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Method for diagnosing acute coronary syndrome

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Method for diagnosing acute coronary syndrome


PAPP-A complexed to proMBP/total PAPP-A. free PAPP-A/PAPP-A complexed to proMBP, or Furthermore, the invention concerns a method for diagnosing an acute coronary syndrome in a person by using as marker either free PAPP-A as such or a ratio free PAPP-A/total PAPP-A, ii) by a direct bioaffinity assay measuring only free PAPP-A. free PAPP-A is determined either i) as a calculated difference between measured total PAPP-A and measured PAPP-A complexed to proMBP, or This invention concerns a bioaffinity assay for quantitative determination in a sample of free PAPP-A, defined as the pregnancy associated plasma protein A (PAPP-A) that is not complexed to the proform of major basic protein (proMBP), wherein
Related Terms: Acute Coronary Syndrome Papp-a Pregnancy Protein A

Inventors: Qiu-Ping Qin, Kim Pettersson
USPTO Applicaton #: #20120264139 - Class: 435 74 (USPTO) - 10/18/12 - Class 435 
Chemistry: Molecular Biology And Microbiology > Measuring Or Testing Process Involving Enzymes Or Micro-organisms; Composition Or Test Strip Therefore; Processes Of Forming Such Composition Or Test Strip >Involving Antigen-antibody Binding, Specific Binding Protein Assay Or Specific Ligand-receptor Binding Assay >To Identify An Enzyme Or Isoenzyme

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The Patent Description & Claims data below is from USPTO Patent Application 20120264139, Method for diagnosing acute coronary syndrome.

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FIELD OF THE INVENTION

This invention relates to a bioaffinity assay for quantitative determination in a sample of free PAPP-A, defined as the pregnancy associated plasma protein A (PAPP-A) that is not complexed to the proform of major basic protein (proMBP). The invention relates further to a method for diagnosing acute coronary syndrome in a person by using free PAPP-A as a marker.

BACKGROUND OF THE INVENTION

The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference.

Pregnancy-associated plasma protein A (PAPP-A) was first identified in the early 1970s as a high-molecular weight constituent found in human late pregnancy serum (1). The concentration in serum increases with pregnancy until term (2). PAPP-A was initially characterized as a homotetramer (1, 3), but it was later demonstrated that circulating PAPP-A in pregnancy was a disulfide-bound 500-kDa heterotetrameric 2:2 complex with the proform of eosinophil major basic protein (proMBP), denoted as PAPP-A/proMBP (4). However, pregnancy serum or plasma is also reported to contain traces (<1%) of uncomplexed PAPP-A (5).

PAPP-A and proMBP are both produced in the placenta during pregnancy but mainly in different cell types. By in situ hybridization, it has been revealed that the vast majority of PAPP-A is synthesized in the syncytiotrophoblast, and all proMBP is synthesized in extravillous cytotrophoblasts (6). Analyses from cloned cDNA demonstrate that the PAPP-A subunit is a 1547-residue polypeptide (7). It contains an elongated zinc-binding motif, three Lin-notch repeats and five short consensus repeats (8).

ProMBP is a glycosylated proteoglycan composed of a strongly acidic 90-residue propiece and a highly basic 117-residue mature form of MBP (9,10). The latter is a cytotoxic protein present in granules of the eosinophil leukoucyte (11). It is released from the eosinophil leukocyte by degranulation, and plays multiple roles in the effector functions of these cells (12). Although in eosinophils mature MBP is generated by proteolytic processing of proMBP, no evidence indicates that MBP can be generated from proMBP of the PAPP-A/proMBP complex. In terms of the role of proMBP in the PAPP-A/proMBP complex, there are studies showing that proMBP acts in vitro as a proteinase inhibitor of PAPP-A (5,13). In addition to PAPP-A, proMBP also forms covalent complex with either angiotensinogen or complement C3dg (14). But the function of proMBP in other complexes remains unknown.

Recently, PAPP-A has been found to be a protease specific for insulin-like growth factors (IGF) binding protein (IGFBP)-4 as well as for IGFBP-5 in vitro (15,16). Notably, the cleavage of IGFBP-4 is in an IGF-dependent manner, whereas the cleavage of IGFBP-5 in an IGF-independent manner. However, the physiological function of PAPP-A in vivo remains to be identified. Insulin-like growth factors-I and -II (IGF-I and IGF-II) play an important role in promoting cell differentiation and proliferation in a variety of biological systems, mediated mainly through the type 1 IGF receptor. The biological activities of IGF-I and -II are modulated by six homologous high-affinity IGF binding proteins, which bind the IGFs and block them from binding to the receptor (17). Cleavage of IGFBP-4 and -5 by PAPP-A causes release of bound IGF, thereby increasing bioavailable IGF for interactions with IGF membrane receptors.

Clinically, reduced serum levels of PAPP-A are associated with Down\'s syndrome (DS) pregnancies (18). As a marker, PAPP-A is now commonly used for screening for DS in the first trimester (19). Only recently, it has been shown that PAPP-A is present in unstable atherosclerotic (coronary and carotid) plaques (20,21), and that its circulating levels are elevated in patients with acute coronary syndromes (ACS) (20,22). Furthermore, occurrence of PAPP-A in the circulation is an independent prognostic stratifier in patients with coronary artery disease (23). So far little is known about the role of PAPP-A in the plaques. Nonetheless, it has been suggested that increased bioavailability of IGFs through IGFBP-4 proteolysis observed in ACS plays a crucial role in the progression of both coronary atherosclerosis and restenosis (20,24).

Technically, measurability of PAPP-A in the circulation is closely associated with PAPP-A molecule structure. Whether the molecular structure of PAPP-A found in the blood of pregnant women is the same as that found in the blood of ACS patient is particularly important. Until now there is no report dealing with this critical issue. And all the assays used to date for PAPP-A measurement in both situations are based on the antibodies specific for PAPP-A subunit of PAPP-A/proMBP complex (20,25,26,27). From a methodological point of view, this fact makes the circulating PAPP-A in pregnancy indistinguishable from that in ACS.

Here we, for the first time, provide data showing that circulating PAPP-A molecule in pregnancy is different from that in ACS. These findings have important clinical implications for earlier and more specific detection of atherosclerosis related-PAPP-A in the circulation.

OBJECT AND

SUMMARY

OF THE INVENTION

The object of this invention is to provide a more sensitive and specific method for diagnosing individuals at risk of acute coronary syndrome at an early stage. Particularly, the aim is to achieve a diagnosing method superior to the commonly used assay based on cardiac troponin I and to the proposed assay based on the use of total PAPP-A as a marker.

Thus, according to one aspect, this invention concerns a bioaffinity assay for quantitative determination in a sample of free PAPP-A, defined as the pregnancy associated plasma protein A (PAPP-A) that is not complexed to the proform of major basic protein (proMBP). According to the invention, free PAPP-A is determined either

i) as a calculated difference between measured total PAPP-A and measured PAPP-A complexed to proMBP, or ii) by a direct bioaffinity assay measuring only free PAPP-A.

According to another aspect, the invention concerns a method for diagnosing an acute coronary syndrome in a person by using as marker either free PAPP-A as such or a ratio free PAPP-A/total PAPP-A, free PAPP-A/PAPP-A complexed to proMBP, or PAPP-A complexed to proMBP/total PAPP-A.

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stats Patent Info
Application #
US 20120264139 A1
Publish Date
10/18/2012
Document #
13536810
File Date
06/28/2012
USPTO Class
435/74
Other USPTO Classes
International Class
01N33/573
Drawings
11


Acute Coronary Syndrome
Papp-a
Pregnancy
Protein A


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