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WO1994024569A1 - Temoin de marqueurs tumoraux - Google Patents

Temoin de marqueurs tumoraux Download PDF

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Publication number
WO1994024569A1
WO1994024569A1 PCT/US1994/003884 US9403884W WO9424569A1 WO 1994024569 A1 WO1994024569 A1 WO 1994024569A1 US 9403884 W US9403884 W US 9403884W WO 9424569 A1 WO9424569 A1 WO 9424569A1
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WO
WIPO (PCT)
Prior art keywords
serum
tumor
level
markers
cea
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Ceased
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PCT/US1994/003884
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English (en)
Inventor
Kathryn Herring
Denise Sandberg
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Baxter Healthcare Corp
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Baxter Diagnostics Inc
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Filing date
Publication date
Application filed by Baxter Diagnostics Inc filed Critical Baxter Diagnostics Inc
Priority to EP94914089A priority Critical patent/EP0647322A1/fr
Priority to JP6523333A priority patent/JPH07508352A/ja
Priority to AU66292/94A priority patent/AU679743B2/en
Publication of WO1994024569A1 publication Critical patent/WO1994024569A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • G01N33/96—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood or serum control standard
    • 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
    • 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
    • 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
    • G01N2333/665—Assays involving proteins derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
    • G01N2333/695—Corticotropin [ACTH]
    • 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
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • 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
    • G01N2333/82—Translation products from oncogenes

