WO2020141157A1 - Procédés et biomarqueurs pour prédire l'efficacité d'un traitement avec des médicaments modulant l'activité de la néprilysine et pour l'évaluer - Google Patents

Procédés et biomarqueurs pour prédire l'efficacité d'un traitement avec des médicaments modulant l'activité de la néprilysine et pour l'évaluer Download PDF

Info

Publication number
WO2020141157A1
WO2020141157A1 PCT/EP2019/087152 EP2019087152W WO2020141157A1 WO 2020141157 A1 WO2020141157 A1 WO 2020141157A1 EP 2019087152 W EP2019087152 W EP 2019087152W WO 2020141157 A1 WO2020141157 A1 WO 2020141157A1
Authority
WO
WIPO (PCT)
Prior art keywords
nep
substrates
intact
bnp
antibodies
Prior art date
Application number
PCT/EP2019/087152
Other languages
English (en)
Inventor
Alexey Genrihovich KATRUKHA
Aleksandr Gennad’evich SEMENOV
Evgeniya Eduardovna FEYGINA
Alexander Borisovich POSTNIKOV
Original Assignee
Hytest Ltd
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
Application filed by Hytest Ltd filed Critical Hytest Ltd
Publication of WO2020141157A1 publication Critical patent/WO2020141157A1/fr

Links

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
    • G01N33/6854—Immunoglobulins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/26—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against hormones ; against hormone releasing or inhibiting factors
    • 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
    • G01N2333/58—Atrial natriuretic factor complex; Atriopeptin; Atrial natriuretic peptide [ANP]; Brain natriuretic peptide [BNP, proBNP]; Cardionatrin; Cardiodilatin
    • 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
    • G01N2800/324—Coronary artery diseases, e.g. angina pectoris, myocardial infarction
    • 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

