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WO1999058974A1 - Procede et dispositif de test d'evaluation de la maturite cervicale a terme avec des isoformes de igfpb-1 fortement phosphorylees - Google Patents

Procede et dispositif de test d'evaluation de la maturite cervicale a terme avec des isoformes de igfpb-1 fortement phosphorylees Download PDF

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Publication number
WO1999058974A1
WO1999058974A1 PCT/FI1999/000390 FI9900390W WO9958974A1 WO 1999058974 A1 WO1999058974 A1 WO 1999058974A1 FI 9900390 W FI9900390 W FI 9900390W WO 9958974 A1 WO9958974 A1 WO 9958974A1
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Prior art keywords
igfbp
cervical
phosphorylated
test device
term
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Ceased
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PCT/FI1999/000390
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English (en)
Inventor
Eeva-Marja Rutanen
Tytti KÄRKKÄINEN
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Medix Biochemica Oy AB
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Medix Biochemica Oy AB
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Priority to AU40426/99A priority Critical patent/AU4042699A/en
Publication of WO1999058974A1 publication Critical patent/WO1999058974A1/fr
Anticipated expiration legal-status Critical
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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
    • G01N33/68—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
    • 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
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4745—Insulin-like growth factor binding protein
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/36—Gynecology or obstetrics
    • G01N2800/368—Pregnancy complicated by disease or abnormalities of pregnancy, e.g. preeclampsia, preterm labour

