5,688,658) play a critical part of the current strategy for early detection of prostate cancer. A problem arises, however, when a modestly abnormal PSA value (4-10 ng/ml) is encountered in the context of a negative digital rectal exam (DRE). Only 20-30% of individuals with such findings will demonstrate carcinoma on biopsy (Kantoff and Talcott, 8(3)
HematollOncol Clinics N Amer
555 (1994)). It has therefore been important to develop strategies that increase the positive predictive value of PSA testing. Such strategies now include establishing age-adjusted normal ranges, determining the free to total PSA ratio, correcting for prostate gland mass (density), and calculating the rate of change of PSA values (Kantoff and Talcott, 8(3)
Hematol.Oncol Clinics N Amer
555 (1994) and Brawer, 45
CA
-
A Cancer J Clinicians
148 (1995)). While each of these strategies has made a contribution, considerable uncertainty nevertheless remains about how to proceed with a patient who is PSA positive and DRE negative.
The present invention provides hope for those patients who have modestly elevated PSA levels, in that additional procedures may be avoided (such as biopsy) or treatment may be initiated earlier in the disease progession. One aspect of the present invention is the effective reduction of available intracellular iron in prostate carcinoma cells prior to administration of a PSA diagnostic test. Most information describing the interaction between iron levels and cancer has been generated in the context of therapeutics, however, and not diagnostics.
Iron is a key nutrient in mammalian health; iron is necessary in proper hemoglobin structure and function (hemoglobin is the primary component of red blood cells), DNA synthesis, and energy transport. In the body, iron is absorbed from food or supplements in the intestine, and transported via the blood to cells by an appropriately-named protein called “transferrin”. Receptors on the cell's surface recognize and bind the iron-carrying transferrin and the iron is then made available to the cell's interior. In certain situations, however, it has been shown to be therapeutically desirable to purposely cause a state of partial iron deficiency.
For example, three types of iron deprivation cancer treatment are currently under study. Deferoxamine (called “DFO” in this application, but also referred to as desferioxamine in the art) is the first treatment, and it is being investigated in the treatment of neuroblastoma (Donfrancesco et al., 4
Anti
-
Cancer Drugs
317 (1993)) and hepatoma (Kountouras et al., 42
Hepato
-
gastroenterol
31 (1995). The second treatment, gallium nitrate, is being investigated in transitional cell carcinoma (Seligman and Crawford, 83(21)
J Nat Cancer Inst
1582 (1991) and lymphoma (Chitambar et al., 20(2)
Am J Clin Oncol
173 (1997)). The third treatment involves the use of monoclonal antibodies against the transferrin receptor. These antibodies have shown promise against lymphomas in animal models (White et al., 50
Can Res
6295 (1990) and Kemp et al., 55
Can Res
3817 (1995)) and in a Phase I clinical trial (Brooks et al., 1
Clin Cancer Res
1259 (1995). It is now clear that all three forms of treatment, and iron deprivation per se, can induce apoptosis (Ul-Haq et al., 23
Exp Hematol
428 (1995); Hileti et al., 89
Br J of Haematol
181 (1995); Fukuchi et al., 350
FEBS Letters
139 (1994); Kovar et al., Abstract 38C13 in 65
Pathobiology
61 (1997).
In related research, iron appears to be a growth factor for tumor cells that metastasize to bone (Rossi and Zetter, 89
Proc Natl Acad Sci USA
6197 (1992). In addition, one effect of suramin (an agent that is active against prostate cancer) is to partially inhibit the binding of transferrin to its receptor (Forsbeck et al., 37
Scand JHaematol
429 (1986). Moreover, the present inventors found that combined iron deprivation/monoclonal antibody treatment produced significant inhibition of growth of prostate carcinoma cell lines in vitro (Kovar et al., 63
Pathobiology
65 (1995). These results then led to a Phase II trial of DFO as a single agent against disseminated prostate cancer (Dreicer et al., 15(4)
Cancer Investigation
311 (1997). In that trial, prostate cancer patients were given consecutive eight hour intravenous infusions of DFO. The DFO treatment was associated with rising PSA levels in eight out of nine patients, even though their disease appeared to be stable by clinical criteria.
The result in Dreicer et al. was contrary to numerous studies which indicated that rising PSA levels indicate recurrent or residual disease. Brawer et al., 33 (5 supp)
Urology
11 (1989); Siddal et al., 12
Eur Uro
1 (1986); Starney et al., 317
N Eng J Med
909 (1987); Lange et al., 141
J Urol
873 (1989); Starney et al., 141
J Urol
1076 (1989) Starney et al., 141
J Urol
1088 (1989) and Chan et al., 33
Clin Chem
1916 (1987).
Additionally, recent research h
Dreicer Robert
Kemp John
Davis Minh-Tam
Schwegman Lundberg Woessner & Kluth P.A.
Ungar Susan
University of Iowa Research Foundation
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