EP1941055A1 - Méthode in vitro pour le diagnostic de maladies neurodégénératives - Google Patents

Méthode in vitro pour le diagnostic de maladies neurodégénératives

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Publication number
EP1941055A1
EP1941055A1 EP06818303A EP06818303A EP1941055A1 EP 1941055 A1 EP1941055 A1 EP 1941055A1 EP 06818303 A EP06818303 A EP 06818303A EP 06818303 A EP06818303 A EP 06818303A EP 1941055 A1 EP1941055 A1 EP 1941055A1
Authority
EP
European Patent Office
Prior art keywords
cps
determination
disease
dementia
alzheimer
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.)
Withdrawn
Application number
EP06818303A
Other languages
German (de)
English (en)
Inventor
Andreas Bergmann
Joachim Struck
Andrea Ernst
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.)
BRAHMS GmbH
Original Assignee
BRAHMS GmbH
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Filing date
Publication date
Application filed by BRAHMS GmbH filed Critical BRAHMS GmbH
Priority to EP06818303A priority Critical patent/EP1941055A1/fr
Publication of EP1941055A1 publication Critical patent/EP1941055A1/fr
Withdrawn legal-status Critical Current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
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/48—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase

Definitions

  • the present invention relates to a novel in vitro method for the diagnosis of neurodegenerative diseases, in particular dementias such as Alzheimer's disease.
  • the invention is based on the fact that it was surprisingly found that an enzyme from the liver, namely the enzyme carbamoyl phosphate synthetase 1 (EC 6.3.4.16, hereinafter always abbreviated CPS 1), and / or physiologically occurring CPS 1 fragments with CPS 1 immunoreactivity in which circulation of Alzheimer's patients, in particular in plasma or serum, is found to be significantly increased and is therefore suitable for use as a humoral biomarker in medical diagnostics for the detection of neurodegenerative diseases.
  • CPS 1 carbamoyl phosphate synthetase 1
  • a diagnosis can also be a negative diagnosis, in which due to the undetectability of a certain disease-typical feature, e.g. the undetectability of a biomarker associated with the disease in a blood sample from a patient that reliably excludes the presence of a specific disease.
  • a certain disease-typical feature e.g. the undetectability of a biomarker associated with the disease in a blood sample from a patient that reliably excludes the presence of a specific disease.
  • biomarkers of great value which can be found elevated in several different diseases and therefore alone, taken alone, do not allow a positive diagnosis of a specific disease - although they are usually in consultation with other clinical or biochemical parameters for the positive diagnosis can be crucial.
  • the diseases to be diagnosed in the present invention are relatively slow-developing, chronic neurodegenerative diseases of non-infectious etiology, especially pre-senile dementias.
  • Dementia diseases are generally referred to as diseases for which a common feature is the loss of acquired intellectual capabilities, especially memory, and normal personality levels as a result of brain damage. Dementias are usually relatively slow-developing diseases of chronic nature. If dementia occurs before old age in middle age, it is referred to as pre-senile dementia, and on the basis of typical symptoms and brain pathological changes, the following diseases or groups of diseases are distinguished: Alzheimer's disease (AD) (Alzheimer's disease) is the most common neurodegenerative dementia disorder, accounting for 2/3 of all dementia cases.
  • AD Alzheimer's disease
  • AD Alzheimer's disease: genes, proteins, and Therapy Physiological Reviews 81: 741-766.
  • Amyloid plaques consist of extraneuronal aggregates of the amyloid ⁇ -protein, while the neurofibrillary tangles mainly contain tau protein and neurofilaments. It is believed that plaque and neurofibrillary formation is the cause of nerve cell death.
  • AD Alzheimer's disease
  • Dementia with Lewy bodies is the second leading cause of dementia after Alzheimer's disease.
  • DLB is characterized by the appearance of so-called Lewy bodies in the brainstem and in the cortex. These Lewy bodies consist predominantly of aggregates of the presynaptic protein (ce-synuclein) and ubiquitin. Lewy body pathology may be associated to varying degrees with Alzheimer's and Parkinson's-type neuropathological changes.
  • DLB also causes the formation of beta-amyloid and senile plaques, but not neurofibrillary tangles (for a review, see MCKEITH IG (2002) Dementia with lewy bodies, British Journal of Psychiatry 180: 144-147, see also GELDMACHER DS (2004), Dementia with Lewy bodies: diagnosis and clinical approach, Cleveland Clinic Journal of Medicine 71: 789-800). Lewy bodies are also present in the brain of patients with Parkinson's disease, albeit in a different distribution.
  • DLB deficiency bowel syndrome
  • the core symptoms of DLB are progressive cognitive impairment, confusion episodes with fluctuating attention and consciousness, parkinsonism, frequent falls and syncope (seizure-type, short-lasting unconsciousness).
