EP2089719A2 - Moyens et procédés d'optimisation d'approches diagnostiques et thérapeutiques dans une maladie artérielle chronique basés sur la troponine t et le nt-probnp - Google Patents

Moyens et procédés d'optimisation d'approches diagnostiques et thérapeutiques dans une maladie artérielle chronique basés sur la troponine t et le nt-probnp

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Publication number
EP2089719A2
EP2089719A2 EP07847226A EP07847226A EP2089719A2 EP 2089719 A2 EP2089719 A2 EP 2089719A2 EP 07847226 A EP07847226 A EP 07847226A EP 07847226 A EP07847226 A EP 07847226A EP 2089719 A2 EP2089719 A2 EP 2089719A2
Authority
EP
European Patent Office
Prior art keywords
amount
cardiac
bnp
type peptide
sample
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
EP07847226A
Other languages
German (de)
English (en)
Inventor
Georg Hess
Andrea Horsch
Dietmar Zdunek
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Roche Diagnostics GmbH
Original Assignee
F Hoffmann La Roche AG
Roche Diagnostics GmbH
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
Priority claimed from EP06124479A external-priority patent/EP1925943A1/fr
Application filed by F Hoffmann La Roche AG, Roche Diagnostics GmbH filed Critical F Hoffmann La Roche AG
Priority to EP07847226A priority Critical patent/EP2089719A2/fr
Publication of EP2089719A2 publication Critical patent/EP2089719A2/fr
Ceased legal-status Critical Current

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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
    • G01N33/6893—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 diseases not provided for elsewhere
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • G01N2333/575—Hormones
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/32—Cardiovascular disorders
    • G01N2800/325—Heart failure or cardiac arrest, e.g. cardiomyopathy, congestive heart failure
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present invention relates to diagnostic means and methods. Specifically, the present invention encompasses a method of diagnosing the cause of cardiac necrosis in a subject comprising determining the amount of a cardiac Troponin and the amount of a BNP -type peptide in a sample of subject suffering from cardiac necrosis and comparing the amount of the said cardiac Troponin and the amount of the said BNP -type peptide to reference amounts, whereby the cause of the cardiac necrosis is to be diagnosed.
  • the present invention further, relates to a method of determining whether a subject suffering from cardiac necrosis is susceptible for a therapy against initial heart failure and a method for determining whether a subject suffering from cardiac necrosis is susceptible for a therapy against coronary heart disease. Also encompassed are diagnostic uses, devices and kits.
  • Heart diseases are the leading cause of morbidity and mortality in the Western hemisphere. The said diseases can remain asymptomatic for long periods of time. However, they may have severe consequences once an acute cardiovascular event, such as myocardial infarction, as a cause of the cardiovascular disease occurs.
  • cardiac necrosis is a disease or disorder of the myocardium which severely affects the function of the heart and which often results in life-threatening myocardial infarction or progression of heart failure (i.e. the so called progressive heart failure).
  • Cardiac necrosis may have diverse causes and, therefore, may require different treatment regimens depending on the said cause.
  • the causes of cardiac necrosis include heart failure as well as coronary heart diseases as well as cardiac myopathy. It is to be understood that as different the said causes are as different are the therapies which can be applied. Specifically, in the case of heart failure a drug based therapy may appear promising while for a coronary heart disease, such as a stenosis of a coronary artery, an invasive therapy will be necessary, e.g., an angioplasty or bypass surgery (for details see Gheorghiade 2006, Circulation 114:1202-1213).
  • the conventional diagnostic techniques for cardiac necrosis include pivotally electrocardiographic measurements. Recently, these conventional techniques have been further strengthened by the analysis of cardiac Troponin I or Troponin T as biomarkers. These diagnostic techniques, however, do not allow determining the cause of a cardiac necrosis without further differential diagnosis. Thus, various different diagnostic measures have to be carried out subsequently in order to determine the cause of cardiac necrosis. However, in cases where such a time consuming diagnostic procedure is impossible or expensive, e.g., for emergency patients, a personalized treatment regimen can not be determined with sufficient accuracy. As a consequence thereof, many patients will receive a treatment regimen which is insufficient or which may have adverse side effects.
  • the present invention thus, relates to a method of diagnosing the cause of cardiac necrosis in a subject comprising: a) determining the amount of a cardiac Troponin and the amount of a BNP- type peptide in a sample of subject suffering from cardiac necrosis; and b) comparing the amount of the said cardiac Troponin and the amount of the said BNP -type peptide to reference amounts, whereby the cause of the cardiac necrosis is to be diagnosed.
  • the method of the present invention preferably, is an in vitro method. Moreover, it may comprise steps in addition to those explicitly mentioned above. For example, further steps may relate to sample pre-treatments or evaluation of the results obtained by the method.
  • the method of the present invention may be also used for monitoring, confirmation, and subclassif ⁇ cation of a subject in need of a cardiac intervention.
  • the method may be carried out manually or assisted by automation.
  • step (a) and/or (b) may in total or in part be assisted by automation, e.g., by a suitable robotic and sensory equipment for the determination in step (a) or a computer-implemented comparison in step (b).
  • diagnosis means identifying the cause of the cardiac necrosis, i.e. the underlying disorder or disease condition resulting in the apparent cardiac necrosis. As will be understood by those skilled in the art, such an assessment is usually not intended to be correct for all (i.e. 100%) of the subjects to be identified. The term, however, requires that a statistically significant portion of subjects can be identified (e.g. a cohort in a cohort study). Whether a portion is statistically significant can be determined without further ado by the person skilled in the art using various well known statistic evaluation tools, e.g., determination of confidence intervals, p-value determination, Student's t-test, Mann- Whitney test etc..