Definitions

  • the present disclosure relates to methods and biomarkers of predicting or monitoring responsiveness to treatment with drugs modulating neprilysin activity (e.g. EntrestoTM).
  • drugs modulating neprilysin activity e.g. EntrestoTM.
  • Heart failure is a complex clinical syndrome and health problem affecting at least 26 million people worldwide and is increasing in prevalence.
  • HF is an inability of the heart to keep up with the demands on it and, specifically, failure of the heart to pump blood with normal efficiency. HF may be due to failure of the right or left or both ventricles.
  • the signs and symptoms can include shortness of breath (dyspnea), asthma due to the heart (cardiac asthma), edema, blueness or duskiness (cyanosis), and hypertrophy of the heart.
  • EF ejection fraction
  • HFmrEF Those with HF and a mid-range EF (HFmrEF where LVEF is 40-50%). Those with HF and a preserved or normal EF (HFpEF where LVEF is
  • HF may also be classified as acute or chronic.
  • Chronic HF is a long-term condition, usually kept stable by the treatment of symptoms.
  • Acute decompensated HF is a worsening of chronic heart failure symptoms which can result in acute respiratory distress.
  • HF has a heterogeneous pathophysiology.
  • the main aim of HF therapy is to improve the pumping function of the heart.
  • the common strategy for HF therapy is renin-angiotensin-aldosterone system (RAAS) inhibition by either suppressing an angiotensin converting enzyme (by inhibitors of angiotensin converting enzyme, ACEi) or blocking angiotensin II receptor (by angiotensin II receptor blockers, ARB).
  • RAAS renin-angiotensin-aldosterone system
  • beta-blockers and mineralocorticoid receptor agonists have been incorporated into the care of patients with HFrEF.
  • neprilysin neutral endopeptidase, NEP
  • NEP neutral endopeptidase
  • NPs natriuretic peptides
  • sacubitril increases the levels of these peptides, causing blood vessel dilation and reduction of extracellular fluid volume via sodium excretion.
  • EntrestoTM the first medication able to target simultaneously the renin-angiotensin-aldosterone system as well as the NP system.
  • EntrestoTM has been shown to reduce risks associated with HF in both chronic and acute HF patients (PARADIGM-HF and PIONEER-HF trials) (1 , 2).
  • NEP is a zinc-dependent neutral endopeptidase present in many tissues and particularly abundant in kidneys. NEP is a type II membrane protein that functions as a membrane-bound endopeptidase, but a circulating enzymatically active form was also described. It has been identified in various body tissues, such as kidneys (mostly), brain, heart, lungs, adrenal glands, gastrointestinal mucosa, thyroid gland, male reproductive system ducts, and placenta, and on the surface of fibroblasts and neutrophils.
  • NEP substrates are quite large, including NPs (A-type NP (ANP), B-type NP (BNP) and C-type NP (CNP)), bradykinin, adrenomedullin, enkephalines, substance P, oxytocin, b-amyloid, fibrinogen, and other blood plasma proteins.
  • ANP A-type NP
  • BNP B-type NP
  • CNP C-type NP
  • bradykinin bradykinin
  • adrenomedullin enkephalines
  • substance P oxytocin
  • b-amyloid b-amyloid
  • fibrinogen fibrinogen
  • the relative affinity of NEP varies among substrates.
  • the primary amino acid sequences of human ANP and human BNP are provided herein as SEQ ID NO: 1 and SEQ ID NO: 2 respectively.
  • Amino acid sequence of human ANP given in one letter amino acid residue code SEQ ID NO:1 : SLRRSSCFGGRMDRIGAQSGLGCNSFRY
  • Amino acid sequence of human BNP given in one letter amino acid residue code SEQ ID NO:2: SPKMVQGSGCFGRKMDRISSSSGLGCKVLRRH
  • NEP The major part of NEP exists as a membrane-bound enzyme; some amount of the enzyme is present as a circulating form. Soluble NEP is generated presumably by the ectodomain shedding or via exosome-mediated secretion (3).
  • Membrane-bound and soluble NEP enzymes exhibit similar affinity for inhibitors, optimal pH, and Km range; however, the maximum reaction rate (Vmax) of soluble NEP is markedly lower than that of the membrane-bound enzyme (4). Therefore, the in vivo enzymatic activity of NEP is believed to be attributed mostly to the tissue- associated isoform.
  • assays that measure concentration (by immunoassays) or activity (assays based on the cleavage of synthetic fluorogenic substrates) of circulating form of NEP were described (5-8).
  • the invention relates to a method for predicting responsiveness of a subject to the treatment with inhibitors of neprilysin (NEP), comprising measuring in a sample obtained from the subject prior to treatment the amount of products produced by NEP from its endogenous substrates or substrates injected prior to analysis; or measuring the ratio of these products to the intact substrates (or to the total amount of cleaved and intact substrates) and classifying the subject as a responsive or non- responsive subject based on the amount of said products generated by NEP-mediated cleavage; or based on the ratio of these products to the intact substrates (or to the total amount of cleaved and intact substrates).
  • NEP neprilysin
  • Figure 1 Schematic representation of the cleavage sites of ANP and BNP by NEP.
  • FIG. 2 Graph showing the kinetics of the in vitro BNP cleavage by NEP.
  • the amount of three BNP neo-epitope forms (BNP-neo5, BNP-neo17 and BNP-neo18) was measured with immunoassays based on polyclonal antibodies specific to the corresponding neo-epitopes (capture antibodies) and anti-BNP antibody 50E1 (epitope 26-32, detection antibodies).
  • BNP cleavage within the ring structure was measured with BNP immunoassay based on anti-BNP antibodies 50E1 (capture antibodies) and antibodies 130 specific to the region 15-22 (detection antibodies).