  • the sensitivity and specificity of the diagnostic criteria show consistently high specificity, but in part a very low sensitivity. This means that DLB is often not diagnosed in clinical practice.
  • Frontotemporal dementia is also referred to as Pick's disease and accounts for approximately 20% of pre-senile dementias.
  • FTD is partly genetic and is one of the so-called tauopathies, which are characterized by an over- or underexpression of a subtype of subtypes or by the expression of a mutated tau protein.
  • FTD is under-diagnosed with a sensitivity of 93% with a specificity of only 23%, with AD being the most common misdiagnosis.
  • vascular dementia refers to diseases in which dementia is triggered by circulatory disorders in the brain.
  • VAD multi-infarct dementia
  • subcortical VAD also referred to as Binswanger's disease
  • Binswanger's Disease is a slowly progressive dementia development that causes pathologic is characterized by cerebrovascular lesions in the cerebral white matter. Clinically, this results in behavioral problems such as agitation, irritability, depression and euphoria as well as a mild memory disorder.
  • Multi-infarct dementia is gradually emerging as a result of several small strokes, also known as transient ischemic attacks (TIAs), which led to the destruction of brain tissue in the cortex and / or subcortical areas.
  • TIAs transient ischemic attacks
  • the strokes may have gone completely unnoticed, the dementia is in this case the first noticeable consequence.
  • MID transient ischemic attacks
  • cognitive abilities associated with severe depression, mood swings, and epilepsy.
  • Diagnosis of dementia is nowadays predominantly based on neuropsychological examinations and the observation of disease progression and its course, using exclusion criteria for certain forms of dementia. These studies provide very ambiguous results in many cases, which the o.g. Explain numbers for the underdiagnosed dementia forms or incorrectly diagnosed cases.
  • the disease-typical brain changes naturally can not be detected directly in living patients, and apparatus-medical examinations of brain functions by means of e.g. X-ray or MRI tomography are complex and expensive.
  • the Ronald and Nancy Reagan Institute of the Alzheimer's Association and the NIA Working Group published guidelines for the criteria for an ideal biomarker for the detection of AD (7).
  • the following criteria should ideally be met by the biomarker: 1. It should be brain specific and detect a fundamental feature of the neuropathology of these disorders.
  • the diagnostic sensitivity and the specificity of at least 80% should be given.
  • the disease-specific change in the biomarker should be manifested at the earliest possible stage of the disease in order to provide appropriate therapeutic measures.
  • AD Alzheimer's dementia
  • the present invention provides such an assay method in the form of an in vitro method for the detection, determination and evaluation of the prognosis and prognosis of neurodegenerative diseases, characterized in that in a biological fluid of a patient suffering from a neurodegenerative disease
  • the presence or concentration of the enzyme carbamoyl phosphate synthetase 1 (CPS 1), and / or physiologically occurring CPS 1 fragments with CPS 1 immunoreactivity, and based on the disease detected Presence and / or concentration of CPS 1 or undetectability of CPS 1 immunoreactivity draws conclusions as to the presence, course, severity or success of neurodegenerative disease therapy.
  • Advantageous or preferred embodiments of a method according to claim 1 are given in the dependent claims 2 to 12.
  • the present invention is based on completely surprising findings of a systematic investigation of a large number of sera and plasmas of patients with the diagnosis "probably Alzheimer's dementia" by means of novel immunoassays for the determination of various biomarkers, which are in the name of the Applicant in the development and clinical Trials are and partly Are the subject of published or unpublished earlier patent applications of the applicant.
  • the determination method for CPS-I in patient plasmas used for the measurements described in the experimental section is a modification of a noncompetitive immunoluminometric sandwich assay for the determination of CPS-I, as described in more detail in WO 03/089933 and EP 1 497 662, respectively Al the applicant is described.
  • CPS 1 and CPS 1 fragments with CPS 1 immunoreactivity did not play a practical role in medical diagnostics.
  • the liver enzyme CPS 1 has never been considered as a possible humoral biomarker.
  • CPS 1 (EC 6.3.4.16) itself has long been well known. It catalyzes the conversion of ammonia, bicarbonate and 2 ATP to form carbamoyl phosphate in the first step of the urea cycle. It also plays a role in the biosynthesis of arginine, which in turn is a substrate for the biosynthesis of NO, for example in an endotoxin shock (see Shoko Tabuchi et al., Regula- tion of Genes for Inducible Nitric Oxide Synthase and Urea Cycle Enzyme in Rat Liver in Endotoxin Shock, Biochemical and Biophysical Research Communications 268, 221-224 (2000)).