Definitions

  • This invention relates generally to the field of stable human serum based controls for use in in vitro diagnostic assays and more specifically to stable human serum based controls for use in monitoring the precision of in vitro diagnostic assays for tumor markers.
  • Tumor markers are substances released by tumor cells into the blood stream.
  • the tumor markers can be detected in serum or other body fluids and are useful for clinically monitoring various malignancies.
  • the term tumor marker has been extended to include cell or tissue characteristics, such as oncogenes or abnormally expressed proteins such as enzymes, hormones, and receptors that are related to and assist in identifying the tumor type.
  • Clinical oncologists measure the presence and/or amount of these markers in bodily fluids to assist them in the diagnosis of the condition, as well as for prognosis and the monitoring of the treatment of the patient.
  • Serum assays of tumor markers are commercially available.
  • serum assays are performed using assay systems such as radioimmunoassay, enzyme immunoassay, fluorescence immunoassays and other clinical analysis techniques.
  • Controlling and monitoring the accuracy, precision, and reliability of these assay systems is critical to ensure that the patient receives the correct treatment and that the results of the assays are medically relevant.
  • Controls generally, are in levels representing specific ranges, for example a high, low, and/or normal range.
  • These commercially available tumor control products include Cancer Antigen Controls, from POL YMEDCO, T-MARKERS QUALITY CONTROL SERUM, from NMS Pharmaceuticals, Inc. and LYPHOCHEK® Tumor Marker Control, from BIO-RAD.
  • Currently available commercial controls lack many of the tumor markers that are required by the clinical oncologists.
  • the currently available commercial controls have limited clarity, limited lyophilized stability and limited reconstituted stability.
  • some of the commercially available controls are only two level controls (i.e. High and Low).
  • the concentrations of some of the components in the commercially available controls are either too high or too low to be completely useful.
  • Tumor markers for use in the controls do not necessarily need the high degree of purity resulting from some of these purification schemes.
  • the human based serum or plasma control according to the present invention preferably contains many of the tumor markers that are utilized by clinical oncologists to diagnose patients.
  • the human based serum or plasma control according to the present invention has enhanced lyophilized and reconstituted stability and has enhanced optical clarity after reconstitution.
  • the human based serum or plasma control of the present invention comprises a base of male human plasma or serum that has been lipid stripped and tumor markers.
  • the tumor markers may include
  • Adenocorticotropic Hormone (ACTH), Aldosterone, Alphafetoprotein (AFP), beta-2-microglobulin (B2M), CA 15-3®, CA 125®, CA 19-9®> CA 19-9® (Registered Trademarks of Centocor Diagnostics, a division of Centocor Inc.), CA 549, Carcinoembryonic -Antigen (CEA), Ferritin, Gastrin, human Chorionic Gonadotropin (hCG), beta hCG, Gamma Enolase (NSE), Prolactin, Prostatic Acid Phosphatase (PAP), Prostatic Specific Antigen (PSA), Tissue Polypeptide Antigen (TPA), Calcitonin and LD-1.
  • a preservative system should also be include in the control.
  • the preservative system should include a preservative that is stable both prior to lyophilization and after lyophilization.
  • a preservative system is necessary in order to ensure reconstituted stability of certain markers especially enzymes that are very sensitive to proteases that are produced by microorganisms.
  • a combination of preservatives are added.
  • the preferred preservative system is a combination of gentamicin sulfate, cycloheximide and Proclin 300 (Rohm and Haas).
  • the Proclin 300 is not effective after lyophilization, however, it is useful in controlling microbial growth during the manufacturing process.
  • the gentamicin sulfate and cycloheximide are used to control growth of microorganisms after reconstitution.
  • Sodium azide is not used mainly due to the hazard of the explosive properties of the azide.
  • the stability of the lyophilized control should be at least about a year and preferably at least about three years.
  • the reconstituted stability of the majority of the components should be at least about seven days and preferably at least about fourteen days.
  • the base of human serum or plasma should be substantially from all male donors in order to preserve the stability of the PAP marker. In the presence of substantially all male serum or plasma, the PAP is very stable.
  • Female serum and plasma may contain antibodies to this enzyme marker. The antibodies would effectively eliminate the PAP from the control solution. If the antibodies are successfully removed or their effects eliminated from the female serum or plasma, the resulting serum or plasma could be utilized as the base material.
  • the content of the lipids in the human serum or plasma must be reduced. The lipid content may be reduced by treating the serum or plasma with fumed silica or dextran sulfate or other known processes. The process used to reduce the lipids must ensure that the content of cholesterol and triglycerides in the human serum or plasma is less than about 20 mg/dL each after processing. There are at least three reasons to reduce the lipid content.