  • Figure 3 Graph showing the kinetics of the in vitro ANP cleavage by NEP.
  • the amount of ANP-neo8 form was measured by the immunoassay based on polyclonal antibodies specific to the neo-epitope (capture antibodies) and PAb anti-ANP antibody (detection antibodies).
  • ANP was measured by the immunoassay based on anti-ANP mAb 23/1 (from Bio-Rad, specific to an epitope within the ring structure of ANP) used as capture antibodies in pair with ANP-specific PAb used as detection antibodies
  • Figure 4 Graph showing the time course of generation and clearance of BNP-neo17 form in rats non-treated (“-”) and treated (“+”) with sacubitril after intravenous injection of human BNP (synthetic). Error bars represent standard error of the mean (SE).
  • Figure 5 Graph showing the time course of generation and clearance of BNP-neo18 form in rats non-treated (“-”) and treated (“+”) with sacubitril after intravenous injection of human BNP (synthetic). Error bars represent standard error of the mean (SE).
  • Figure 6 Graph showing the time course of generation and clearance of BNP-neo5 form in rats non-treated (“-”) and treated (“+”) with sacubitril after intravenous injection of human BNP (synthetic). Error bars represent standard error of the mean (SE).
  • Figure 7 Graph showing the time course of generation and clearance of ANP-neo8 form in rats non-treated (“-”) and treated (“+”) with sacubitril after intravenous injection of human BNP (synthetic). Error bars represent standard deviation (SD).
  • Figure 8 graph showing the time course of clearance of ANP in rats non-treated (“-”) and treated (“+”) with sacubitril after intravenous injection of human ANP (synthetic). Error bars represent standard error of the mean (SE).
  • Figure 9 Diagram showing BNP-neo17/total BNP ratio in HF plasma.
  • the present invention is intended to provide methods and biomarkers for predicting efficacy and evaluation of treatment with drugs modulating neprilysin (NEP) activity, including methods for predicting responsiveness and monitoring
  • this invention provides methods of measuring the products produced by NEP from natriuretic peptides (NPs) or other substrates to use as biomarkers for a selection of heart failure (HF) patients for treatment and/or monitoring the efficacy of treatment with NEP inhibitor(s).
  • the present invention provides antibodies as well as epitopes of antibodies, specific to the forms of NPs produced by NEP-mediated cleavage. Antibodies specific to particular epitopes are suitable for the precise immunodetection of specific forms of natriuretic peptides generated by NEP-mediated cleavage in the presence of other (e.g. intact) forms of corresponding substrates.
  • the method of measuring the products produced by NEP- mediated cleavage from NPs or other substrates of the present invention can be used for selection of target HF patients for a safe and efficacious treatment and/or monitoring the efficacy of treatment with NEP inhibitors including EntrestoTM.
  • NEP inhibitors including EntrestoTM.
  • the described here forms of NPs generated in the result of NEP-mediated cleavage are also suggested as blood biomarkers to be used as diagnostic and prognostic biomarkers for a cardiovascular disease.
  • various embodiments of this invention include measuring the amount of products produced by NEP from bradykinin, adrenomedullin, enkephalines, substance P, oxytocin, b-amyloid, fibrinogen, or other blood plasma proteins, or substrates injected prior to analysis, to predicting efficacy and evaluation of treatment with drugs modulating NEP activity, and evaluating the activity of NEP, including both soluble and membrane forms of NEP.
  • NEP neuropeptide
  • Potential substrates of NEP to be used for this purpose include NPs (ANP, BNP, CNP), bradykinin, adrenomedullin, enkephalines, substance P, oxytocin, b-amyloid, fibrinogen, or other blood plasma protein substrates of NEP.
  • measuring the amount of products (or the ratio to intact forms (or to the total amount of cleaved and intact substrates)) produced by NEP-mediated cleavage from its endogenous substrates or substrates injected into the organism prior to analysis will take into account the inherent NEP of the organism (tissue and circulating enzyme).
  • NPs are of particular importance: these molecules are circulating physiologically active peptides that promote many effects, such as vasodilation, natriuresis and diuresis, as well as inhibition of RAAS.
  • NPs are crucial in HF due to their cardioprotective effects.
  • the use of NEP inhibitors in patients with HF is aimed to increase the levels of active NPs and as a consequence to enhance the compensation mechanisms mediated by NPs.
  • the level of active NPs in the circulation depends not only on the degradation rate, but also on the production level and the efficiency of processing of inactive precursor molecules, not susceptible to NEP cleavage. As both production and degradation of active NPs may vary among individuals, this might cause different response to the treatment by NEP inhibitors in different patients.
  • NP restoration potential NP restoration potential
  • Patients with active NEP and high level of production of active forms of NPs are expected to benefit from the treatment with NEP inhibitors, whereas patients with low NEP activity and/or low levels of active forms of NPs (low NP-RP) may have only a modest if any effect from the treatment with drugs inhibiting NEP.
  • the evaluation of NP-RP could be very useful for the safe and efficacious use of NEP inhibitors for the treatment of HF.
  • ANP and BNP are present in the circulation in concentrations, which are high enough for their reliable immunodetection.