  • CPS 1 is to be distinguished from the cytosolic enzyme CPS 2 (EC 2.7.2.5.), which also plays a role in the urea cycle, but processes the substrate glutamine. It is known that CPS 1 is localized in mitochondria and occurs in liver tissue in this form in large quantities (it accounts for 2-6% of total liver protein). Its amino acid sequence and genetic localization has been known for a long time (see Haraguchi Y. et al., Cloning and Sequence of a cDNA encoding Human Carbamyl Phosphate Synthase I: Molecular Analysis of Hyperammoniae, Gene 1991, Nov. 1, 107 (2): See also the publication WO 03/089933 A1 of the Applicant).
  • CPS 1 The measurements described in the present application constitute the first report of the occurrence of CPS 1 in the circulation of patients with neurodegenerative diseases, in particular patients diagnosed with Alzheimer's disease. So far, CPS 1, and also only in Applicant's studies, has only been used in serum or plasma of sepsis patients (see WO 03/089933 A1). Sepsis patients, whose high-acuity potentially life-threatening disease is typically monitored and treated in intensive care units, represent a distinct patient population of patients with neurodegenerative diseases suffering from long-term developing disease.
  • the modification takes into account the fact disclosed in WO 03/089933 A1 that the species having CPS 1 immunoreactivity to be found in the circulation is at least predominantly the complete, or at least substantially complete, enzyme CPS 1 itself.
  • a second antibody is used which binds to amino acids 781 to 794 of said sequence.
  • CPS 1 as a biomarker
  • use of CPS 1 as a biomarker within the meaning of the present application is not only the direct immunological determination of CPS 1 in in vitro samples for diagnostic purposes, but also a use of CPS 1 or CPS 1 fragments, or antibodies for their selective determination, for the production of assay kits, or a Use for the production of assay components, for example of poly- or monoclonal antibodies, which are usually also provided, for example, in immobilized and / or labeled form in assay kits for the indicated diseases, or of standard and reference substances.
  • CPS 1 or CPS 1 immunoreactivity in the determination according to the invention of CPS 1 or CPS 1 immunoreactivity, depending on the assay design, a simultaneous determination both of CPS 1 in the form of the essentially complete molecule and in the form of other possibly present in the biological fluid, shorter fragments (physiologically occurring partial peptides) of the complete CPS 1 can be done.
  • CPS 1 immunoreactivity this is intended to reflect this metrology to avoid an unduly narrower interpretation of the teachings of the present invention.
  • the CPS 1 determination should, if appropriate, also be carried out indirectly for the purpose of determining an enzyme activity which corresponds to the CPS 1 activity or the residual activity of the CPS 1 fragments in the blood . Because CPS 1 does not occur in healthy individuals in the circulation, measurable CPS 1 enzyme activity in the blood of a patient may be a diagnostically significant indicator of a serious disorder in the patient's health. It should also be noted at this point that the activity of an enzyme, which is normally localized inside the cell and only there unfolds its functional effect, in the circulation per se is to be evaluated negatively and therefore as such may contribute to aggravating a disease state.
  • CPS 1 The actual determination of CPS 1 may be made not only in the manner concretely described in the experimental section, but in any suitable manner known per se, with immunoassays of suitable assay design being preferred.
  • the methods for determining CPS 1 immunoreactivity in a biological sample can be any known immunodiagnostic methods used to detect and measure antigens.
  • CPS 1 is determined by a ligand binding assay using specific antibodies suitable for binding and labeling in immobilized or labeled form.
  • the determination method can be adapted to the chip technology or designed as a rapid test (point-of-care test).
  • the immunodiagnostic determination is carried out as a heterogeneous sandwich immunoassay, in which one of the antibodies is bound to any solid phase, for example the walls of coated test tubes. or coated on microtiter plates, for example made of polystyrene, or on particles, for example magnetic particles, while the other antibody carries a residue which represents a directly detectable label or a selective linkage with allows a label and the detection of the formed sandwich structures is used.
  • a delayed or subsequent immobilization using suitable solid phases is also possible.
  • all labeling techniques which can be used in assays of the type described can be used, for which labels with radioisotopes, enzymes, fluorescence, chemiluminescence or bioluminescence labels and directly optically detectable color labels, such as, for example, gold atoms and dye particles, as used in particular for so-called point of-care (POC) or rapid tests are used.
