WO2001048479A1 - Procede de determination de la possibilite d'avortement spontane ou d'accouchement premature et reactif associe - Google Patents

Procede de determination de la possibilite d'avortement spontane ou d'accouchement premature et reactif associe Download PDF

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Publication number
WO2001048479A1
WO2001048479A1 PCT/JP2000/009301 JP0009301W WO0148479A1 WO 2001048479 A1 WO2001048479 A1 WO 2001048479A1 JP 0009301 W JP0009301 W JP 0009301W WO 0148479 A1 WO0148479 A1 WO 0148479A1
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WIPO (PCT)
Prior art keywords
premature birth
possibility
antibody
abortion
concentration
Prior art date
Application number
PCT/JP2000/009301
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English (en)
Japanese (ja)
Inventor
Takaji Kurosu
Original Assignee
Fuji Chemical Industries, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fuji Chemical Industries, Ltd. filed Critical Fuji Chemical Industries, Ltd.
Priority to AU22272/01A priority Critical patent/AU2227201A/en
Publication of WO2001048479A1 publication Critical patent/WO2001048479A1/fr

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Classifications

    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/689—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to pregnancy or the gonads

Definitions

  • the present invention relates to a method for determining the possibility of premature birth and a reagent therefor.
  • a PL is a general term for autoantibodies to phospholipids such as anti-cardiolipin antibody (aGL) ⁇ anti-phosphatidylserine antibody (aPS) and lupus anticoagulant (LA).
  • aGL anti-cardiolipin antibody
  • aPS anti-phosphatidylserine antibody
  • LA lupus anticoagulant
  • APS antiphospholipid antibody syndrome
  • a PL is recognized antigen is not a phospholipid itself, yS 2 -glycoprotein I (S 2 GP I) and proteinC that caused structural changes to form a phospholipid complexes, prote INS, such AnexinV ( Since all reported as cof actors, studies on this cofactor have been promoted, and many reports have been published on aPL associated with habitual miscarriage and thrombosis and cofactor involvement. . However, a conclusion has not yet been reached as to how PL causes blood clots in living organisms.
  • TM thrompomodulin
  • the present invention provides a method for determining the possibility of abortion prematurely, which comprises measuring the TM in a body fluid.
  • the present invention also provides a reagent for determining the possibility of abortion prematurely, which comprises an antithrombomodulin antibody.
  • the present invention a method has been provided which can more accurately determine the possibility of premature birth than the conventional method. If the potential for miscarriage is accurately demonstrated, precautionary measures can be taken to reduce miscarriages. Therefore, the present invention is expected to greatly contribute to safe childbirth.
  • FIG. 2 is a diagram showing the time-dependent change in serum TM concentration of aPL-negative pregnant women at the first consultation and the change in aPL-positive negative.
  • TM is a coagulation inhibitory factor present on vascular endothelial cells, and is released into the blood when injuries such as inflammation occur in blood vessels.
  • TM released into the blood binds to thrombin and has the anticoagulant effect of losing thrombin clotting activity.
  • this thrombin ⁇ TM complex activates protein C and activates protein S.
  • Blood TM has been conventionally used as a marker for determining whether blood vessels have inflammation. However, the use of blood TM as a marker for determining the possibility of premature birth has not been known or suggested.
  • the body fluid used in the method of the present invention examples include, but are not limited to, blood (including serum and plasma), urine, vaginal secretion, and cervical secretion. Among them, it is preferable to use blood, especially serum or plasma.
  • the TM concentration in a body fluid is measured, and the value is compared with a normal value. That is, as specifically shown in the following examples, when premature birth occurs, the TM concentration in the body fluid increases several weeks before (particularly about 4 to 6 weeks before).
  • TM in body fluids of normal pregnant women pregnant women who reached term delivery without any signs of urgency or pregnancy toxicity
  • SD standard deviation
  • TM Panacera trade name, manufactured by Fuji Pharmaceutical
  • the threshold value is not necessarily limited to the above value or the above-mentioned average + 2 SD value, and can be set as appropriate according to the purpose of the determination (for example, whether it is a screening purpose or a definite diagnosis purpose). . For example, if you want to determine as few possible pregnant women as to have a premature birth for screening purposes, the threshold may be set, for example, in the range of the average of normal pregnant women + 1 SD to the average + 2 SD, or almost certainly.
  • the threshold may be set, for example, in the range of +2 SD to +4 SD for normal pregnant women.
  • the threshold in the case of serum TM concentration measured using "Panasera" (trade name) manufactured by Fuji Pharmaceutical Co., Ltd. is lower than 3.8 FU / ml, for example, in the range of 3.0 FU / ml to 3.7 FU / ml. It is also possible to set within a higher range, for example, from 3.9 FU / ml to 5.0 FU / ml.
  • the determination may be made based on whether the TM concentration in the sample is statistically significantly higher than that of a normal pregnant woman.
  • the method of the present invention has higher accuracy than the conventional aPL-based diagnostic method.
  • kits for TM measurement using sandwich ELISA are commercially available, in which the antibody sensitized with an anti-TM monoclonal antibody is used as the first antibody, and the enzyme-labeled anti-TM monoclonal antibody is used as the second antibody.
  • concentration of TM in body fluid can be easily measured according to the package insert of "Panasera” (trade name) manufactured by Fuji Pharma Co., Ltd.
  • the TM concentration in the body fluid may be measured by any method, and the measuring method is not limited at all.
  • the immunoassay consists of an anti-thrombomodulin antibody (either polyclonal or monoclonal antibody) It measures the concentration of thrombomodulin in body fluids using an antigen-antibody reaction with jurin.
  • the immunoassay that can be used is not limited to the sandwich ELISA described above, and any known immunoassay can be employed. That is, when classified based on the measurement principle, there are a San German method, a competitive method, an agglutination method, etc., and any of these methods can be adopted.
  • the method for determining the possibility of miscarriage of the present invention may be performed in combination with another diagnostic method, and in some cases, the accuracy may be further improved. For example, if the aPL in blood changes from negative to positive in addition to the TM in the body fluid, and if the aPL in the blood changes from negative to positive, and the TM concentration in the body fluid rises rapidly, the risk of premature birth is high Can be determined to be very high.
  • the present invention further provides a reagent for determining the possibility of abortion prematurely, which comprises an anti-TM antibody.
  • This reagent can be used for the various well-known immunoassays described above by a well-known method.
  • the blood TM concentrations of 43 pregnant women were measured over time. The measurement was performed using 50 juI of serum collected from each pregnant woman as a sample and using the TM Panacera TM (trade name) manufactured by Fuji Pharmaceutical Co., Ltd., which is a commercial TM measurement kit for sandwich ELISA. It was performed by sandwich ELISA according to the usual method described.
  • aPL anti-cardiolipin antibody (aCL) and anti-phosphatidylserine antibody (aPS) were measured. When at least one of them was positive, aPL was determined to be positive.
  • aCL and aPS are measured by sandwich ELISA using microplate did.
  • 100 I of protamine sulfate was dispensed into each well of the microplate and allowed to stand at room temperature for 30 minutes.
  • the heart-derived cardiolipin solution manufactured by SI GMA
  • concentration: 20 ⁇ gZmI or L- ⁇
  • -phosphatidyl-L-serine solution manufactured by SIGM A
  • concentration: 20 u gZml was dispensed at 10 OI, left overnight at 4 ° C, and washed three times with PBST.
  • test serum or standard serum diluted 50-fold was dispensed, left at room temperature for 1.5 hours, and washed three times with PBST.
  • a peroxidase-labeled anti-human IgG antibody manufactured by SIGMA
  • a peroxidase-labeled anti-human IgM antibody manufactured by SIGMA
  • a peroxidase-labeled anti-human IgM antibody manufactured by SIGMA
  • diluted to an appropriate concentration were dispensed in 1 OO ju I each, and 1 ml at room temperature. After standing for 5 hours, the plate was washed three times with PBST.
  • 0.4 mM 0-phenylenediamine 100 / iI was dispensed, and allowed to stand at room temperature for 30 minutes.
  • Figures 1 and 2 show the results of 15 representative cases among the 43 cases.
  • Figure 1 shows the results for pregnant women who were aPL-positive at the first visit
  • Figure 2 shows the results for pregnant women who were aPL-negative at the first visit.
  • Cases 1, 2, 9, and 10 were premature births, and the other cases were term births.
  • the first and second pregnancies with positive aPL and premature birth in cases 1 and 2 and cases 3 and 4 showing signs of urgency showed a rapid rise in blood TM level, but the symptoms recovered after treatment In cases 3 and 4, the ascent curve thereafter stopped.
  • TM2 continues to rise.
  • the M-value increase in Case 1 that resulted in miscarriage shortly after treatment was rapid.
  • the TM value increased before the occurrence of miscarriage or imminent miscarriage. Since no increase was observed in normal pregnant women, TM measurement was easy to distinguish between normal and abnormal.