  • Third, the amount of the product(s) generated by NEP may indicate the potential for improvement of HF patients, as NPs exhibit compensatory physiological effects. Cleavage of ANP and BNP by NEP results in the formation of novel proteolytic epitopes, which are not present in intact molecules.
  • neo-epitope forms are expected to be present in the circulation of HF patients and concentrations of such forms are expected to vary depending on the activity of NEP and the levels of active NPs, reflecting differences in NP-RPs in different individuals.
  • the amount of neo-epitope forms can be measured by means of immunoassays based on antibodies specific to neo-epitopes generated by NEP- mediated cleavage.
  • the present invention features methods and biomarkers for predicting efficacy and evaluation of treatment with drugs modulating NEP activity, including methods for predicting responsiveness and monitoring responsiveness to NEP inhibitors.
  • Such a method could be useful for pre-treatment discrimination of patients who might benefit from NEP inhibition-based therapy (e.g. EntrestoTM).
  • NEP inhibition-based therapy e.g. EntrestoTM.
  • This implementation falls into the realm of a companion diagnostic approach, which is rapidly moving to the cardiovascular disease area.
  • the invention also features immunoassay methods based on antibodies specific to neo-epitopes of ANP and BNP suggested for specific measurements of the products of ANP and BNP cleavage by NEP.
  • the described method can be used for selection of the target HF patients for the safe and efficacious treatment and/or monitoring the efficacy of treatment with NEP inhibitors.
  • the described here forms of NPs generated in the result of NEP-mediated cleavage are also suggested as blood biomarkers to be used as diagnostic and prognostic biomarkers for a cardiovascular disease.
  • various embodiments of this invention include measuring the amount of products produced by NEP from other substrates of NEP, e.g. bradykinin, adrenomedullin, enkephalines, substance P, oxytocin, b-amyloid, fibrinogen, or other blood plasma protein substrates of NEP, or substrates injected prior to analysis, to predicting efficacy and evaluation of treatment with drugs modulating NEP activity and evaluating the activity of NEP, including both soluble and membrane forms of NEP.
  • substrates of NEP e.g. bradykinin, adrenomedullin, enkephalines, substance P, oxytocin, b-amyloid, fibrinogen, or other blood plasma protein substrates of NEP, or substrates injected prior to analysis, to predicting efficacy and evaluation of treatment with drugs modulating NEP activity and evaluating the activity of NEP, including both soluble and membrane forms of NEP.
  • the present invention also relates to immunoassay methods based on antibodies specific to neo-epitopes of NEP substrates suggested for specific measurements of the products of their cleavage by NEP.
  • Example 1 NEP-mediated cleavage of ANP and BNP is expected to generate proteolytic epitopes that are absent in the intact peptides.
  • ANP Human ANP is known to be primarily cleaved by NEP at two sites - between Cys7-Phe8 and between Gly16-Ala17. Given this, there are four proteolytic epitopes that are absent in the intact ANP (neo-epitopes), which can be generated by the action of NEP - ANP-neo7 (comprising Cys-7 at the C-terminus), ANP-neo8 (comprising Phe-8 at the N-terminus), ANP-neo16 (comprising Gly-16 at the C- terminus) and ANP-neo17 (comprising Ala-17 at the N-terminus) (neo - stands for neo epitope).
  • Human BNP is known to be primarily cleaved by NEP at two sites - between Met4-Val5 and between Arg17-lle18. Given this, there are three proteolytic epitopes that are absent in the intact peptide (neo-epitopes), which can be generated by the action of NEP - BNP-neo5 (comprising Val-5 at the N-terminus), BNP-neo17 (comprising Arg-17 at the C-terminus) and BNP-neo18 (comprising lle-18 at the N- terminus).
  • NEP - BNP-neo5 comprising Val-5 at the N-terminus
  • BNP-neo17 comprising Arg-17 at the C-terminus
  • BNP-neo18 comprising lle-18 at the N- terminus.
  • Figure 1 The schematic representation of neo-epitope ANP and BNP forms generated by the action of NEP are shown in Figure 1.
  • Example 2 Production of polyclonal antibodies specific to neo-epitope forms of ANP and BNP
  • ANP-neoA8 BNP-neo5, BNP-neo17 and BNP- neo18 forms by means of immunoassays
  • PAbs rabbit polyclonal antibodies
  • PAbs specific to AN P-neo8, BNP-neo5, BNP-neo17 and BNP-neo18 were purified from rabbit serum by affinity chromatography on a matrix with immobilized neo- epitope-containing peptides. This step was preceded by negative affinity
  • Example 3 Detection of neo-epitope forms produced from BNP and ANP by NEP- mediated cleavage in vitro.
  • the produced polyclonal antibodies against three BNP neo-epitopes were used to develop specific sandwich-type immunoassays to detect neo-epitope forms of BNP.
  • the developed assays were shown to have a good performance.
  • BNP cleavage reaction For in vitro BNP cleavage reaction we used 1000 ng/mL human BNP (synthetic, from Bachem) in 50 mmol/L Tris-HCI, pH 7.4, 150 mmol/L NaCI, 0.1% Triton X-100. The final concentration of NEP (from R&D, recombinant expressed in CHO cells) was 6.3 nmol/L. The experimental probes and control sample without NEP were incubated at 37°C for 2 hours and analyzed by using sandwich-type immunoassays based on polyclonal antibodies against BNP-neo5, BNP-neo17 and BNP-neo18 in pairs with 50E1 antibody.
  • BNP immunoassay based on anti-BNP mAb 50E1 (capture antibodies) and mAb 130 (from HyTest) specific to the region 15-22 (detection antibodies) was used to measure the total amount of BNP.
  • the kinetic of production of BNP-neo5, BNP-neo17 and BNP-neo18 forms from BNP by the action of NEP is shown in Figure 2.
  • ANP- neoA8 we also tested the generation of one of neo-epitope ANP forms, ANP- neoA8, by the action of NEP in vitro.