  • Preferred confidence intervals are at least 90%, at least 95%, at least 97%, at least 98% or at least 99 %.
  • the p- values are, preferably, 0.1, 0.05, 0.01, 0.005, or 0.0001. More preferably, at least 60%, at least 70%, at least 80% or at least 90% of the subjects of a population can be properly identified by the method of the present invention.
  • Diagnosing according to the present invention includes monitoring, confirmation, subclassification and prediction of the relevant disease, symptoms or risks therefor.
  • Monitoring relates to keeping track of an already diagnosed disease.
  • Confirmation relates to the strengthening or substantiating a diagnosis already performed using other indicators or markers.
  • Subclassification relates to further defining a diagnosis according to different subclasses of the diagnosed disease, e.g. defining according to mild and severe forms of the disease.
  • cardiac necrosis refers to necrotic cells or tissue of the myocardium.
  • necrotic cells or tissue areas can be determined electrocardiographic techniques because the necrotic cells or areas shall influence the electric field produced by a physiologically operating, i.e. beating, heart.
  • Low blood pressure, elevated intraventricular pressure or coronary heart diseases as well as cardiac myopathy are well known disorders which result in a reduced perfusion of the myocardium and, consequently, in cardiac necrosis.
  • a cardiac myopathy in accordance with the present invention relates to a disorder affecting the myocardium accompanied by mechanical or electrophysiological alterations.
  • the disorder may be accompanied by hypertrophia or dilatation of the heart ventricles.
  • Cardiac myopathy may result, e.g., from inflammatory diseases of the myocardium or may be caused by toxic compounds (see also Maron 2006, Circulation 113:1807-1816). It is well established that cardiac necrosis is accompanied by worsening of the function of the heart. This disorder is also called progressive heart failure and shall result in an ischemic cardiac myopathy. Accordingly, it is to be understood that the method of the present invention can be also applied to diagnose the cause of ischemic cardiac myopathy, e.g. as a result of a progressive heart failure or coronary heart disease.
  • the causes of cardiac necrosis and, thus, progressive heart failure are either a coronary heart disease resulting in a reduced blood flow throughout the coronary vessels and consequently to hypoxic or ischemic areas in the myocardium.
  • hypoxia or ischemia of the myocardium and, thus, cardiac necrosis accompanied by a progressive heart failure may also result from an initial heart failure.
  • Ischemia which may be responsible for the cardiac necrosis referred to herein may be a reversible or persisting (i.e. permanent) ischemia.
  • Persisting ischemia is characterized in that the myocardium is inappropriately supplied by blood and, thus, hypoxic, even in a resting subject, i.e. not applied to physical or pharmacological stress, e.g., bicycle exercise or dipyridamol.
  • the reversible ischemia is characterized in that the inappropriate blood supply of the myocardium occurs only upon application of physical or pharmacological stress.
  • cardiac necrosis may be also the result of other causes and, thus, is not necessarily accompanied by ischemia.
  • coronary heart diseases encompass coronary artery diseases including stenosis, atherosclerosis of the coronary vessels or occlusions, such as thromboembolic occlusions within the coronary vessel system.
  • subject as used herein relates to animals, preferably mammals, and, more preferably, humans.
  • the subject referred to in accordance with the aforementioned method suffers from a cardiac necrosis or exhibits the symptoms accompanied therewith, i.e. being at least suspect to suffer from cardiac necrosis.
  • sample refers to a sample of a body fluid, to a sample of separated cells or to a sample from a tissue or an organ.
  • Samples of body fluids can be obtained by well known techniques and include, preferably, samples of blood, plasma, serum, or urine, more preferably, samples of blood, plasma or serum.
  • Tissue or organ samples may be obtained from any tissue or organ by, e.g., biopsy.
  • Separated cells may be obtained from the body fluids or the tissues or organs by separating techniques such as centrifugation or cell sorting.
  • cell-, tissue- or organ samples are obtained from those cells, tissues or organs which express or produce the peptides referred to herein.
  • cardiac Troponin refers to all Troponin iso forms expressed in cells of the heart and, preferably, the subendocardial cells. These isoforms are well characterized in the art as described, e.g., in Anderson 1995, Circulation Research, vol. 76, no. 4: 681-686 and Ferrieres 1998, Clinical Chemistry, 44: 487-493.
  • cardiac Troponin refers to Troponin T and/or Troponin I, and, most preferably, to Troponin T. It is to be understood that isoforms of Troponins may be determined in the method of the present invention together, i.e. simultaneously or sequentially, or individually, i.e. without determining the other isoform at all. Amino acid sequences for human Troponin T and human Troponin I are disclosed in Anderson, loc cit and Ferrieres 1998, Clinical Chemistry, 44: 487-493.
  • cardiac Troponin encompasses also variants of the aforementioned specific Troponins, i.e., preferably, of Tropoinin T or Troponin I. Such variants have at least the same essential biological and immunological properties as the specific cardiac Troponins. In particular, they share the same essential biological and immunological properties if they are detectable by the same specific assays referred to in this specification, e.g., by ELISA Assays using polyclonal or monoclonal antibodies specifically recognizing the said cardiac Troponins.
  • a variant as referred to in accordance with the present invention shall have an amino acid sequence which differs due to at least one amino acid substitution, deletion and/or addition wherein the amino acid sequence of the variant is still, preferably, at least 50%, 60%, 70%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% identical with the amino sequence of the specific Troponin.