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Chemical & Material Sciences (AREA)
  • Urology & Nephrology (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Immunology (AREA)
  • Microbiology (AREA)
  • Food Science & Technology (AREA)
  • Biotechnology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Reproductive Health (AREA)
  • Pregnancy & Childbirth (AREA)
  • Gynecology & Obstetrics (AREA)
  • Cell Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

L'invention concerne un procédé de détermination de la possibilité d'avortement spontané ou d'accouchement prématuré, cette possibilité pouvant être déterminée de manière exacte par rapport à des procédés existants, ainsi qu'un réactif s'utilisant dans ledit procédé. Ce procédé consiste à mesurer la thrombomoduline contenue dans un fluide corporel. Une concentration sensiblement supérieure à la normale de thrombomoduline dans le fluide corporel indique une probabilité plus élevée d'avortement spontané ou d'accouchement prématuré.
PCT/JP2000/009301 1999-12-28 2000-12-27 Procede de determination de la possibilite d'avortement spontane ou d'accouchement premature et reactif associe WO2001048479A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU22272/01A AU2227201A (en) 1999-12-28 2000-12-27 Method of judging the possibility of abortion/premature birth and reagent therefor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP11/372554 1999-12-28
JP37255499 1999-12-28

Publications (1)

Publication Number Publication Date
WO2001048479A1 true WO2001048479A1 (fr) 2001-07-05

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2000/009301 WO2001048479A1 (fr) 1999-12-28 2000-12-27 Procede de determination de la possibilite d'avortement spontane ou d'accouchement premature et reactif associe

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AU (1) AU2227201A (fr)
WO (1) WO2001048479A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6447391A (en) * 1987-04-01 1989-02-21 Mitsubishi Gas Chemical Co Monoclonal antibody and use thereof
WO1991006857A1 (fr) * 1989-11-02 1991-05-16 Teijin Limited Procede d'analyse immunologique de la thrombomoduline humaine, et reactif et kit utilises a cet effet

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6447391A (en) * 1987-04-01 1989-02-21 Mitsubishi Gas Chemical Co Monoclonal antibody and use thereof
WO1991006857A1 (fr) * 1989-11-02 1991-05-16 Teijin Limited Procede d'analyse immunologique de la thrombomoduline humaine, et reactif et kit utilises a cet effet

Also Published As

Publication number Publication date
AU2227201A (en) 2001-07-09

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