Definitions

  • the present invention is related to improved methods and test devices for assessing cervical ripeness at term, and for predicting susceptibility of delivery and/or determining the cause and origin of the minor amounts of IGFBP-1 present in cervical samples with immunoassays capable of differentiating phosphorylated and nonphosphorylated isoforms of insulin- like growth factor binding protein 1 (IGFBP-1) .
  • the invention is also related to the use of specific binding substances capable of recognizing highly phosphorylated decidua-derived isoforms of IGFBP-1 different from amniotic fluid-derived phosphorylated isoforms for predicting the risk of preterm delivery and for properly timing the labor induction in preterm, term and postterm pregnancies.
  • IGFBP-1 Insulin- like growth factor binding protein- 1
  • placental protein-12 Insulin-like growth factor binding protein- 1
  • the objective of the present invention is to provide a method and test device by the aid of which the problem, i.e. the uncertainty of the cause and origin of IGFBP-1 could be solved.
  • the problem i.e. the uncertainty of the cause and origin of IGFBP-1 could be solved.
  • amniotic fluid mostly contains nonphosphorylated and/or less phosphorylated IGFBP-1, whereas cervical ripeness and susceptibility of delivery should be diagnosed with methods and test devices assessing the presence of phosphorylated isoforms of IGFBP-1.
  • FIG. 1 IGFBP-1 concentrations in ripe (Bishop scores > 6) and unripe (Bishop scores ⁇ 5) cervices and changes in cervical IGFBP-1 concentrations at 6-hour intervals after consecutive application of PGE2 gel in women with unripe cervix measured by immunoenzymometric assay 1 (monoclonal antibody 6305 as the solid phase) .
  • the first cervical swab specimens were taken before the first cervical assessment.
  • Horizontal lines denote medians with the end of each line denoting ripe cervix allowing amniotomy.
  • Each square denotes treatment failure followed by a cesarean section.
  • FIG. 2 IGFBP-1 concentrations in ripe (Bishop scores ⁇ 6) and unripe (Bishop scores ⁇ 5) cervices and changes in cervical IGFBP-1 concentrations at 6-hour intervals after consecutive application of PGE2 gel in women with unripe cervix measured by immunoenzymometric assay 2 (monoclonal antibody 6303 as the solid phase) .
  • the first cervical swab specimens were taken before the first cervical assessment.
  • Horizontal lines denote medians with the end of each line denoting ripe cervix allowing amniotomy.
  • Each square denotes treatment failure followed by a cesarean section.
  • Figure 3 Receiver operating characteristic curves: sensitivity (true-positive rate) and 100-specificity (false-positive rate) for various values of cervical IGFBP-1 concentrations ( ⁇ g/L) measured by two immunoenzymometric assays, assay 1 ( Figure 3a) and assay 2 ( Figure 3b) in predicting cervical maturity (Bishop scores >5) .
  • the diagonal line represents the line of unity, i.e. the expected curve if there were no relation between the predictor and outcome.
  • the term "susceptibility of delivery” is correlated to the ripeness of cervix and indicates that labor will soon start spontaneously or that it can be started artificially without causing undue and prolonged suffering and pains to the mother and child. Alternatively it means that delivery is imminent.
  • the possibility to assess cervix ripeness can be used to predict a risk of preterm delivery.
  • the assessment of cervical ripeness can be used for improved timing of e.g. artificial induction of labor.
  • cervical ripeness or maturity means the natural maturing process preceeding delivery and which is assessed e.g. by palpation as Bishop scores.
  • PROM means premature rupture of membranes.
  • the premature rupture of membrane results in escape of amniotic fluid and the condition can be diagnosed by different means as described above including immunochemical test methods, which recognize the presence of elevated levels of IGFBP-1.
  • essentially blood free cervical sample means that the cervical sample is visually blood free. Naturally, the essentially blood free condition can be determined with appropriate tests and determination methods, but there is no need for auxiliary tests to ensure essential freeness of blood.
  • immunochemical test method includes any conventional or new quantitative, semiquantitative and or qualitative immunoassays, including such with detection based on enzyme markers, radioactive markers, fluorescent markers or visible particulate markers.
  • the immunochemical tests can be performed as homogenous or heterogenous tests in liquid or dry state or combinations thereof.
  • the tests include latex-agglutination-tests, immunochromatographic immunometric assays, ELISA, EIA, RIA, FIA, etc.
  • immunochemical test method means rapid, one step-, no wash-, yes/no-, bedside or chair-side immunoassays, which do not require elaborate equipments and laboratory facilities.
  • a higher proportion of less phophorylated IGFBP-1 is an indication that the IGFBP-1 originates from amniotic fluid (assay 1)
  • a higher proportion of the highly phosphorylated IGFBP-1 than less phosphorylated IGFBP-1 indicates that the IGFBP-1 originates from cervix (assay 2) .
  • IGFBP-1 means the major secretory protein of human decidua (Julkunen M et al . , FEBS Lett 1988; 236: 295-302; Rutanen E-M et al . , Endocrinology 1985; 116: 1304-9) and its concentration in the amniotic fluid is 100 to 1000 -fold higher than that in serum (Rutanen E-M et al . , Am J Obstet Gynecol 1982; 144 : 460-3) .
  • IGFBP-1 exists in five electrophoretically and chromatographically distinct isoforms. IGFBP-1 is phosphorylated in serine residues (Ser 191 , Ser 11 ⁇ , Ser 1 ⁇ , containing 70%, 5% and 25% of incorporated phosphate when tested with 32 P-labelled IGFBP-1) . (Frost & Tseng, 266 (1991) , 18082-18088); Jones et al . , 268 (1993), 1125-1131. The phosphorylated isoforms also have greater affinity towards IGF.
