WO1996041167A1 - Dosages et necessaires de diagnostic permettant de detecter la relaxine, leurs procedes et utilisations - Google Patents

Dosages et necessaires de diagnostic permettant de detecter la relaxine, leurs procedes et utilisations Download PDF

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Publication number
WO1996041167A1
WO1996041167A1 PCT/US1996/007400 US9607400W WO9641167A1 WO 1996041167 A1 WO1996041167 A1 WO 1996041167A1 US 9607400 W US9607400 W US 9607400W WO 9641167 A1 WO9641167 A1 WO 9641167A1
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Prior art keywords
relaxin
cancer
biological sample
disorder
serum
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PCT/US1996/007400
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English (en)
Inventor
Christian Schwabe
Edward P. Amento
Mark Erikson
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Connective Therapeutics, Inc.
Medical University Of South Carolina
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Application filed by Connective Therapeutics, Inc., Medical University Of South Carolina filed Critical Connective Therapeutics, Inc.
Priority to AU58011/96A priority Critical patent/AU5801196A/en
Publication of WO1996041167A1 publication Critical patent/WO1996041167A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/26—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against hormones ; against hormone releasing or inhibiting factors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • G01N33/57488—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving compounds identifable in body fluids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/575—Hormones
    • G01N2333/64—Relaxins