  • ANP cleavage reaction we used 40000 ng/mL ANP (synthetic, from Bachem) in 50 mmol/L Tris-HCI, pH 7.4, 150 mmol/L NaCI, 0.1 % Triton X-100. The final concentration of NEP (from R&D, recombinant expressed in CHO cells) was 1 nmol/L.
  • a PAb against ANP-neoA8 was used as a coat antibody in pair with ANP-specific PAb used as detection antibodies in the assay for ANP-neo8 form.
  • the total amount of ANP was measured by the immunoassay based on anti-ANP mAb 23/1 (from Bio-Rad, specific to an epitope within the ring structure of ANP) used as capture antibodies in pair with ANP-specific PAb used as detection antibodies.
  • the kinetic of production of ANP-neoA8 form from ANP by the action of NEP is shown in Figure 3.
  • Example 4 In vivo studies of neo-epitope forms generation
  • ANP and BNP cleavage by NEP in circulation we injected a mix of ANP and BNP into rats with or without NEP inhibition by sacubitril and measured the neo-epitope forms of ANP and BNP as well as total ANP and BNP in plasma samples at several time points.
  • ANP and BNP kinetics with sacubitril treatment the same rats were used 48 h after the control experiment.
  • sacubitril is converted into an active sacubitrilat by endogenous esterase.
  • a sacubitril suspension in 2 ml of 0.9% NaCI at a final dosage of 100 mg/kg was administered orally (at a concentration expected to provide effective NEP inhibition in rats the mixture of ANP and BNP was injected after 1 h, similarly to the control.
  • Blood sampling was performed identically with and without prior sacubitril treatment. Blood samples were collected from the femoral artery immediately before NP administration (0 min) and at time points of 1 , 2, 4, 8 and 20 min post injection using tubes containing 2.75 pi of 0.5 M EDTA, 2.75 mI of 100x protease inhibitor mixture and 2.75 mI of activated sacubitrilat (the final concentrations of inhibitors were 20 mM aprotinin, 5 mmol/L (4-(2-aminoethyl)benzenesulfonyl fluoride - AEBSF, 10 mmol/L benzamidine and 20 pmol/L sacubitrilat) to prevent possible NP degradation after sample collection.
  • BNP-neo17 we analyzed the presence of one of BNP neo-epitope forms, BNP-neo17, and its portion to total BNP pool in human circulation. To investigate this, we measured total BNP and BNP-neo17 in plasma samples obtained from HF patients. EDTA- plasma samples were obtained from 32 patients (aged between 60 and 84 years) who were hospitalized for acutely decompensated HF (NYHA class 11— IV). All patients were treated according to standard procedures based on current guidelines for HF measurement. None of them received ARNi or other NEP inhibition-based therapy.
  • Venous blood was collected into Vacuette®K3-EDTA blood collection tubes and centrifuged immediately at 2000xg and RT for 15 min. The supernatant was then transferred into tubes containing lyophilized protease inhibitor mixture; final
  • concentrations were: 20 pmol/L aprotinin, 5 mmol/L AEBSF, 10 mmol/L benzamidine and 20 pmol/L sacubitrilat to prevent NP degradation after blood sample collection. After thorough mixing, plasma samples were frozen and kept at -70°C until analysis.
  • the total BNP level (cleaved and noncleaved BNP) was measured by the automated single epitope sandwich BNP immunoassay (SES-BNPTM assay). The measurements were done by ET Healthcare Pylon BNP assay, performed at ET Healthcare, Palo Alto, CA.
  • cleavage reaction For the cleavage reaction we incubated 75 pl_ of sepharose coupled to plasma proteins with 1-10 pg of recombinant NEP in 10 mM Tris- HCI, pH 7.5, 150 mM NaCI, 10 mM ZnCL for 2-18 hours at 37 °C.
  • the trypsinized and not trypsinized samples were desalted with ZipTip C18 (Millipore) and then analyzed by LC-MS/MS with AmaZon Speed ETD (Bruker) LC-ESI-MS n analytic platform.
  • Table 1 The list of potential NEP substrates identified by LC-MS/MS-based methods.
  • Velazquez EJ Morrow DA, DeVore AD, Duffy Cl, Ambrosy AP, McCague K, et al.
  • Soluble neprilysin is predictive of cardiovascular death and heart failure hospitalization in heart failure patients. Journal of the American College of Cardiology 2015;65:657-65.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Biochemistry (AREA)
  • Urology & Nephrology (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Organic Chemistry (AREA)
  • Biophysics (AREA)
  • Biotechnology (AREA)
  • Cell Biology (AREA)
  • Genetics & Genomics (AREA)
  • Microbiology (AREA)
  • Endocrinology (AREA)
  • Food Science & Technology (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne des procédés et des biomarqueurs de prédiction ou de surveillance de la réactivité à un traitement avec des médicaments modulant l'activité de la néprilysine (par exemple, Entresto TM). Plus particulièrement, l'invention concerne un procédé de prédiction de la réactivité d'un sujet au traitement avec des inhibiteurs de néprilysine (EPN), comprenant : la mesure dans un échantillon prélevé sur le sujet avant le traitement de la quantité de produits générés par les EPN à partir de ses substrats endogènes; ou la mesure du rapport de ces produits sur les substrats intacts (ou à la quantité totale de substrats clivés et intacts); et à classifier le sujet en tant que sujet sensible ou non sensible sur la base de la quantité desdits produits générés par le clivage à médiation par EPN; ou sur la base du rapport de ces produits sur les substrats intacts (ou à la quantité totale de substrats clivés et intacts).
PCT/EP2019/087152 2018-12-31 2019-12-30 Procédés et biomarqueurs pour prédire l'efficacité d'un traitement avec des médicaments modulant l'activité de la néprilysine et pour l'évaluer WO2020141157A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201862786825P 2018-12-31 2018-12-31
US62/786,825 2018-12-31