  • Variants may be allelic variants or any other species specific homologs, paralogs, or orthologs.
  • the variants referred to herein include fragments of the specific cardiac Troponins or the aforementioned types of variants as long as these fragments have the essential immunological and biological properties as referred to above. Such fragments may be, e.g., degradation products of the Troponins. Further included are variants which differ due to posttranslational modifications such as phosphorylation or myristylation.
  • brain natriuretic peptide (BNP)-type peptides relates to pre-proBNP, proBNP, NT-proBNP, and BNP and variants thereof having the same predictive potential (see e.g. Bonow, 1996, Circulation 93: 1946-1950).
  • the aforementioned pre-pro peptide of the brain natriuretic peptide (having 134 amino acids in length) comprises a short signal peptide, which is enzymatically cleaved off to release the pro peptide (108 amino acids).
  • the pro peptide is further cleaved into an N-terminal pro peptide (NT -pro peptide, 76 amino acids) and the active hormone (32 amino acids).
  • BNP is metabolised in the blood, whereas NT-proBNP circulates in the blood as an intact molecule and as such is eliminated renally.
  • the in-vivo half-life of NTproBNP is 120 min longer than that of BNP, which is 20 min (Smith 2000, J Endocrinol. 167: 239-46.). Preanalyses are more robust with NT-proBNP allowing easy transportation of the sample to a central laboratory (Mueller 2004, Clin Chem Lab Med 42: 942-4.). Blood samples can be stored at room temperature for several days or may be mailed or shipped without recovery loss.
  • the most preferred BNP -type peptide referred to herein is human NT-proBNP.
  • the human NT-proBNP as referred to in accordance with the present invention, is a polypeptide comprising, preferably, 76 amino acids in length corresponding to the N-terminal portion of the human NT-proBNP molecule.
  • the structure of the human BNP and NT-proBNP has been described already in detail in the prior art, e.g., WO 02/089657, WO 02/083913 or Bonow loc. cit.
  • human NT-proBNP as used herein is human NT-proBNP as disclosed in EP 0 648 228 Bl.
  • NT-proBNP referred to in accordance with the present invention further encompasses allelic and other variants of said specific sequence for human NT-proBNP discussed above.
  • variant polypeptides which are on the amino acid level at least 60 % identical, more preferably at least 70 %, at least 80 %, at least 90 %, at least 95 %, at least 98% or at least 99 % identical, to human NT-proBNP.
  • proteolytic degradation products which are still recognized by the diagnostic means or by ligands directed against the respective full-length peptide.
  • variant polypeptides having amino acid deletions, substitutions, and/or additions compared to the amino acid sequence of human NT-proBNP as long as the said polypeptides have NT- proBNP properties.
  • NT-proBNP properties as referred to herein are immunological and/or biological properties.
  • the NT-proBNP variants have immunological properties (i.e. epitope composition) comparable to those of NT-proBNP.
  • the variants shall be recognizable by the aforementioned means or ligands used for determination of the amount of the natriuretic peptides.
  • Biological and/or immunological NT-proBNP properties can be detected by the assay described in Karl et al.
  • variants in accordance with the present invention are also a peptide or polypeptide which has been modified after collection of the sample, for example by covalent or non-covalent attachment of a label, particularly a radioactive or fluorescent label, to the peptide.
  • Determining the amount of the peptides or polypeptides referred to in this specification relates to measuring the amount or concentration, preferably semi-quantitatively or quantitatively. Measuring can be done directly or indirectly.
  • Direct measuring relates to measuring the amount or concentration of the peptide or polypeptide based on a signal which is obtained from the peptide or polypeptide itself and the intensity of which directly correlates with the number of molecules of the peptide present in the sample.
  • a signal sometimes referred to herein as intensity signal -may be obtained, e.g., by measuring an intensity value of a specific physical or chemical property of the peptide or polypeptide.
  • Indirect measuring includes measuring of a signal obtained from a secondary component (i.e. a component not being the peptide or polypeptide itself) or a biological read out system, e.g., measurable cellular responses, ligands, labels, or enzymatic reaction products.
  • determining the amount of a peptide or polypeptide can be achieved by all known means for determining the amount of a peptide in a sample.
  • Said means comprise immunoassay devices and methods which may utilize labeled molecules in various sandwich, competition, or other assay formats.
  • Said assays will develop a signal which is indicative for the presence or absence of the peptide or polypeptide.
  • the signal strength can, preferably, be correlated directly or indirectly (e.g. reverse- proportional) to the amount of polypeptide present in a sample.
  • Further suitable methods comprise measuring a physical or chemical property specific for the peptide or polypeptide such as its precise molecular mass or NMR spectrum.
  • Said methods comprise, preferably, biosensors, optical devices coupled to immunoassays, biochips, analytical devices such as mass- spectrometers, NMR- analyzers, or chromatography devices.
  • methods include micro-plate ELISA-based methods, fully-automated or robotic immunoassays (available for example on ElecsysTM analyzers), CBA (an enzymatic Cobalt Binding Assay, available for example on Roche-HitachiTM analyzers), and latex agglutination assays (available for example on Roche-HitachiTM analyzers).
  • determining the amount of a peptide or polypeptide comprises the steps of (a) contacting a cell capable of eliciting a cellular response the intensity of which is indicative of the amount of the peptide or polypeptide with the said peptide or polypeptide for an adequate period of time, (b) measuring the cellular response.
  • the sample or processed sample is, preferably, added to a cell culture and an internal or external cellular response is measured.
  • the cellular response may include the measurable expression of a reporter gene or the secretion of a substance, e.g. a peptide, polypeptide, or a small molecule.