Definitions

  • the present invention relates to methods for determining predisposition towards disease, diagnosing diseases or disorders, monitoring the ablation of cancers and monitoring relaxin-related therapeutic drug programs.
  • the present invention is based, in part, on the observation that elevated relaxin levels correlate with the occurrence, prognosis, and clinical course of various human malignancies, as well as pregnancy.
  • the present invention further relates to assays and kits for the determination of relaxin levels in body fluids or tissue samples, and uses thereof.
  • the peptide hormone relaxin is a member of the insulin-related family of hormones which includes insulin (Blundell and Humbel, 1980, Nature 287:781- 787) , insulin-like-growth factor-I and -II (Blundell and Humbel, 1980, Nature 287:781-787) , bombyxin (Jhoti et al . , 1987, FEBS Lett . 219:419-425) . and molluscan insulin-related peptide (Smit et al . , 1989, Nature 331:535-538) .
  • each of the peptides of the insulin- related family share primary and structural homology.
  • these peptides share the structural feature of three disulfide bonds at corresponding locations.
  • the hormones of this family consist of two polypeptide chains linked by two interchain disulfide bonds. Notwithstanding their similar structure, the peptides comprising the insulin-related family are functionally distinct. Cooper et al. , 1989, Prog. Growth Factor Res . .1:99- 105.
  • Relaxin comprising approximately 6000 daltons, has been purified from a variety of species including porcine, murine, equine, shark, tiger, rat, dogfish and human.
  • two genes encoding relaxin have been identified, designated as (HI) and (H2) .
  • H2 HI
  • H2 a gene encoding relaxin
  • Hudson et al. , 1983, Nature 301:628-631; Hudson et al . , 1984, EMBO J . 2:2333-2339; U.S. Patents Nos. 4,758,516 and 4,871,670 Only one of the genes, the gene encoding relaxin (H2) , has been found to be transcribed in the ovary.
  • relaxin Although most abundantly found in the female during pregnancy in the corpora lutea, relaxin has also been detected in the non-pregnant female as well as in the male. For example, relaxin has also been isolated from or identified in the placenta (Stewart and Papkoff, 1986, Endocrinology 119:1093-1099) and seminal fluid (Sarosi et al . , 1983, Endocrinology 112:1860-1861; Weiss, 1989, Biol . Re prod. 40:197- PATENT
  • bioassays have been used for the measurement of active relaxin during pregnancy and non-pregnancy.
  • These bioassays generally lack sensitivity, specificity and precision (Sherwood, 1979, Methods of Hormone Radioimmunoassay edn 2.:875-886), thus necessitating the development of sensitive and specific immunoassays. Sherwood et al .
  • Lucas et al have developed a double- antibody enzyme-linked immunosorbent assay (ELISA) for the detection of hRLX in serum and plasma which is as sensitive and specific as the RIA described above.
  • ELISA enzyme-linked immunosorbent assay
  • the present invention is directed to methods for the diagnosis of human malignancies and to determine and monitor the clinical course thereof.
  • malignancies include ovarian cancers, prostate cancers, testicular cancers, and breast cancer.
  • the malignancies are grouped on the basis of whether such malignancies share a common relaxin producing phenotype and may be detected by the expression of relaxin.
  • the present invention is directed to: (1) the determination of elevated relaxin levels in the body fluids and/or tissue samples of patients to determine that patient's predisposition towards malignancies, (2) diagnosing such malignancies, (3) monitoring the advent of metastases following ablation of the malignancy, (4) monitoring therapeutic drug programs comprising the use of relaxin and (5) imaging and thereby identifying tumor and/or metastatic sites.
  • the basis of the present invention is the inventors' unexpected discovery that certain malignant tissues including ovarian, cervix, prostate, testicular, breast and other cancers having a common relaxin producing phenotype (e . g . colon- and lung cancers) secrete relaxin.
  • certain malignant tissues including ovarian, cervix, prostate, testicular, breast and other cancers having a common relaxin producing phenotype (e . g . colon- and lung cancers) secrete relaxin.
  • the present invention is further directed to assays and kits for the determination of relaxin levels in the plasma, serum, urine, and/or tissue of patients for the diagnosis of human malignancies, including ovarian cancers, prostate cancers, testicular cancers, breast cancers, colon cancers, and lung cancers. More specifically, the assays and kits of the present invention are used for the determination of predisposition or presence of such malignancies, and/or to determine and monitor the ablation of cancer by known treatment specimens.
  • the present invention is directed to monitoring the course of human pregnancy by monitoring relaxin levels during the pregnancy term.
  • the assays and kits of the present invention are comprised of labelled antibodies for use in imaging.
  • relaxin means human relaxin, including full length relaxin or a portion of the relaxin molecule that retains biological activity [as described in U.S. Patent No. 5,023,321, preferably recombinant human relaxin (H2)] and other active agents with relaxin-like activity, including relaxin- like factor [as described in co-pending application entitled "Relaxin-Like Factor And Methods And Uses
  • Relaxin can be made by any method known to those skilled in the art, preferably as described in U.S. Patents No. 4,835,251 and in co-pending U.S. Serial Nos. 07/908,766 (PCT US90/02085) propeland 08/080,354 (PCT US94/0699) .