  • small amount of IGFBP-1 means the amounts of IGFBP-1 detectable in cervical secretion of women with intact membranes at term.
  • the cervical IGFBP-1 concentration was ⁇ 50 ⁇ g/L in 63 of 64 samples.
  • the values given are specific for the PROM TEST developed by Oy Medix Biochemica Ab for diagnosing PROM. The specific values for detecting limits should be determined individually for each test used.
  • elevated level of IGFBP-1 means "high concentration level” of different IGFBP-1 :s found in the cervix sample containing amniotic fluid.
  • binding substance means e.g. antibodies, receptors and/or ligands, but especially antibodies capable of recognizing the highly phosphorylated isoform of IGFBP-1 and differentiating them from antibodies specifically recognizing less phosphorylated or nonphosphorylated IGFBP-1.
  • the most preferred binding substance is MAb 6303, which recognizes the highly phosphorylated isoform of IGFBP-1.
  • the Mabs 6305 and 6303 which have been shown to recognize differentially different phosphoforms of IGFBP-1 (Westwood M et al. J Clin Endocrinol Metab 1994; 79: 1735-41).
  • Mab 6305 detects both nonphosphorylated and some phosphoforms of IGFBP-1, but fails to bind the highly phosphorylated isoform. Thus, Mab 6305 is used in the IEMA TEST, (Medix Biochemica) and in the PROM TEST (Medix Biochemica) designed for the diagnosis of ruptured fetal membranes (Rutanen ⁇ -M et al., Clin Chim Acta 1996; 253: 91-101).
  • test device includes any test strips, dishes, test tubes, etc., which allow an immunoassay capable of assessing the presence or absence of phosphorylated isoforms of IGFBP-1 to be preformed thereon or therein.
  • test kit means a package combination comprising one or more test devices for assessing phosphorylated isoforms of IGFBP-1 and optionally the nonphosphorylated isoform of IGFBP-1 either in the same or a separate test device as well as optional reagents, sampling devices as well as instructions .
  • the phosphorylation status of IGFBP-1 in different body fluids and tissues is known to vary (Westwood M, J Clin Endocrinol Metab 1994; 79: 1735-41; Martina NA et al . , J Clin Endocrinol Metab 1997; 82: 1874-1898.
  • the nonphosphorylated isoform predominates, but the phosphorylated isoforms exist as well.
  • Human decidual cells are known to secrete predominantly the phosphorylated isoform of IGFBP-1, 10
  • IGFBP-1 phosphorylation degree
  • the present inventors performed a study designed to clarify the origin of IGFBP-1 in cervical secretion in women with apparently intact membranes and to examine whether IGFBP-1 in cervical secretion reflects cervical ripeness in order to evaluate whether the assessment of insulin-like growth factor binding protein-1 (IGFBP-1) in cervical secretion could serve in prediction of cervical ripeness.
  • IGFBP-1 insulin-like growth factor binding protein-1
  • nonphosphorylated IGFBP-1 is the predominant isoform in decidua and maternal serum. However, in the late stages of gestation it is primarily the most highly phosphorylated form that is present, as in non-pregnant serum. As gestation progresses all of the phosphorylated isoforms are observed in decidua, and all but the most phosphorylated form can be detected in amniotic fluid. Antibody that recognizes the nonphosphorylated isoform of IGFBP-1 was selected for the Medix Biochemica PROM-test as the specificity-determining antibody, to ensure that the test favoured the isoform always found in amniotic fluid.
  • PROM premature rupture of membranes
  • an isoform of IGFBP-1 is detectable in cervical secretion, where its concentration rises with cervical ripening.
  • the assessment of the phosphorylated IGFBP-1 isoform in cervical secretion in patients with intact membranes provides an additional tool for evaluation of cervical ripeness and for prediction of the prognosis of labor induction in preterm and term pregnancies. Rapid bed-side or chair-side test designed for this purpose can easily be adapted for clinical use.
  • Microtiter wells (Nunc, Maxisorb, Roskilde, Denmark) were coated with 150 ⁇ L of antibody in 50 mM phosphate buffer (10 ⁇ g/mL) , pH 6.0. After overnight incubation, the wells were washed with PBS-Tween (0.05%), blocked with 0.5% bovine albumin (BSA) in 50 mM phosphate buffer, dried, and used for the assay. In the assay, 50 ⁇ L of assay buffer (50 mM Na2HP ⁇ 4 ,
  • the end-points for the study included comparison of the IGFBP-1 concentration given by the two assays and comparison of cervical IGFBP-1 concentrations in the unripe and ripe cervix, as well as the changes in the cervical IGFBP-1 levels after consecutive PGE2 applications. If amniotomy could not: be performed (Bishop scores ⁇ 6) after 18 hours and 3 applications of PGE2 gel, the treatment was judged as a failure .
  • the Mann-Whitney test was used for the comparison of the cervical IGFBP-1 levels in women with unripe and ripe cervix.
  • the Wilcoxon signed rank test was used to analyze the differences in IGFBP-1 levels before and after PGE2 treatment.
  • the Chi-square test was used for four-fold tablets with Yates' correction when appropriate. Continuous variables with normal distribution were compared by the two-tailed t-test. A P value ⁇ 0.05 was considered significant.
  • the receiver-operating characteristic (ROC) curves were established by plotting the 15
  • a cesarean section (CS) was performed in two cases for failed cervical ripening ( Figures 1 and 2), in three cases for failure to progress, and in two cases for fetal asphyxia. The neonatal outcome in all these women was uneventful (Table I) .
  • the IGFBP-1 concentration in each sample of the amniotic fluid was 1.9 to 5.9 times greater by assay 1 than that by assay 2 (Table II) .
  • IGFBP-1 concentrations in amniotic fluid measured by assay 1 (detecting nonphosphorylated and lesser phosphorylated isoforms of IGFBP-1) and by assay 2 (recognizing the highly phosphorylated isoform of IGFBP-1) .
  • IGFBP-1 ( ⁇ g/L)