  • the stability of added tumor markers which are easily denatured or oxidized is increased when the lipid content is reduced. This is because when the lipids break down, they form oxidation by ⁇ products that can interfere with the stability of some of the markers.
  • the breakdown of lipids results in turbid solutions.
  • the lipid reduction aids in the reconstitution process.
  • the lyophilized control reconstitutes immediately upon the addition of the liquid when the lipids are eliminated.
  • the reconstitution time of the lyophilized control is delayed by between about 15 to 30 minutes if serum or plasma containing normal amounts of lipids are utilized.
  • the serum or plasma that is utilized as the base for the control should be assayed for the tumor markers that will be added prior to the addition of those tumor markers.
  • Table I is a classification of the various types of tumor markers that are added to the base material.
  • Table II lists the tumor markers and the types of cancers that are usually associated with that marker.
  • the tumor markers that are added into the base material must be relatively pure - that is not cross contaminated with other markers or contaminated with interfering substances. It is best to use sources of tumor markers that are native human forms; however, it has been found that many of the human source tumors produce more than one marker.
  • this raw source makes it difficult to formulate a control with an accurate amount of each tumor marker.
  • the tumor marker could end up being added in an amount that is too high to be useful for low or normal control levels.
  • the tumor markers must be purified to remove cross-contamination.
  • the tumor markers that are to be added to the base material should be assayed to determine the presence of cross-contaminants and known interfering substances.
  • B2M may be purified from urine that has been collected from patients having renal failure. Particulates are removed and the urine is diafiltered into an appropriate buffer and concentrated.
  • the B2M a protein, has an approximate molecular weight of about 11,000 daltons; thus, it can be purified using size exclusion chromatography such as gel filtration chromatography. Preferred gel materials are Ultragel ACA 54 or its equivalents.
  • the fractions containing the B2M are pooled and concentrated to preferably at least about 1 g/dL, then the outcome of the purification can be determined using such known methods as electrophoresis.
  • the B2M is tested by commercially available immunoassay.
  • the B2M is stable when stored either at about 2-8 C or frozen at less than about -20 C.
  • the resulting B2M may contain up to as much as about 70% of impurities of immunoglobulins without effecting the usefulness of the B2M..
  • CA 125 is a marker that is specific to ovarian cancer. This marker may be found in ascites fluid that is collected from patients with ovarian cancer. The ascites fluid contains two marker, CA 125 and TPA. The contamination level of the TPA is very high; thus, in order to add an accurate amount of each of CA 125 and TPA, the markers must be separated. Both of these markers are shed into the serum during tumor growth and due to the similarities of these markers the separation of them is difficult. It was discovered that TPA binds to a hydrophobic interaction chromatography media, Phenyl Sepharose (Pharmacia), in the presence of phosphate buffer at about a physiological pH. A phosphate buffer of about 50 mM phosphate at a pH of about 7.2 is preferred.
  • Phenyl Sepharose Phenyl Sepharose
  • the ascites fluid is applied onto a column of Phenyl Sepharose.
  • the majority of the CA 125 does not bind to the Phenyl Sepharose and flows directly though the column and is collected.
  • the column is then washed with the phosphate buffer to which has been added about 2.5 M urea. This buffer elutes the remaining CA 125.
  • the column is then washed with the phosphate buffer to which has been added about 6 M urea.
  • the TPA is eluted with this buffer and collected.
  • chromatography using Phenyl Sepharose requires a high salt concentration for binding to occur.
  • the TPA binds without a high salt concentration.
  • the separated proteins are buffer exchanged to remove the urea and are concentrated to a protein level of preferably about greater than lg/dL.
  • the separation of the proteins may be confirmed by assaying the separated proteins using commercially available immunoassay techniques.
  • CEA , CA 19-9 and TPA are often obtained from the same source; thus, they must be separated from each other.
  • CEA is a large glycoprotein of about 200,000 daltons and is found at elevated levels in the serum of patients with colon cancer.
  • CEA is an oncofetal antigen that is expressed during intra-uterine life and disappears after birth. Oncofetal antigens reappear in situations of repair or neoplastic growth in the organs where they appeared during gestation.
  • CA 19-9 is a tumor mucin antigen.
  • Tumor mucins are high molecular weight glycoprotein from about 200,000 daltons to 1000 kDA and contain from about 25% to 80% carbohydrate. As a tumor marker
  • CA 19-9 is elevated in patients with pancreatic cancer and gastrointestinal cancer.
  • SW 1116 is a human cell line developed from a colorectal carcinoma.
  • the cancer cells excrete the antigens into a cell growth media.
  • the cell growth medium is collected and frozen as it is produced.