  • the expression or substance shall generate an intensity signal which correlates to the amount of the peptide or polypeptide.
  • determining the amount of a peptide or polypeptide comprises the step of measuring a specific intensity signal obtainable from the peptide or polypeptide in the sample.
  • a specific intensity signal may be the signal intensity observed at an m/z variable specific for the peptide or polypeptide observed in mass spectra or a NMR spectrum specific for the peptide or polypeptide.
  • Determining the amount of a peptide or polypeptide may, preferably, comprises the steps of (a) contacting the peptide with a specific ligand, (b) (optionally) removing non-bound ligand, (c) measuring the amount of bound ligand.
  • the bound ligand will generate an intensity signal.
  • Binding according to the present invention includes both covalent and non-covalent binding.
  • a ligand according to the present invention can be any compound, e.g., a peptide, polypeptide, nucleic acid, or small molecule, binding to the peptide or polypeptide described herein.
  • Preferred ligands include antibodies, nucleic acids, peptides or polypeptides such as receptors or binding partners for the peptide or polypeptide and fragments thereof comprising the binding domains for the peptides, and aptamers, e.g. nucleic acid or peptide aptamers.
  • Methods to prepare such ligands are well-known in the art. For example, identification and production of suitable antibodies or aptamers is also offered by commercial suppliers. The person skilled in the art is familiar with methods to develop derivatives of such ligands with higher affinity or specificity. For example, random mutations can be introduced into the nucleic acids, peptides or polypeptides.
  • Antibodies as referred to herein include both polyclonal and monoclonal antibodies, as well as fragments thereof, such as Fv, Fab and F(ab) 2 fragments that are capable of binding antigen or hapten.
  • the present invention also includes single chain antibodies and humanized hybrid antibodies wherein amino acid sequences of a non- human donor antibody exhibiting a desired antigen-specificity are combined with sequences of a human acceptor antibody.
  • the donor sequences will usually include at least the antigen-binding amino acid residues of the donor but may comprise other structurally and/or functionally relevant amino acid residues of the donor antibody as well.
  • the ligand or agent binds specifically to the peptide or polypeptide.
  • Specific binding according to the present invention means that the ligand or agent should not bind substantially to ("cross- react" with) another peptide, polypeptide or substance present in the sample to be analyzed.
  • the specifically bound peptide or polypeptide should be bound with at least 3 times higher, more preferably at least 10 times higher and even more preferably at least 50 times higher affinity than any other relevant peptide or polypeptide.
  • Nonspecific binding may be tolerable, if it can still be distinguished and measured unequivocally, e.g. according to its size on a Western Blot, or by its relatively higher abundance in the sample. Binding of the ligand can be measured by any method known in the art. Preferably, said method is semi-quantitative or quantitative. Suitable methods are described in the following.
  • binding of a ligand may be measured directly, e.g. by NMR or surface plasmon resonance.
  • an enzymatic reaction product may be measured (e.g. the amount of a protease can be measured by measuring the amount of cleaved substrate, e.g. on a Western Blot).
  • the ligand may exhibit enzymatic properties itself and the "ligand/peptide or polypeptide" complex or the ligand which was bound by the peptide or polypeptide, respectively, may be contacted with a suitable substrate allowing detection by the generation of an intensity signal.
  • the amount of substrate is saturating.
  • the substrate may also be labeled with a detectable lable prior to the reaction.
  • the sample is contacted with the substrate for an adequate period of time.
  • An adequate period of time refers to the time necessary for an detectable, preferably measurable, amount of product to be produced. Instead of measuring the amount of product, the time necessary for appearance of a given (e.g. detectable) amount of product can be measured.
  • the ligand may be coupled covalently or non-covalently to a label allowing detection and measurement of the ligand.
  • Labeling may be done by direct or indirect methods. Direct labeling involves coupling of the label directly (covalently or non-covalently) to the ligand. Indirect labeling involves binding (covalently or non-covalently) of a secondary ligand to the first ligand. The secondary ligand should specifically bind to the first ligand. Said secondary ligand may be coupled with a suitable label and/or be the target (receptor) of tertiary ligand binding to the secondary ligand. The use of secondary, tertiary or even higher order ligands is often used to increase the signal.
  • Suitable secondary and higher order ligands may include antibodies, secondary antibodies, and the well-known streptavidin-biotin system (Vector Laboratories, Inc.).
  • the ligand or substrate may also be "tagged" with one or more tags as known in the art. Such tags may then be targets for higher order ligands.
  • Suitable tags include biotin, digoxygenin, His-Tag, Glutathion-S- Transferase, FLAG, GFP, myc-tag, influenza A virus haemagglutinin (HA), maltose binding protein, and the like.
  • the tag is preferably at the N-terminus and/or C-terminus.
  • Suitable labels are any labels detectable by an appropriate detection method.
  • Typical labels include gold particles, latex beads, acridan ester, luminol, ruthenium, enzymatically active labels, radioactive labels, magnetic labels ("e.g. magnetic beads", including paramagnetic and superparamagnetic labels), and fluorescent labels.
  • Enzymatically active labels include e.g. horseradish peroxidase, alkaline phosphatase, beta-Galactosidase, Luciferase, and derivatives thereof.
  • Suitable substrates for detection include di-amino-benzidine (DAB), 3,3'-5,5'-tetramethylbenzidine, NBT- BCIP (4-nitro blue tetrazolium chloride and 5-bromo-4-chloro-3-indolyl-phosphate, available as ready-made stock solution from Roche Diagnostics), CDP-StarTM (Amersham Biosciences), ECFTM (Amersham Biosciences).