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Abstract

La présente invention concerne des procédés améliorés et des dispositifs de test permettant d'évaluer la maturité cervicale, de prédire le déclenchement de l'accouchement et/ou de déterminer les causes et les origines des quantités moindres d'IGFBP-1 présentes dans les échantillons cervicaux à dosages immunologiques capables de différencier des isoformes phosphorylées et non-phosphorylées de la protéine 1 de liaison du facteur de croissance de substances apparentées à l'insuline (IGFBP-1). L'invention concerne également l'utilisation de substances de liaison spécifiques, particulièrement les anticorps capables de reconnaître les isoformes phosphorylées de IGFBP-1 permettant de prédire le déclenchement de l'accouchement et de déterminer correctement le début du travail lors d'accouchements avant-terme, à terme et après-terme.
PCT/FI1999/000390 1998-05-12 1999-05-10 Procede et dispositif de test d'evaluation de la maturite cervicale a terme avec des isoformes de igfpb-1 fortement phosphorylees Ceased WO1999058974A1 (fr)

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AU40426/99A AU4042699A (en) 1998-05-12 1999-05-10 Method and test device for assessing cervical ripeness at term with highly phosphorylated isoforms of igfbp-1

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FI981049A FI981049A7 (fi) 1998-05-12 1998-05-12 Menetelmä ja koeväline kohdunkaulan kypsyyden arvioimiseksi IGFBP-1:n fosforyloiduilla isomuodoilla
FI981049 1998-05-12

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007002483A1 (fr) * 2005-06-24 2007-01-04 Beckman Coulter, Inc. Dosage immunologique de proteines phosphorylees
US7892774B2 (en) 1992-06-29 2011-02-22 Oy Medix Biochemica Ab Diagnostic method for determining the susceptibility to delivery and reagent kit for use therefor
FR3048287A1 (fr) * 2016-02-26 2017-09-01 Biosynex Procede de detection d'accouchement imminent
US10689704B2 (en) 2015-03-06 2020-06-23 Imperial College Of Science, Technology And Medicine Method for predicting cervical shortening and preterm birth
CN117288966A (zh) * 2023-11-27 2023-12-26 山东康华生物医疗科技股份有限公司 一种联合检测igf-1和igfbp-3的试剂盒及其所用裂解液、缓冲液

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992012426A1 (fr) * 1990-12-31 1992-07-23 Oy Medix Biochemica Ab Procede de diagnostic permettant de detecter une rupture des membranes f×tales et son kit d'essai
WO1994000765A1 (fr) * 1992-06-29 1994-01-06 Oy Medix Biochemica Ab Procede diagnostique de determination de la susceptibilite a l'accouchement, et kit de reactifs associe
WO1997042504A1 (fr) * 1996-05-07 1997-11-13 Diagnostic Systems Laboratories, Inc. Essai immunologique de la proteine-1 fixatrice du facteur de croissance du type insuline dans sa globalite

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992012426A1 (fr) * 1990-12-31 1992-07-23 Oy Medix Biochemica Ab Procede de diagnostic permettant de detecter une rupture des membranes f×tales et son kit d'essai
WO1994000765A1 (fr) * 1992-06-29 1994-01-06 Oy Medix Biochemica Ab Procede diagnostique de determination de la susceptibilite a l'accouchement, et kit de reactifs associe
WO1997042504A1 (fr) * 1996-05-07 1997-11-13 Diagnostic Systems Laboratories, Inc. Essai immunologique de la proteine-1 fixatrice du facteur de croissance du type insuline dans sa globalite

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
N.A. MARTINA ET AL: "Gestational Age-Dependent Expression of Insulin-Like Growth Factor-Binding Protein-1 (IGFBP-1) Phosphoisoforms in Human Extraembryonic Cavities, Maternal Serum and Decidua Suggests Decidua as the Primary Source...", JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM, vol. 82, no. 6, 1997, pages 1894 - 1898 *
RIITA KOISTINEN ET AL: "Phosphorylation of insulin-like growth factor-binding protein-1 increases in human amniotic fluid and decidua from early to late pregnancy", CLINICA CHIMICA ACTA, vol. 215, 1993, pages 189 - 199 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7892774B2 (en) 1992-06-29 2011-02-22 Oy Medix Biochemica Ab Diagnostic method for determining the susceptibility to delivery and reagent kit for use therefor
WO2007002483A1 (fr) * 2005-06-24 2007-01-04 Beckman Coulter, Inc. Dosage immunologique de proteines phosphorylees
US10689704B2 (en) 2015-03-06 2020-06-23 Imperial College Of Science, Technology And Medicine Method for predicting cervical shortening and preterm birth
US11149315B2 (en) 2015-03-06 2021-10-19 Imperial College Of Science, Technology, And Medicine Method for predicting cervical shortening and preterm birth
FR3048287A1 (fr) * 2016-02-26 2017-09-01 Biosynex Procede de detection d'accouchement imminent
CN117288966A (zh) * 2023-11-27 2023-12-26 山东康华生物医疗科技股份有限公司 一种联合检测igf-1和igfbp-3的试剂盒及其所用裂解液、缓冲液
CN117288966B (zh) * 2023-11-27 2024-02-27 山东康华生物医疗科技股份有限公司 一种联合检测igf-1和igfbp-3的试剂盒及其所用裂解液、缓冲液

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FI981049A7 (fi) 1999-11-13
AU4042699A (en) 1999-11-29
FI981049A0 (fi) 1998-05-12

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