  • the cell supernatant is thawed and concentrated about 20 times.
  • the concentrated supernatant is buffer exchanged into buffers such as phosphate buffers at physiological pHs.
  • the preferred buffer is 50 mM phosphate at about pH 7.2.
  • CEA, CA 19-9 and TPA are somewhat different, they are all glycoproteins and are very difficult to separate by typical chromatography methods. Precipatation methods using perchloric acid treatment to precipatate the CEA have been suggested, however the process results in a low yield of the purified markers.
  • the CEA is not required to be obtained from this method, it is preferred to combine the fractions from the Phenyl Sepharose column and then wash the Phenyl Sepharose column with a phosphate buffer, preferably 50 mM phosphate at pH 7.2, containing from about 2 to 3 M urea to remove any additional CA 19-9. The eluant is collected. All of the fractions containing CA 19-9 and CA 19-9 with CEA are combined. The column is next eluted with the same buffer but also containing about 6 M urea. The TPA is eluted and collected.
  • a phosphate buffer preferably 50 mM phosphate at pH 7.2, containing from about 2 to 3 M urea to remove any additional CA 19-9.
  • the eluant is collected. All of the fractions containing CA 19-9 and CA 19-9 with CEA are combined.
  • the column is next eluted with the same buffer but also containing about 6 M urea.
  • the TPA is eluted
  • the CA 19-9/CEA containing pool is buffer exchanged to remove the urea and concentrated to at least about 1 g/dL.
  • the CA 19-9 in the concentrate by freezing the concentrate. Long term freezing of the CA 19-9 results in a loss of activity of the CEA, however the activity of the CA 19-9 is preserved. Thus, the entire purification process can be simplified.
  • the length of freezing time can be determined by testing aliquots of the concentrate for the presence of CEA by immunoassay techniques. The approximate recovery can be up to 100%.
  • the fractions containing the CEA/CA 19-9 can be discarded. Then, only the fractions containing CA 19-9 are pooled and concentrated.
  • the TPA is also buffer exchanged and concentrated as described above.
  • the recovery of the TPA can also be up to about 100%.
  • Cross- contamination is determined using immunoassay techniques.
  • the CEA can be obtained as described above using the monoclonal antibody method or it may be obtained from other commercially available sources.
  • the CEA should be tested for cross- contamination with immunoassay methods prior to use in a control. If contamination is detected, the CEA must be purified using one of the methods known in the art, preferably the affinity method described above.
  • NSE is obtained from fresh or freshly frozen human brain. Purified NSE may be obtained commercially. The preferred method for purification is accomplished by preparing a homogenate of the brain, centrifuging the homogenate and collecting the supernatant. Next the supernatant is pelleted using 40% ammonium sulfate. The pellet is resuspended in a 10 mM Tris-phosphate buffer and dialyzed against the buffer then concentrated. The concentrate is chromatographed on DE- 52 and eluted with a 0.15 M -0.35 M NaCl gradient. The peak containing the NSE is dialyzed, lyophilized and fractionated on Sephadex G 150 or the like. Polybufferexchanger chromatofocussing is used to focus the NSE. The NSE is then eluted and finally fractionated on G-150 (Superfine).
  • AFP must be purified.
  • AFP is an oncofetal antigen like CEA.
  • AFP is a glycoprotein expressed in fetal liver and digestive tract. In adults elevated levels of this antigen in serum is associated with malignant hepatoma and in some cases of ovarian and testicular cancers.
  • the best source of this antigen is human cord serum collected at the time of birth. This serum contains high levels of AFP (about 60,000 ng/mL) and contains only one contaminating tumor marker, Prolactin.
  • AFP from the Prolactin is accomplished using ion exchange chromatography.
  • the cord serum is applied onto a cation exchange resin.
  • the AFP binds to the column but the majority of the Prolactin does not bind to the column.
  • the serum is added to the column, and the Prolactin is washed through the column.
  • the Prolactin can be collected.
  • the AFP can then be eluted off of the column using about 0.2 to 0.3 M sodium chloride with the buffer.
  • the isolated AFP is then concentrated to about lmg/mL.
  • the AFP purified in this manner may contain large quantities of albumin. However, this contaminant is not a problem since the serum or plasma based material contains albumin.
  • the purified AFP can be tested using immunoassay procedures.
  • the other tumor markers such as ACTH, aldosterone, hCG, beta- hCG, CA 15-3, CA 549, Calcitonin, Ferritin, Gastrin, PAP, PSA, Prolactin and LD-1 are available commercially from several sources. These other markers can be obtained purified or can be purified by procedures well known in the art. For each tumor marker, cross- contamination can be assessed by immunoassay techniques.
  • the LD-1 is added as a component of LDH by determining the amount of LD-1 present in LDH.
  • the solutions for the controls are formulated by first assaying the plasma or serum and all the specific tumor markers that are used to spike the plasma or serum.
  • Table IV shows the target values for each of the specific tumor marker at each of the three levels of controls that are prepared. Calculations are performed by subtracting the concentration of each marker in the serum or plasma from the mean targeted value in Table IV, then adding the appropriate amount of each marker to each of the three levels of controls.