  • a suitable enzyme-substrate combination may result in a colored reaction product, fluorescence or chemo luminescence, which can be measured according to methods known in the art (e.g. using a light-sensitive film or a suitable camera system). As for measuring the enyzmatic reaction, the criteria given above apply analogously.
  • Typical fluorescent labels include fluorescent proteins (such as GFP and its derivatives), Cy3, Cy5, Texas Red, Fluorescein, and the Alexa dyes (e.g. Alexa 568). Further fluorescent labels are available e.g. from Molecular Probes (Oregon). Also the use of quantum dots as fluorescent labels is contemplated.
  • Typical radioactive labels include 35 S, 125 I, 32 P, 33 P and the like. A radioactive label can be detected by any method known and appropriate, e.g. a light-sensitive film or a phosphor imager.
  • Suitable measurement methods according the present invention also include precipitation (particularly immunoprecipitation), electrochemiluminescence (electro-generated chemiluminescence), RIA (radioimmunoassay), ELISA (enzyme- linked immunosorbent assay), sandwich enzyme immune tests, electrochemiluminescence sandwich immunoassays (ECLIA), dissociation-enhanced lanthanide fluoro immuno assay (DELFIA), scintillation proximity assay (SPA), turbidimetry, nephelometry, latex- enhanced turbidimetry or nephelometry, or solid phase immune tests.
  • the amount of a peptide or polypeptide may be, also preferably, determined as follows: (a) contacting a solid support comprising a ligand for the peptide or polypeptide as specified above with a sample comprising the peptide or polypeptide and (b) measuring the amount peptide or polypeptide which is bound to the support.
  • the ligand preferably chosen from the group consisting of nucleic acids, peptides, polypeptides, antibodies and aptamers, is preferably present on a solid support in immobilized form.
  • Materials for manufacturing solid supports include, inter alia, commercially available column materials, polystyrene beads, latex beads, magnetic beads, colloid metal particles, glass and/or silicon chips and surfaces, nitrocellulose strips, membranes, sheets, duracytes, wells and walls of reaction trays, plastic tubes etc.
  • the ligand or agent may be bound to many different carriers. Examples of well-known carriers include glass, polystyrene, polyvinyl chloride, polypropylene, polyethylene, polycarbonate, dextran, nylon, amyloses, natural and modified celluloses, polyacrylamides, agaroses, and magnetite.
  • the nature of the carrier can be either soluble or insoluble for the purposes of the invention.
  • Suitable methods for fixing/immobilizing said ligand are well known and include, but are not limited to ionic, hydrophobic, covalent interactions and the like. It is also contemplated to use "suspension arrays" as arrays according to the present invention (Nolan 2002, Trends Biotechnol. 20(l):9-12).
  • the carrier e.g. a microbead or microsphere
  • the array consists of different microbeads or microspheres, possibly labeled, carrying different ligands.
  • Methods of producing such arrays for example based on solid-phase chemistry and photo-labile protective groups, are generally known (US 5,744,305).
  • amount encompasses the absolute amount of a polypeptide or peptide, the relative amount or concentration of the said polypeptide or peptide as well as any value or parameter which correlates thereto or can be derived therefrom.
  • values or parameters comprise intensity signal values from all specific physical or chemical properties obtained from the said peptides by direct measurements, e.g., intensity values in mass spectra or NMR spectra.
  • values or parameters which are obtained by indirect measurements specified elsewhere in this description e.g., response levels determined from biological read out systems in response to the peptides or intensity signals obtained from specifically bound ligands.
  • comparing encompasses comparing the amount of the peptide or polypeptide comprised by the sample to be analyzed with an amount of a suitable reference source specified elsewhere in this description. It is to be understood that comparing as used herein refers to a comparison of corresponding parameters or values, e.g., an absolute amount is compared to an absolute reference amount while a concentration is compared to a reference concentration or an intensity signal obtained from a test sample is compared to the same type of intensity signal of a reference sample.
  • the comparison referred to in step (b) of the method of the present invention may be carried out manually or computer assisted.
  • the value of the determined amount may be compared to values corresponding to suitable references which are stored in a database by a computer program.
  • the computer program may further evaluate the result of the comparison, i.e. automatically provide the desired assessment in a suitable output format.
  • the reference amount is to be chosen so that either a difference or a similarity in the compared amounts allows identifying those subjects which belong into the group of subjects suffering from a cardiac necrosis either caused by initial heart failure or by a coronary heart disease.
  • the term "reference amounts" as used herein refers to amounts of the polypeptides which allow identifying a subject suffering from a cardiac necrosis either caused by initial heart failure or by a coronary heart disease. Accordingly, the reference may either be derived from (i) a subject known to suffer from a cardiac necrosis caused by initial heart failure or (ii) a subject known to suffer from a cardiac necrosis caused by a coronary heart disease. Moreover, the reference amounts, preferably, define thresholds. Suitable reference amounts or threshold amounts may be determined by the method of the present invention from a reference sample to be analyzed together, i.e. simultaneously or subsequently, with the test sample.
  • a preferred reference amount serving as a threshold may be derived from the upper limit of normal (ULN), i.e. the upper limit of the physiological amount to be found in a population of subjects (e.g. patients enrolled for a clinical trial).
  • the ULN for a given population of subjects can be determined by various well known techniques.
  • a suitable technique may be to determine the median of the population for the peptide or polypeptide amounts to be determined in the method of the present invention.
