Adam12, A Novel Marker For Abnormal Cell Function

Abstract

The present invention provides a method, an assay and a kit for providing an indication of abnormal cell function. The present inventors describes ADAM12 as a overall general marker for abnormal cell function, and the present inventor for the first time demonstrate that ADAM12 is an important indicator of fetal chromosomal disease and placenta function. Specifically ADAM12 is a good marker for e.g. Downs's syndrome, trisomy 18, preeclampsia, Turner syndrome in both first and second trimester. The present inventors developed an enzyme-linked immunosorbent assay (ELISA) and a time-resolved immunofluorometric assay for the quantification of ADAM12 in serum. The present application demonstrates in several examples the variation of the ADAM12 level in fetal abnormality and/or adverse pregnancy outcomes correlated gestational age when compared to normal controls. It is an object of the invention to provide an improvement of the existing marker tests that exhibits a decreased false positive rate.

1 - 17 . (canceled) 
     
     
         18 . A method for screening for a fetal abnormality selected from the group consisting of preeclampsia, trisomy 18, trisomy 13, Turner Syndrome, and non-Turner sex chromosome abnormalities (NTSCA), in a fetus, said method comprising the steps of:
 a) determining the level of ADAM12 in a biological sample obtained from an individual by detecting
 1) ADAM12 polypeptide and/or 
 2) a polynucleotide coding for ADAM12 expression, and/or 
 3) specific ADAM12 protease activity, preferably by detecting cleavage of IGFBP-3, a derivative thereof, or any other suitable substrate for ADAM12; 
   b) comparing said level with a reference level;   c) identifying whether the level is different from said reference level and evaluating whether the fetus has an increased risk of said fetal abnormality chosen from the group consisting of preeclampsia, trisomy 18, trisomy 13, Turner Syndrome, and non-Turner sex chromosome abnormalities (NTSCA), if the level is different from the reference level.   
     
     
         19 . A method according to  claim 18 , wherein said biological sample is selected from the group consisting of blood, urine, pleural fluid, oral washings, tissue biopsies, and follicular fluid. 
     
     
         20 . A method according to  claim 18 , wherein said biological sample is selected from the group consisting of blood, plasma and serum. 
     
     
         21 . A method according to  claim 20 , wherein said biological sample is serum. 
     
     
         22 . A method according to  claim 18 , wherein the fetal abnormality is preeclampsia. 
     
     
         23 . A method according to  claim 22 , wherein the level of ADAM12 in said biological sample is the level of ADAM12 polypeptide. 
     
     
         24 . A method according to  claim 22 , wherein the biological sample is blood, plasma, and/or serum. 
     
     
         25 . A method according to  claim 22 , wherein the gestation age independent ADAM12 (MOM) is used in conjunction with biometric, serological or clinical information to derive a risk for developing preeclampsia. 
     
     
         26 . A method according to  claim 18 , wherein the fetal abnormality is trisomy 18. 
     
     
         27 . A method according to  claim 18 , wherein the fetal abnormality is trisomy 13. 
     
     
         28 . A method according to  claim 18 , wherein the fetal abnormality is Turner Syndrome. 
     
     
         29 . A method according to  claim 18 , wherein the fetal abnormality is non-Turner sex chromosome abnormalities (NTSCA). 
     
     
         30 . A method according to  claim 18 , wherein ADAM12 is assessed as a first trimester marker. 
     
     
         31 . A method according to  claim 18 , wherein ADAM12 is assessed as a second trimester marker. 
     
     
         32 . A method according to  claim 18 , wherein the ADAM12 level is combined with values from at least one marker selected from the group consisting of alpha feto-protein (AFP), unconjugated oestrol (uE3), human chorionic gonadotrophin (hCG), free alpha sub-unit of hCG (free α-hCG), free beta sub-unit of hCG (free β-hCG), beta-core hCG, hyperglycosylated hCG (ITG), placental growth hormone (PGH), inhibin, preferably dimeric inhibin-A (inhibin A), pregnancy-associated plasma protein A (PAPP-A), Complexes of PAPP-A with proMBP (proform of major basic protein), ProMBP, ProMBP complexes with angiotensinogen and/or complement factors and split products, Schwangerschaftsprotein 1 (SP1), Cancer antigen 125 (CA125), Prostate specific antigen (PSA), Leukocyte enzymes, fetal DNA, fetal RNA, fetal cells, stem cells, oestradiol, Ultrasound markers, Nuchal translucency, Femur length, Absence of nasal bone, Hyperechogenic bowel, Echogenic foci in the heart, Choroids plexus cysts, Hydronephrosis, Fetal malformations, Steroids, Peptides, Chemokines, Interleukins (e.g. IL-6, IL-4, IL-1), Tumor necrosis factor, Transforming growth factor alpha and beta, Acute phase reactants, C-reactive protein, Fibronectin, Maternal or fetal Single nucleotide polymorphisms, e.g. promoter region polymorphisms in TNFbeta and mannan-binding lectin, Complement components, HLA-G and HLA molecules. 
     
     
         33 . A method according to  claim 18 , wherein gestational age independent (MOM) or value of ADAM12 is calculated for use in risk assessment. 
     
     
         34 . A method according to  claim 18 , wherein the sample is obtained prior to gestational age of week 11 and/or after gestational age of week 12.