  • the tumor markers are added to the serum or plasma according to the stability of each marker. Markers such as B2M, AFP, Prolactin, hCG, Beta-hCG, CA-15-3, CA-19-9, CA 549, CA 125, CEA, Ferritin,
  • TPA, and LD-1 may be added and adjusted within a few days of lyophilization as long as the temperature of the serum or plasma is controlled within about 2 to 10 C. If all the materials are kept at between about 2-10 C, the ACTH, Gastrin, gamma enolase, and calcitonin (markers which have short term liquid stability) may be added up to about six hours prior to lyophilization. Preferably these markers are added immediately prior to lyophilization and the additions and adjustments are done at low temperatures, that is 2-10 C.
  • Each of the three levels of liquid controls are lyophilized using standard methods!
  • the bottles containing the lyophilized controls are sealed under vacuum and then stored at about 4C.
  • the controls are reconstituted with water or other appropriate liquids such as buffers.
  • the results can be used to determine the pre-lyophilization level of ACTH that is necessary to recover a specific post lyophilization level of ACTH.
  • the stability of all of the markers in the lyophilized control was determined to be four weeks at a stressed temperature of 37 C. See,
  • Table V This is thought to correspond to about 3 years when stored at 2-8 C.
  • a reconstituted stability of at least two weeks was found for all markers except ACTH, gastrin and calcitonin. See, Table VI. The ACTH, gastrin and calcitonin must be used shortly after reconstituting with liquid. It was also found that the reconstituted stability can be prolonged for 30 days for all analytes except NSE, gastrin and calcitonin by freezing aliquots of the reconstituted material at -20C. See, Table VII. The stability of the gastrin and calcitonin can be prolonged for seven days by freezing aliquots of the reconstituted material at -20C.
  • a urine concentrate was prepared by collecting urine from patients with renal failure. The urine was pooled and sodium azide at
  • the urine was filtered through a membrane of less than 0.3 microns to remove all particulates and microbes. The urine was then diafiltered against seven volumes of 50 mM Tris buffer, pH 8.0 and concentrated to a volume 100 times the original volume. For example, 100 liters was concentrated to 1 liter.
  • the concentrated urine was adjusted to a total protein concentration of about 9.0 g/dL using the above buffer.
  • Ultragel ACA 54 column The sample size is dependent upon the column size and is equivalent to 2.5% of the total volume of the media.
  • the length of the column must be about 100 cm for effective separation of the proteins. Fractions containing the B2M were combined, pooled and concentrated to about 1 g/dL.
  • a buffer containing about 50 mM phosphate at pH 7.2 with increasing amounts of urea was applied to the column.
  • the TPA was eluted with urea at about 6M.
  • the TPA containing fractions were pooled and concentrated then diafiltered to remove the 6M urea.
  • the CA 19-9 fractions undergo long term storage to remove the activity of any CEA that contaminates the CA 19-9.
  • Delipidated serum from males was filtered through the following sequences of filters: a prefilter, a 1.2 micron filter, a 0.8 micron filter, a 0.45 micron filter and a 0.22 micron filter.
  • the filtered serum was refrigerated.
  • Proclin 300 from Rohm and Haas was added at a concentration of 1 mL per liter of serum.
  • the serum was divided into two pools of about 1.92 liters per pool - designated as Pool 1 and Pool 2.
  • the serum was assayed for amounts of ACTH, Aldosterone, B2M, hCG, beta-hCG, CA 15-3, CA 19-9, CA 125, CA 549, calcitonin, CEA, Ferritin, gastrin, NSE, PAP, PSA, Prolactin, TPA, and LD-1 using immunoassay techniques.
  • Each of the markers were obtained through purifications as described herein or were obtained commercially. The amount of each marker was determined. An amount of each marker necessary to reach the values given in Table IV, Level I ranges were added to Pool 1. An amounts of each marker to reach the values given in Table IV, Level III ranges were added to Pool 2. The amounts of marker were assayed and any adjustments were made by either by adding additional amounts of marker.
  • Three milliliters aliquots from Pool 1 (Level 1) were filled into vials that had been chilled in a freezer for about one hour and three milliliter aliquots from Pool 2 (Level 3) were filled into vials that had been chilled in a freezer for about one hour.
  • the vials were lyophilized, sealed under a vacuum and stored at about 4C.
  • Adenocortitropic Hormone Lung (ACTH)
  • Beta 2 Microglobulin Bone Marrow
  • PAP Prostatis Acid Phosphatase Prostate
  • PSA Prostate Specific Antigen Prostate
  • Adenocorticotropic Hormone pg/mL 35 (20-50) 65 (50-80) 400 (350-450
  • Alpha-Fetoprotein ng/mL 10 (7-13) 75 (65-85) 250 (230-270
  • Aldosterone pg/dL 50 (30-70) 110 (95-125) 700 (650-750
  • Thyrocalcitonin pg/mL 30 (20-40) 110 (100-120) 600 (550-650
  • Gastrin pg/mL 60 (50-70) 200 (190-210) 400 (390-410)
  • LDH-1 U/L 150 (130-170) 250 (240-260) 350 (340-360)
  • Prolactin ng/mL 5 (3-7) 20 (18-22) 150 (140-160)
  • Tissue Polypeptide Antigen U/L 30 (25-35) 100 (90-100) 500 (490-510)
  • CA 15-3, Ca 19-9, CA 125 are trademarks of Centocor Diagnostics, a division of Centocor