  • the ULN for a cardiac Troponin and, in particular, for Troponin T referred to herein preferably, varies between 0.001 ng/ml and 0.01 ng/ml. More preferably, the ULN for the said cardiac Troponin is 0.001 ng/ml.
  • the ULN for a BNP- type peptide and, in particular, for NT-proBNP referred to herein, preferably, varies between 100 and 150 pg/ml. More preferably, the ULN for the said BNP -type peptide is 125 pg/ml.
  • a combination of a cardiac Troponin such as Troponin T and a BNP -type peptide such as NT-proBNP as biomarkers are sufficient to resolve the cause of cardiac necrosis in a reliable and efficient manner.
  • the techniques which are currently used to resolve the cause of cardiac necrosis are both, time consuming and cost intensive.
  • the techniques can usually not be implemented in portable systems.
  • the method of the present invention allows a reliable, fast and less cost intensive diagnosis and can be implemented even in portable assays, such as test stripes. Therefore, the method is particularly well suited for diagnosing emergency patients.
  • the method of the present invention is to be carried out on a sample of a subject and, therefore, has a drastically reduced risk of causing adverse side effects which can not be avoided at least for the invasive prior art techniques. Thanks to the findings of the present invention, a suitable therapy for a subject can be reliably selected. Severe side effects caused by the wrong treatment of patients can be avoided. As described below in detail, therapies for the diseases or disorders accompanied with the cardiac necrosis are different.
  • said reference amounts are the upper limits of normal (ULN) for the cardiac Troponin and the BNP -type peptide.
  • an increased amount of the cardiac Troponin and an increased amount of the BNP -type peptide is indicative for a cardiac necrosis caused by initial heart failure. Also, in a preferred embodiment of the method of the present invention, an increased amount of the cardiac Troponin and an amount of the BNP -type peptide being not increased is indicative for cardiac necrosis caused by a coronary heart disease.
  • the present invention also relates to a method of determining whether a subject suffering from cardiac necrosis is susceptible for a therapy against initial heart failure comprising: a) determining the amount of a cardiac Troponin and the amount of a BNP- type peptide in a sample of a subject suffering from cardiac necrosis; and b) comparing the amount of the said cardiac Troponin and the amount of said BNP -type peptide to reference amounts, whereby it is to be determined whether the subject is susceptible to a therapy against initial heart failure.
  • determining whether a subject suffering from cardiac necrosis is susceptible for a therapy against initial heart failure means assessing whether a subject will be susceptible for a therapy against initial heart failure or not. As will be understood by those skilled in the art, such an assessment is usually not intended to be correct for all (i.e. 100%) of the subjects to be identified. The term, however, requires that a statistically significant portion of subjects can be identified (e.g. a cohort in a cohort study). Whether a portion is statistically significant can be determined without further ado by the person skilled in the art using various well known statistic evaluation tools. Further details on said statistical evaluation are to be found elsewhere in this specification.
  • therapy against initial heart failure encompasses drug-based as well as other therapies of heart failure. More preferably, said therapy against initial heart failure is selected from the group consisting of: medicament based therapy, preferably, administration of ACE Inhibitors, administration of ⁇ -Blockers, administration of digital ATI and/or AT2 Blockers, administration of inotropic drugs, assist device-based therapies, interventional therapy is cardiac resynchronisation therapy (CRT) or based on implantation of a cardioverter defibrillator (ICD) and heart transplantation.
  • medicament based therapy preferably, administration of ACE Inhibitors, administration of ⁇ -Blockers, administration of digital ATI and/or AT2 Blockers, administration of inotropic drugs, assist device-based therapies, interventional therapy is cardiac resynchronisation therapy (CRT) or based on implantation of a cardioverter defibrillator (ICD) and heart transplantation.
  • CTR cardiac resynchronisation therapy
  • ICD cardioverter defibrillator
  • the said medicament is an ACE inhibitor, preferably captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, or trandolapril, an AT-I receptor blocking agent, preferably, candesartan, losartan, or valsartan, a ⁇ -recpetor blocking agent, preferably, bisoprolol, carvedilol, metoprolol or succinate, or an an aldosterone antagonist, preferably, spironolacton or eplerenone.
  • an AT-I receptor blocking agent preferably, candesartan, losartan, or valsartan
  • a ⁇ -recpetor blocking agent preferably, bisoprolol, carvedilol, metoprolol or succinate, or an an aldosterone antagonist, preferably, spironolacton or eplerenone.
  • said reference amounts are the upper limits of normal (ULN) for the cardiac Troponin and the BNP -type peptide.
  • an increased amount of the cardiac Troponin and an increased amount of the BNP -type peptide is indicative for a subject being susceptible for a therapy against initial heart failure.
  • the method of the present invention may further comprise a supplementary diagnostic technique selected from the group consisting of: echocardiography, computed tomography, NMR-based diagnostics, electrocardiography, x-ray diagnostics of the thorax and spirometry.
  • a supplementary diagnostic technique selected from the group consisting of: echocardiography, computed tomography, NMR-based diagnostics, electrocardiography, x-ray diagnostics of the thorax and spirometry.
  • the present invention also encompasses a method for determining whether a subject suffering from cardiac necrosis is susceptible for a therapy against coronary heart disease comprising a) determining the amount of cardiac Troponin and the amount of a BNP -type peptide in a sample of a subject suffering from cardiac necrosis; and b) comparing the amount of the said cardiac Troponin and the amount of the said BNP -type peptide to reference amounts, whereby it is to be determined whether the subject is susceptible to a therapy against coronary heart disease.