  • Relaxin has been considered primarily as a hormone of reproduction. More specifically, it has been widely reported that relaxin modulates the restructuring of connective tissues in target organs to obtain the required changes during pregnancy and
  • the subject invention is based on the inventors' unexpected discovery that a variety of malignant
  • tissues including ovarian, cervix, prostate, testicular, breast and other cancers including subsets of colon and lung cancers, secrete relaxin, either fortuitously or for undefined physiological purposes.
  • the secretion level for relaxin appears to directly correlate with the aggressive nature of the cancer and the progression of the disease.
  • assessment of the relaxin levels secreted by such tumors is a valuable tool for diagnosis and prognosis of the _ c relevant malignancies.
  • the present invention is directed to the determination of relaxin secretion related to the predisposition or presence of cancers which share a common relaxin producing phenotype (e.g. ovarian, prostate, testicular and breast cancer) .
  • the advantages of the present invention are particularly admirant in the case of the group of cancers related to ovarian cancer as the ability of detect and provide early diagnosis of such cancer is particularly beneficial.
  • Ovarian cancer is typically only successfully treated when identified at a very early stage. Notwithstanding early diagnosis, ovarian cancer is further problematic in that assessing the amount of residual ovarian cancer and monitoring its response to treatment is extremely difficult. For example, while many germ cell tumors can be successfully subclassified and the course of the disease monitored by utilizing the markers ⁇ - fetoprotein (Sell et al . , 1976, International J. Cancer 18 . :574-80) , and /3-human chorionic gonadotropin (Perlin et al . , 1975, Cancer 37:215-225) , such specific and accurate markers are not available for the stromal and epithelial varieties or ovarian cancer. Thus, there is a substantial need for methods of early diagnosis, and also for reliable, non-invasive methods of monitoring treatment to support investigation of new therapies.
  • the methods and assays of the present invention for the measurement of relaxin in body fluids such as blood or blood fractions, urine and ascites fluid, or tissue samples may be used for a variety of clinical purposes.
  • determination of relaxin secretion can be employed to determine the presence of several human malignancies which can be characterized by the secretion of relaxin.
  • the methods and assays of the present invention may be used for the diagnosis of ovarian, breast, prostate, testicular and other types of cancer having common relaxin producing phenotype, and further a certain subset of colon and lung cancers.
  • determination of relaxin levels may be useful for the determination of predisposition for such types of cancer.
  • elevated relaxin levels in the body fluid of the patient can readily be detected in general standard check-ups, they will indicate predisposition for malignancies which are related to the secretion of relaxin.
  • Patients identified to be predisposed can then be monitored on a regular basis for changes in relaxin levels in their body fluids, facilitating an early diagnosis of a malignancy. Early start of suitable therapeutic treatment will significantly increase the chances to successfully cure the disease.
  • the methods and assays of the present invention can also be used to determine and monitor the ablation of cancer by known treatment regimens.
  • such methods and assays can be used as follow-up therapy to detect metastases following, for example, surgical removal of malignant tumors.
  • the assays and methods of the present invention can be conducted using labelled, and preferably radiolabelled, antibodies for use in imaging to, for example, identify and/or locate tumors and metastases.
  • the methods and assays of the present invention can be used outside the context of cancer.
  • the present invention can be used to monitor pregnancy by measuring relaxin levels throughout the pregnancy term. It has been observed that relaxin levels during normal healthy pregnancy steadily increase or remain constant throughout the pregnancy term. In contrast, in unhealthy pregnancies, the relaxin levels will decrease or fluctuate.
  • the present invention as it pertains to monitoring pregnancy, relies on this observation.
  • the methods and assays of the present invention can also be used to monitor therapeutic drug programs comprising relaxin administration.
  • immunoassays including radioimmunoassay ⁇ and ELISA, known in the art, may be employed for the determination of relaxin levels.
  • the ELISA may be conducted according to known protocols which are described in, for example, Voller, et al. , 1988, "Enzyme-Linked Immunosorbent Assay," In: Manual Of Clinical Immunology, 2d Ed. , edited by Rose and Friedman, pp. 359-371, Am. Soc. of Microbiology, Washington, D.C. Said protocols may be modified to specifically detect for the presence of relaxin. See e .g . , Lucas et al . , supra .
  • a variety of different biological samples may be employed for the measurement of relaxin secreted by malignant tissues, such as ovarian, breast, prostate, testicular and other cancers having common relaxin producing phenotype.
  • Blood a convenient biological sample and readily to obtain, is suitable for diagnostic assays for the determination of elevated relaxin levels related to the occurrence of malignancies.
  • Relaxin can be measured in either whole blood, plasma or serum.
  • blood or blood fractions are suitable diagnostic samples for the diagnosis of many types of cancer which correlate with the secretion of relaxin, such as ovarian, prostate, breast, cervix, testicular, and other types and subsets of cancer. Since readily to obtain, blood or blood fractions are preferred for determination of predisposition or presence of such malignancies, as well as follow-up therapy to determine the onset of metastases following ablation of the cancer.
