Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
2000-03-31
2003-04-01
Jones, Dameron L. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
C424S009100, C424S001110, C424S001650, C424S009300, C424S001490
Reexamination Certificate
active
06540980
ABSTRACT:
BACKGROUND OF THE INVENTION
Endometriosis, the ectopic implantation of endometrial glands and stroma in regions remote from the uterine cavity, affects approximately 15% of women in their 30's-40's and is the cause of 35-45% of female infertility cases. Some women remain asymptomatic while others experience chronic pain. Mitchell in Endometriosis: Contemporary Concepts and Clinical Managment. (Schenker R, ed.: Lippincott, 1989). Endometriosis is usually confined to the pelvis, but extrapelvic sites have been reported in nearly all organs of the abdominal cavity. In addition, the thorax, skin, muscles, peripheral nerves, brain and spinal column are occasionally affected, as are surgical scars and the genital tract. Areas that are frequently involved include the abdominal wall, small intestines, appendix, urinary tract, and lymph nodes. Pauerstein, “Clinical presentation and diagnosis” in Endometriosis: Contemporary Concepts and Clinical Management (Schenker, ed. Lippincott 1989).
Methods to detect endometriosis have included: (a) serum immunoassays [CA-125, endometrial antibodies]; (b) imaging techniques [US, CT and MRI]; and (c) laparoscopic examination [reviewed by Pauerstein, supra]. Neither immunoassay approach is considered sufficiently sensitive. Barbieri, Fertil. Steril. 45:767-772 (1989); Chihal et al., Fertil. Steril. 46:408-420 (1986). Imaging approaches have met with varying degrees of success, with US and CT exhibiting the least sensitivity and specificity. Chihal et al., Fertil. Steril. 46:408-420 (1986); Fishman et al., J. Comput. Assist. Tomogr. 7:257-263 (1983).
MRI consistently demonstrates anatomic tissue planes, and has been useful for diagnosing several disorders of the female pelvis (Mitchell et al., Radiology 160:425-429 (1986)), however the signal intensity of endometriomas by MRI is very variable ranging from strong to relatively weak. MRI is useful for detecting the hemorrhagic masses due to a decrease in the signal intensity resulting from deoxyhemoglobin and hemosiderin. Other cysts cannot be distinguished from endometriomas (Zawin et al., Radiology 171:693-697(1989)) and resolution is often weak if lesions are not of high density. Furthermore, small adhesions, important in staging, are not seen by MRI. In the most promising report, an MRI sensitivity of 71% and a specificity of 82% was noted for 88 evaluable endometriotic lesion. Zawin et al., supra. In another study, sensitivity, specificity, and accuracy were 64%, 60%, and 63%, respectively. MRI could not be used to accurately detect extra-ovarian endometrial adhesions, and intraperitoneal implants. Nor did results correlate with surgical assessment of severity. Arrive et al., Radiology 171:687-692 (1989).
The optimal diagnostic tool to date is laparoscopy, resulting in about 90% correct diagnosis. Dmowski et al., Fertil Steril 67:238-43 (1997). There are however, circumstances in which direct visualization is difficult or inaccurate, such as, minimal lesions, adhesions that obscure visualization, ovarian endometriomas, and atypical non-pigmented endometriosis. Schenken et al., Prog. Clin. Biol. Res. 323:137-148 (1990). It is not, however, unusual to find patients who are normal on laparoscopy, that present with severe disease less than one-year later. Id. The invasiveness of the procedure may also be limiting preventing repeat examination to monitor efficacy of therapy and/or recurrence. Hence a need for a better detection system is needed.