  • the two antibodies can also have parts of a detection system of the type described below in connection with homogeneous assays.
  • the inventive method can also be designed as a homogeneous method in which the sandwich complexes formed from the two antibodies and the CPS to be detected 1 remain suspended in the liquid phase.
  • Such techniques can be designed in particular as fluorescence amplification or fluorescence quenching detection methods.
  • a particularly preferred such method involves the use of paired detection reagents such as those described in US-A-4,822,733, EP-Bl-180492 or EP-B1- 539 477 and the prior art cited therein.
  • FIG. 1 shows a typical calibration curve for the determination of
  • FIG. 2 shows the results of the measurement of CPS-I concentrations in EDTA plasmas of patients with the diagnosis "probably Alzheimer's dementia” (wsAD), compared to the results of the same measurements in age-matched control persons without signs of Alzheimer's dementia.
  • a first peptide sequence 1 (EFEGQPVDFVDPNKQN) corresponding to amino acids 184-199 of the sequence of human CPS 1 (see peptide PCEN17 according to WO 03/089933), and a second peptide sequence (FHGTSSRIGSSMKS), which corresponds to the amino acids 781-794 of the sequence of the human CPS 1.
  • Each peptide was synthesized in a form provided with an amino-terminal cysteine residue (CysO) by Jerini (Berlin, Germany). The synthesized peptides used for the subsequent immunizations are shown in the sequence listing as SEQ ID NO: 1 and SEQ ID NO: 2, respectively.
  • the two synthesized peptides were conjugated to the Limulus polyphemus hemocyanin and, as described in WO 03/089933, polyclonal antibodies in sheep were obtained by the company. Micropharm (Carmarthenhire, UK).
  • the antibodies were purified by ligand-specific affinity purification.
  • the Cys (0) peptides 1 and 2 were first coupled to SulfoLink gel from Pierce (Boston, USA). The binding was carried out according to the instructions of the manufacturer.
  • the gel material was mixed with 25 ml of the respective antiserum pool and incubated overnight at room temperature with gentle swirling.
  • the serum-gel mixtures were transferred to polycarbonate columns and excess serum was removed.
  • the columns were then washed with 250 ml of PBS to remove unbound serum proteins.
  • the desorption of the bound antibodies was carried out by elution of the column with 50 mM citric acid (pH 2.2).
  • the eluate was collected in fractions of 1 ml.
  • the protein concentration of each fraction was determined by means of the BCA protein assay kit from Perbio (Bonn, Germany), and the fractions with a protein content> 1 mg / ml were combined.
  • the affinity-purified antibodies were buffer exchanged by dialysis in PBS and then stored after re-determination of protein content at 4 0 C.
  • the purified antibodies against the peptide corresponding to the amino acid sequence 781-794 were immobilized on polystyrene tubes (Startubes, 12 mm ⁇ 75 mm, Greiner, Germany).
  • the antibody solutions were diluted to a protein concentration of 6.7 ⁇ g / ml with PBS and pipetted 300 ⁇ l per tube (equivalent to 2 ⁇ g of antibody per tube). These were incubated for 20 h at room temperature and then washed 3 times with 4 ml of PBS. Until further use, the tubes were stored at 4 ° C.
  • the antibody to the peptide corresponding to amino acid sequence 184-199 (1 mg / ml in PBS) was incubated with acridinium ester N-hydroxy-succinimide (1 mg / ml in acetonitrile, InVent, Co., Ltd.). Hennigsdorf Germany) luminescence-labeled.
  • 200 ⁇ l of antibody were mixed with 4 ⁇ l of acridinium ester, incubated for 20 min, and free acridinium ester compounds were saturated by addition of 40 ⁇ l of a 50 mM glycine solution.
  • the labeling batch was separated from free acridinium ester by HPLC on a BioSil 400 gel filtration column (BioRad, Kunststoff, Germany). The mobile phase used was PBS.
  • the standard material used was a pool of plasmas from human patients with SIRS with particularly high CPS 1 concentrations.
  • the CPS 1 concentration of this pool was arbitrarily set at 150 U / ml.
  • standards were prepared by serial dilution with CPS 1 -free human plasma of healthy subjects, to which arbitrary concentrations according to their dilution were attributed.
  • FIG. 1 A typical standard curve with the corresponding relative concentrations is shown in FIG.
  • the analytical assay sensitivity is 0.9 U / ml.
  • the controls have an age median of 67.9 ⁇ 12.4 years, and the wsAD patients have a median age of 73.3 + 9.4 years.
  • the cut-off of the assay was set at 0.9 U / ml (relative units per ml), which corresponds to the analytical sensitivity of the assay.
  • relative CPS 1 concentrations of more than 0.9 U / ml were measured.
  • the measurable CPS 1 concentrations of 89 out of 115 controls are below 0.9 U / ml.
  • Alzheimer's patients can be differentiated from controls with a specificity of 77.4% and a sensitivity of 86.7%. The difference between the two groups is highly significant (P value ⁇ 0.0001). The medial concentration of the controls was below the sensitivity of the test, whereas Alzheimer's patients had a medial CPS 1 concentration of 1.76 U / ml.