  • Urine is another readily available biological sample for the .determination of elevated relaxin levels related to the occurrence of malignancies. As true for blood derived diagnostic samples, urine appears to be suitable for diagnosis of the whole variety of cancers which relate to the secretion of relaxin.
  • ascites fluids of the patient are used as a sample.
  • Ascites fluids provide the most concentrated levels of relaxin and therein appear to be the mosl abundant and the easiest to measure. Ascites fluid can readily be obtained by methods known by the skilled artisan.
  • tumor derived tissue samples can be obtained for the determination of relaxin production.
  • the preferred use for the determination of relaxin production by a certain tissues will be to locate the malignancy responsible for the elevation of relaxin levels in the body fluids of the patient.
  • the tumor derived tissue sample is obtained by small needle biopsy.
  • Oncology Serum Bank were subjected to assays for the determination of the relaxin levels.
  • the double coded samples were considered to represent a reasonable sampling of the bank's contents. No discrimination between men and women has been made for tumors of the non-reproductive organs. The results are set forth in
  • the patient received Adiamycin, Cytoan and cis-platinum throughout the course of the disease. Prior to enrollment in the study, the patient additionally received L- phenylalanine mustard. Upon entry into the study, the tumor mass was very large and non-operable.
  • the radioimmunoassay for the determination of relaxin levels in biological samples is performed with a rabbit anti-relaxin antibody and a monotyrosyl relaxin tracer.
  • the second antibody is a goat commercial anti-rabbit immunoglobulin D antibody, coupled to a Whatman cellulose powder with aid cyanogen bromide. Samples and standards are preincubated with the first antibody for three hours.
  • the 125 I-labeled tyrosyl relaxin tracer is added and incubation continued for an additional two hours.
  • the second antibody is added and the incubation continued for another hour with vigorous shaking.
  • Samples are centrifuged and the amount of radioactivity in the pellets is measured in a gamma-counter.
  • the amount of relaxin in unknown samples and standards is inversely proportional to the amount of radioactivity in the pellet. Relaxin in unknown samples can then be quantitated by comparison against a standard curve generated with known concentrations of relaxin.
  • Monotyrosyl relaxin is prepared by reacting N- formyltyrosine-N-hydroxysuccinimide (1.5 equivalents) with one equivalent of porcine relaxin in 50% dioxane,
  • the tyrosine content is measured by amino acid analysis.
  • PBS Phosphate Buffered Saline
  • Buffer Diluent PBS/0.5% BSA/0.05% Polysorbate 20/0.01% Thimerosal
  • Serum Diluent (pooled normal human male serum or equivalent prepared according to the following steps: a. Spin at 625 x g for 20 minutes if necessary and filter through a 0.45 mm filter before use. New pools must be compared to previously used pools. b. Add 0.01% Thimerosal to pool, said product being stored at -10°C or below and expiring five years from the date of preparation. c. Store thawed serum at 2-8°C. d. Expiration of thawed serum is 1 month from the thaw date.
  • Plasma diluent (pooled normal human male plasma or equivalent) prepared according to the following steps: a. Spin at 625 x g for 20 minutes before use. New pools must be compared to previously used pools. b. Add 0.01% Thimerosal to pool. c. Store at -10°C or below (Expiration is 2 years form the date of preparation. d. Store thawed plasma at 2-8°C. Expiration of thawed plasma is 1 month from the thaw date.
  • Coating Buffer (0.05 M Sodium Carbonate Buffer, pH 9.6 ⁇ 0.1) which is stored at 2-8°C (wherein expiration is two weeks from the date of preparation) .
  • Substrate Diluent Sodium Phosphate/Citrate buffer, pH 5.0 ⁇ 0.1 (19.2 g/1 citric acid in 0.2 M Sodium phosphate, dibasic (28.4 g Na 2 HP0 4 /l) ) which is stored at 2-8°C and wherein expiration is one month from the date of preparation.
  • Substrate Solution Any of the following preparations may be used.
  • Substrate Solution (OPD/Substrate Diluent) without H 2 0 2 added can be stored at ambient temperature for up to one hour.
  • Substrate Solution must be at ambient temperature before adding to plate.
  • Non-immune Goat Immunoglobulin (IgG) (Cappel Lot #6006-0080 or equivalent) reconstituted to approximately 0.5 mg/ml according to product instructions which is stored at -10°C or below. Expiration is two years from the date of preparation. After thawing, store at 2-8°C. Expiration of thawed aliquots is 1 month from the date of thaw.
  • Standard dilution schedule Comparable dilutions to equivalent concentration may be made. Assuming concentration of Standard Stock I to be 10 ⁇ g/ml, dilutions will be as follows:
  • Control preparation Dilute controls in appropriate Assay Diluent to fall within the low, middle and high areas of the standard curve.
  • Serum and plasma samples with dilutions of greater than 1/20 may also be diluted in Buffer Diluent, but a minimum dilution of 1/20 is required for optimal recovery in an assay using Buffer Diluent.
  • Protocol The following protocol was used to conduct the ELISA described herein.
  • Step 2. Wash as in Step 2. with only one wash cycle. 5. Pipette goal IgG to a inal concentration of 0.02 mg/ml to all diluted standards, controls, and samples except those in a buffer matrix.
  • Sample concentration is determined by entering data into a 4-parameter logistic curve fitting program.