Radiolabeled antibodies are a class of imaging agents for the detection of sites of disease. Goldenberg et al., Semin. Cancer Biol. 1:217-25 (1990); Goldenberg, Am. J. Med. 94:297-312 (1993). Results with
131
I-labeled intact IgG have shown a general sensitivity of 80-90%. Murray et al., Diag. Oncol. 2:234-241 (1992); Larson, Cancer Res. 50:892-898 (1990). A specific antibody conjugated with a short half-life radionuclide, might be useful for immunoimaging of endometriosis, as it has been for the detection of primary and metastatic tumor lesions. Although RAID was first developed to identify malignant tissue, other applications have resulted, such as imaging myocardial infarction (Khaw et al., J. Nucl. Med. 28:1671-1678 (1987)), thrombi (Oster et al., Proc. Natl Acad. Sci. 82:3465-3468 (1985)), inflammation (Locher et al., Nucl. Med. Comm. 7:659-660 (1986)), and atherosclerotic plaques (Khaw et al., J. Nucl. Med. 32:1005-1012 (1991)).
Two case reports using immunoscintigraphy to image endometriosis have been presented. Kennedy used
131
I or
111
In labeled OC-125 F(ab′)
2
anti-CA-125 with 89% sensitivity and 33% specificity to detect pelvic and pulmonary sites. Kennedy et al., Br. J. Obstet. Gyn. 97:667-670 (1990); Kennedy et al., Br. J. Obstet. Gyn. 98:600-601 (1991). The poor specificity is due (in part) to the inappropriate selection of CA-125 as a marker for endometriosis, which although elevated in some endometriosis patients, is not considered appropriate for screening. Barbieri, supra. To apply the technology of radioimmunoscintigraphy to clinical endometriosis imaging, [1] A suitable antigen found on most/all endometriotic specimens, must be selected; [2] An antibody with specificity for this antigen must be available.
Several antibodies raised to normal human endometrium exist (e.g., ENDOM5, ENDOM7, NEND3) that cross-react with endometriosis, and thus offer promise in diagnostic and therapeutic applications. Kruitwagen et al., Eur. J. Obstet. Gyn. Reprod. Biol. 19:51-64 (1992). In addition, antibodies recognizing either epithelial glycoproteins or mucins (e.g., RS-7, MA-5) found in solid tumors also react with endometriosis. However, the lack of specificity of these two groups of antibodies renders them inappropriate for specific endometriosis targeting.
Thus, a need exists in the art for techniques useful in detecting endometriosis. These techniques would overcome the art-based deficiencies discussed above. In addition, there is a need for improved methods of treating endometriosis once it has been detected.
SUMMARY OF THE INVENTION
It is therefore an object of the invention to provide kits and methods for overcoming the above-listed deficiencies in the art. According to this object, a kit for detecting or treating endometriosis is provided. This kit generally contains targeting agent, which is composed of an eosinophil peroxidase-binding component and a diagnostic or therapeutic accessory component, depending on the diagnostic or therapeutic application. In one embodiment, the peroxidase-binding component can be an antibody or an antibody fragment. Where the accessory component is for diagnostic use, it may be a detectable label, like a radionuclide, a fluorescent marker or an enzyme. Where the accessory component is for therapy, it may be a cytoablative agent. In another embodiment, the targeting agent, instead of containing a diagnostic or therapeutic accessory component, is adapted to receive such a component.
Also according to this object, a method of diagnosing endometriosis is provided. In one aspect, this method entails contacting endometrial tissue with an agent that has an eosinophil peroxidase-binding component and a detectable label, and then detecting that agent. The peroxidase-binding component can be, for example, an antibody or an antibody fragment. The detectable label may be, for example, a radionuclide, a fluorescent label or an enzyme. In different embodiments, this method, in part or in whole, may be accomplished in vivo or ex vivo.
Also according to this object, a method of treating endometriosis is provided. This method involves administering to an endometriosis patient an effective amount of an agent made up of an eosinophil peroxidase-binding component and a cytoablative agent. The peroxidase-binding component may be an antibody, an antibody fragment or the like.
DETAILED DESCRIPTION OF THE INVENTION
Eosinophil Peroxidase (EPO) is an intracellular enzyme that is released from eosinophils as they degranulate. Samoszuk et al., Lab. Invest. 56:394-400 (1987). T
Blumenthal Rosalyn D.
Goldenberg David M.
Samoszuk Michael
Center for Molecular Medicine and Immunology
Foley & Lardner
Jones Dameron L.
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