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Abstract

L'invention concerne une méthode in vitro pour le dépistage, la détermination du degré de gravité, l'évaluation de l'évolution et le pronostic de maladies neurodégénératives, lequel procédé consiste à déterminer la présence et/ou la concentration de la carbamoylphosphate synthétase 1 (CPS 1) dans un liquide biologique d'un patient souffrant d'une maladie neurodégénérative ou chez lequel une telle maladie est soupçonnée et à tirer des conclusions sur l'existence, l'évolution, le degré de gravité ou la réussite d'une thérapie de cette maladie neurodégénérative en fonction de la présence et/ou de la concentration de CPS 1 constatée ou de l'indétectabilité d'une immunoréactivité de la CPS 1.
EP06818303A 2005-10-26 2006-10-26 Méthode in vitro pour le diagnostic de maladies neurodégénératives Withdrawn EP1941055A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP06818303A EP1941055A1 (fr) 2005-10-26 2006-10-26 Méthode in vitro pour le diagnostic de maladies neurodégénératives

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP05023420A EP1780287A1 (fr) 2005-10-26 2005-10-26 Procédé in vitro destiné au diagnostic de maladies neurodégénératives
PCT/EP2006/010352 WO2007048617A1 (fr) 2005-10-26 2006-10-26 Methode in vitro pour le diagnostic de maladies neurodegeneratives
EP06818303A EP1941055A1 (fr) 2005-10-26 2006-10-26 Méthode in vitro pour le diagnostic de maladies neurodégénératives

Publications (1)

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EP1941055A1 true EP1941055A1 (fr) 2008-07-09

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EP05023420A Withdrawn EP1780287A1 (fr) 2005-10-26 2005-10-26 Procédé in vitro destiné au diagnostic de maladies neurodégénératives
EP06818303A Withdrawn EP1941055A1 (fr) 2005-10-26 2006-10-26 Méthode in vitro pour le diagnostic de maladies neurodégénératives

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EP (2) EP1780287A1 (fr)
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WO (1) WO2007048617A1 (fr)

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Publication number Priority date Publication date Assignee Title
DE102006021406B4 (de) * 2006-05-08 2008-08-07 B.R.A.H.M.S Aktiengesellschaft In vitro Verfahren zur Früherkennung von arznei- und suchtmittelinduzierten Leberschäden und zur Erkennung der bereits erreichten Stufe der Leberschädigung
US20080126119A1 (en) * 2006-11-24 2008-05-29 General Electric Company, A New York Corporation Systems, methods and apparatus for a network application framework system
DE102006056337A1 (de) * 2006-11-29 2008-06-05 B.R.A.H.M.S Ag In vitro Verfahren zur Diagnose und Frühdiagnose von neurodegenerativen Erkrankungen

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Publication number Priority date Publication date Assignee Title
EP1355159A1 (fr) * 2002-04-19 2003-10-22 B.R.A.H.M.S Aktiengesellschaft Utilisation de fragments de carbamyl phosphate synthetase I (CPS 1) pour le diagnostic de maladies inflammatoires et de la septicémie
EP1355158A1 (fr) * 2002-04-19 2003-10-22 B.R.A.H.M.S Aktiengesellschaft Procédé pour diagnose des maladies inflammatoires et infections par détermination de la phosphoprotéine LASP-1 comme marqueur inflammatoire

Non-Patent Citations (1)

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Title
See references of WO2007048617A1 *

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WO2007048617A1 (fr) 2007-05-03
US20090311719A1 (en) 2009-12-17
EP1780287A1 (fr) 2007-05-02
JP2009513960A (ja) 2009-04-02

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