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Abstract

La présente invention se rapporte à l'observation selon laquelle l'augmentation des niveaux de relaxine dans les fluides corporels est liée aux types, à l'évolution clinique, au pronostic et aux changements métaboliques de diverses affections malignes humaines. L'invention concerne en outre des procédés de détermination des niveaux de relaxine dans les fluides corporels, destinés au diagnostic de diverses affections malignes, et elle concerne également des dosages et nécessaires de diagnostic destinés à la détermination des niveaux de relaxine dans le plasma, le sérum, les tissus et/ou l'urine.
PCT/US1996/007400 1995-06-07 1996-05-16 Dosages et necessaires de diagnostic permettant de detecter la relaxine, leurs procedes et utilisations WO1996041167A1 (fr)

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AU58011/96A AU5801196A (en) 1995-06-07 1996-05-16 Relaxin diagnostic assays and kits, and methods and uses thereof

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US48839995A 1995-06-07 1995-06-07
US08/488,399 1995-06-07

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1399537A2 (fr) * 2001-04-03 2004-03-24 Curagen Corporation Polypeptides therapeutiques, acides nucleiques les codant, et procedes d'utilisation
US7833526B2 (en) 2000-10-04 2010-11-16 Molecular Medicine Research Institute Methods of modulating apoptosis by administration of relaxin agonists or antagonists

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BRITISH JOURNAL OF CANCER, Volume 70, issued 1994, BANI et al., "Differentiation of Breast Cancer Cells In Vitro is Promoted by the Concurrent Influence of Myoepithelial Cells and Relaxin", pages 900-904. *
JOURNAL OF BIOLOGICAL CHEMISTRY, Volume 265, No. 16, issued 05 June 1990, OSHEROFF et al., "Preparation of Biologically Active 32P-Labeled Human Relaxin Displaceable Binding to Rat Uterus Cervix and Brain", pages 9396-9401. *
JOURNAL OF ENDOCRINOLOGY, Volume 140, No. 2, issued February 1994, STEMMERMANN et al., "Immunocytochemical Identification of a Relaxin-like Protein in Gastrointestinal Epithelium and Carcinoma: a Preliminary Report", pages 321-325. *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7833526B2 (en) 2000-10-04 2010-11-16 Molecular Medicine Research Institute Methods of modulating apoptosis by administration of relaxin agonists or antagonists
US8119136B2 (en) 2000-10-04 2012-02-21 Molecular Medicine Research Institute Methods of modulating apoptosis by administration of relaxin agonists or antagonists
US9534034B2 (en) 2000-10-04 2017-01-03 Molecular Medicine Research Institute Methods of modulating apoptosis by administration of relaxin agonists or antagonists
EP1399537A2 (fr) * 2001-04-03 2004-03-24 Curagen Corporation Polypeptides therapeutiques, acides nucleiques les codant, et procedes d'utilisation
EP1399537A4 (fr) * 2001-04-03 2006-09-06 Curagen Corp Polypeptides therapeutiques, acides nucleiques les codant, et procedes d'utilisation

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