  • determining whether a subject suffering from cardiac necrosis is susceptible for a therapy against coronary heart disease means assessing whether a subject will be susceptible for a therapy against coronary heart disease or not. As will be understood by those skilled in the art again, such an assessment is usually not intended to be correct for all (i.e. 100%) of the subjects to be identified. The term, however, requires that a statistically significant portion of subjects can be identified (e.g. a cohort in a cohort study). Whether a portion is statistically significant can be determined without further ado by the person skilled in the art using various well known statistic evaluation tools. Further details on said statistical evaluation are to be found elsewhere in this specification.
  • the term "therapy against coronary heart disease” encompasses drug-based as well as invasive therapies against a coronary heart disease. More preferably, the therapy against coronary heart disease is selected from the group consisting of: administration of inhibitors of thrombocyte aggregation, preferably, aspirin or clopidogrel, and cardiac interventions.
  • Preferred cardiac interventions in accordance with the present invention are specifically selected from the group consisting of percutaneous coronary angioplasty, percutaneous transluminal coronary balloon angioplasty, laser angioplasty, coronary stent implantation, bypass implantation or intraluminal techniques aiming to restore blood flow, vessel patency, stabilize plaque, and/or reduce intracoronary thrombus load.
  • said reference amount are the upper limits of normal (ULN) for the cardiac Troponin and the BNP -type peptide.
  • an increased amount of the cardiac Troponin and an amount of the BNP -type peptide being not increased as indicative for a subject being susceptible for a therapy against coronary heart disease.
  • the method of the present invention may further comprise a supplementary diagnostic technique selected from the group consisting of: angiography, echocardiography, computer tomography, NMR-based diagnostics, electrocardiography, x-ray diagnostics of the thorax and spirometry.
  • a supplementary diagnostic technique selected from the group consisting of: angiography, echocardiography, computer tomography, NMR-based diagnostics, electrocardiography, x-ray diagnostics of the thorax and spirometry.
  • the present invention encompasses the use of a cardiac Troponin and a BNP- type peptide for the preparation of a diagnostic composition for diagnosing the cause of cardiac necrosis in the subject, for determining whether a subject suffering from cardiac necrosis is susceptible for a therapy against initial heart failure or for determining whether a subject suffering from cardiac necrosis is susceptible for a therapy against coronary heart disease.
  • the present invention also includes a method of monitoring the success of a therapy against coronary heart disease comprising:
  • a BNP -type peptide is also determined in the said first and second sample.
  • a decrease in the amount of the said BNP -type peptide will be, furthermore, indicative of success of the applied treatment regimen.
  • the present invention encompasses a method of monitoring the success of a therapy against initial heart failure comprising:
  • monitoring as used herein relates to keeping track of the effects caused by a treatment regimen to the amounts of NT-proBNP and/or the cardiac Troponin. It is to be understood that the amounts must be determined at least prior and after the onset of the said treatment regimen. However, the amounts may be determined at other stages, too.
  • uccess refers to at least an amelioration of the prognosis, symptoms or clinical signs accompanied with the diseases, i.e. coronary heart disease or initial heart failure.
  • the present invention also relates to a diagnostic device adapted for carrying out any one of the methods of the preset invention comprising means for the determination of the amount of cardiac Troponin and the amount of a BNP -type peptide in a sample of a subject suffering from cardiac necrosis and means for preparing the said amounts to reference amounts.
  • the term "device” as used herein relates to a system of means comprising at least the aforementioned means operatively linked to each other as to allow the prediction.
  • Preferred means for determining the amount of a cardiac Troponin and a BNP -type peptide as well as means for carrying out the comparison are disclosed above in connection with the method of the invention. How to link the means in an operating manner will depend on the type of means included into the device. For example, where means for automatically determining the amount of the peptides are applied, the data obtained by said automatically operating means can be processed by, e.g., a computer program in order to obtain the desired results. Preferably, the means are comprised by a single device in such a case.
  • Said device may accordingly include an analyzing unit for the measurement of the amount of the peptides or polypeptides in an applied sample and a computer unit for processing the resulting data for the evaluation.
  • the computer unit preferably, comprises a database including the stored reference amounts or values thereof recited elsewhere in this specification as well as a computer-implemented algorithm for carrying out a comparison of the determined amounts for the polypeptides with the stored reference amounts of the database.
  • Computer-implemented as used herein refers to a computer-readable program code tangibly included into the computer unit.
  • the means for comparison may comprise control stripes or tables allocating the determined amount to a reference amount.
  • the test stripes are, preferably, coupled to a ligand which specifically binds to the peptides or polypeptides referred to herein.
  • the strip or device preferably, comprises means for detection of the binding of said peptides or polypeptides to the said ligand.
  • Preferred means for detection are disclosed in connection with embodiments relating to the method of the invention above.
  • the means are operatively linked in that the user of the system brings together the result of the determination of the amount and the diagnostic or prognostic value thereof due to the instructions and interpretations given in a manual.
  • the means may appear as separate devices in such an embodiment and are, preferably, packaged together as a kit. The person skilled in the art will realize how to link the means without further ado.
  • Preferred devices are those which can be applied without the particular knowledge of a specialized clinician, e.g., test stripes or electronic devices which merely require loading with a sample.
  • the results may be given as output of raw data which need interpretation by the clinician.
  • the output of the device is, however, processed, i.e. evaluated, raw data the interpretation of which does not require a clinician.
  • Further preferred devices comprise the analyzing units/devices (e.g., biosensors, arrays, solid supports coupled to ligands specifically recognizing the natriuretic peptide, Plasmon surface resonace devices, NMR spectrometers, mass- spectrometers etc.) and/or evaluation units/devices referred to above in accordance with the method of the invention.