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Abstract

Témoin stable à base de sérum ou de plasma pour diagnostiquer des tumeurs, ledit témoin contenant des marqueurs tumoraux adaptés au diagnostic de tumeurs. Le sérum ou le plasma a une teneur réduite en lipides. Un procédé de préparation du témoin est également décrit.
PCT/US1994/003884 1993-04-22 1994-04-08 Temoin de marqueurs tumoraux Ceased WO1994024569A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP94914089A EP0647322A1 (fr) 1993-04-22 1994-04-08 Temoin de marqueurs tumoraux
JP6523333A JPH07508352A (ja) 1993-04-22 1994-04-08 腫瘍マーカー対照
AU66292/94A AU679743B2 (en) 1993-04-22 1994-04-08 Tumor marker control

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US5200193A 1993-04-22 1993-04-22
US08/052,001 1993-04-22

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WO1994024569A1 true WO1994024569A1 (fr) 1994-10-27

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JP (1) JPH07508352A (fr)
AU (1) AU679743B2 (fr)
CA (1) CA2137784A1 (fr)
WO (1) WO1994024569A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0040058A1 (fr) * 1980-05-08 1981-11-18 Corning Glass Works Procédé pour la détection d'antigène oncofétale, pour la détection du cancer, pour analyser le traitement anti-cancéreux et kit de diagnostic propre audit procédé
US4489167A (en) * 1981-06-02 1984-12-18 Baxter Travenol Laboratories, Inc. Methods and compositions for cancer detection
EP0351117A2 (fr) * 1988-07-11 1990-01-17 Dade International Inc. Témoin stable de contrôle à base de sérum humain
WO1991016632A1 (fr) * 1990-04-12 1991-10-31 Board Of Regents, The University Of Texas System Proteines de reponse aux chocs thermiques et au stress et pronostic du cancer
WO1992008976A1 (fr) * 1990-11-19 1992-05-29 Onco Medics B.V. Procede de determination d'acide sialique lie aux lipides et compris dans du plasma

Patent Citations (5)

* Cited by examiner, † Cited by third party
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EP0040058A1 (fr) * 1980-05-08 1981-11-18 Corning Glass Works Procédé pour la détection d'antigène oncofétale, pour la détection du cancer, pour analyser le traitement anti-cancéreux et kit de diagnostic propre audit procédé
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CA2137784A1 (fr) 1994-10-27
AU679743B2 (en) 1997-07-10
AU6629294A (en) 1994-11-08
JPH07508352A (ja) 1995-09-14
EP0647322A1 (fr) 1995-04-12

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