  • the present invention relates to a diagnostic kit adapted for carrying out any one of the methods of the present invention comprising means for the determination of the amount of a cardiac Troponin and the amount of a BNP -type peptide in a sample of a subject suffering from cardiac necrosis and means for comparing the said amounts to reference amounts.
  • kit refers to a collection of the aforementioned means, preferably, provided in separately or within a single container.
  • the container also preferably, comprises instructions for carrying out the method of the present invention.
  • Figure 1 Linear regression analysis of NT-proBNP and Troponin T in patients suffering from ischemic cardiac myopathy.
  • Figure 2 Linear regression analysis of NT-proBNP and Troponin T in patients suffering from coronary heart disease.
  • Figure 3 Linear regression analysis of NT-proBNP and Troponin T in a subgroup of patients suffering from 3-vessel disease.
  • FIG. 4 Linear regression analysis of NT-proBNP and Troponin T in patients suffering from cardiac necrosis which have been subjected to physical stress (bicycle exercise) and pharmacological stress.
  • Example 1 NT-proBNP and Troponin T in patients with coronary heart disease
  • NT-proBNP and sensitive Troponin T was measured in blood samples of a total of 235 patients suffering from stable coronary heart disease. NT-proBNP was measured using the
  • ElecsysTM assay and Troponin T was assayed by the sensitive Troponin T test purchased from Roche Diagnostics. Patients were subjected to a detailed cardiologic investigation including echocardiography and coronary angioplasty. The coronary heart disease was subclassified into 1-, 2- or 3-vessel diseases, whereby stenosis of more than 50% should occur per vessel.
  • the two biomarkers were analyzed by statistical linear regression analysis. As shown in Figure 2, a correlation of NT-proBNP and sensitive Troponin T was found with a correlation R value of 0.0667. Patients having an increased Troponin T level and a normal NT-proBNP exhibited a substantial stenosis when investigated by angiography while patients having an elevated NT-proBNP level and an elevated Troponin T showed no such substantial stenosis when investigated by angiography. Similar results were obtained for a subgroup of patients suffering from the 3-vessel disease (see Figure 3).
  • Example 2 NT-proBNP and Troponin T of patients suffering from cardiac necrosis as investigated by thallium scintigraphy A total of 143 patients who underwent thallium scintigraphy for suspected significant coronary artery disease were studied.
  • Single-photon emission computed tomography myocardial perfusion (SPECT) imaging was carried out as follows: Thallium was administered at peak stress, and imaging was performed immediately thereafter. Four hours later, a repeat imaging was performed. A 17 segment myocardial model was used for semiquantitative analysis. Two nuclear cardiologists unaware of biomarker results categorized the images as having no perfusion defects, only reversible perfusion defects, and fixed perfusion defects. Patients with a combination of reversible, partially reversible, and fixed perfusion defects were excluded from primary analysis and evaluated separately.
  • SPECT single-photon emission computed tomography myocardial perfusion

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Abstract

La présente invention concerne des moyens et des procédés diagnostiques. Spécifiquement, la présente invention comprend un procédé destiné à diagnostiquer la cause d'une nécrose cardiaque chez un sujet comprenant la détermination de la quantité de troponine cardiaque et de la quantité d'un peptide de type BNP dans un échantillon d'un sujet souffrant de nécrose cardiaque et la comparaison de la quantité de ladite troponine cardiaque et de la quantité dudit peptide de type BNP à des quantités de référence, moyennant quoi la cause de la nécrose cardiaque sera diagnostiquée. La présente invention concerne en outre un procédé de détermination du fait qu'un sujet souffrant de nécrose cardiaque est sensible ou non à une thérapie contre une insuffisance cardiaque initiale et un procédé de détermination du fait qu'un sujet souffrant d'une nécrose cardiaque est sensible ou non à une thérapie contre une maladie coronarienne. Les utilisations, dispositifs et kits diagnostiques sont également compris.
EP07847226A 2006-11-21 2007-11-20 Moyens et procédés d'optimisation d'approches diagnostiques et thérapeutiques dans une maladie artérielle chronique basés sur la troponine t et le nt-probnp Ceased EP2089719A2 (fr)

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EP07847226A EP2089719A2 (fr) 2006-11-21 2007-11-20 Moyens et procédés d'optimisation d'approches diagnostiques et thérapeutiques dans une maladie artérielle chronique basés sur la troponine t et le nt-probnp
PCT/EP2007/062562 WO2008061978A2 (fr) 2006-11-21 2007-11-20 Moyens et procédés d'optimisation d'approches diagnostiques et thérapeutiques dans une maladie artérielle chronique basés sur la troponine t et le nt-probnp

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EP2324358A1 (fr) * 2008-07-23 2011-05-25 F. Hoffmann-La Roche AG Surveillance de la thérapie anti-angiogénique
EP3225994A1 (fr) 2010-08-26 2017-10-04 Roche Diagnostics GmbH Utilisation de biomarqueurs pour l'évaluation d'une transition précoce d'hypertension artérielle vers une insuffisance cardiaque
EP2730923A1 (fr) * 2012-11-09 2014-05-14 Roche Diagniostics GmbH Orientation de thérapie à base de cTnT et NtproBNP pour l'insuffisance cardiaque
EP2899544B1 (fr) * 2014-01-28 2018-12-26 Roche Diagnostics GmbH Biomarqueurs pour l'évaluation du risque et la surveillance thérapeutique chez des patients atteints d'insuffisance cardiaque et traités en fonction de peptide natriurétique de type B
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