Publications (1)

Publication Number Publication Date
WO2020141157A1 true WO2020141157A1 (fr) 2020-07-09

Family

ID=69104448

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2019/087152 WO2020141157A1 (fr) 2018-12-31 2019-12-30 Procédés et biomarqueurs pour prédire l'efficacité d'un traitement avec des médicaments modulant l'activité de la néprilysine et pour l'évaluer

Country Status (1)

Country Link
WO (1) WO2020141157A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040176914A1 (en) * 2001-04-13 2004-09-09 Biosite Incorporated Methods and compositions for measuring biologically active natriuretic peptides and for improving their therapeutic potential
WO2006088700A2 (fr) * 2005-02-17 2006-08-24 Abbott Laboratories Anticorps se liant au peptide bnp humain specifique du noyau
WO2008056034A1 (fr) * 2006-11-10 2008-05-15 Hytest Ltd. Standards stables pour des immunodosages de bnp

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040176914A1 (en) * 2001-04-13 2004-09-09 Biosite Incorporated Methods and compositions for measuring biologically active natriuretic peptides and for improving their therapeutic potential
WO2006088700A2 (fr) * 2005-02-17 2006-08-24 Abbott Laboratories Anticorps se liant au peptide bnp humain specifique du noyau
WO2008056034A1 (fr) * 2006-11-10 2008-05-15 Hytest Ltd. Standards stables pour des immunodosages de bnp

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
BAYES-GENIS ABARALLAT JGALAN ADE ANTONIO MDOMINGO MZAMORA E ET AL.: "Soluble neprilysin is predictive of cardiovascular death and heart failure hospitalization in heart failure patients", JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, vol. 65, 2015, pages 657 - 65, XP029138938, DOI: 10.1016/j.jacc.2014.11.048
BAYES-GENIS ANTONI ET AL: "Neprilysin and Natriuretic Peptide Regulation in Heart Failure", CURRENT HEART FAILURE REPORTS, CURRENT SCIENCE INC., PHILADELPHIA, PA, US, vol. 13, no. 4, 3 June 2016 (2016-06-03), pages 151 - 157, XP035998161, ISSN: 1546-9530, [retrieved on 20160603], DOI: 10.1007/S11897-016-0292-X *
BAYES-GENIS APRICKETT TCRICHARDS AMBARALLAT JLUPON J.: "Soluble neprilysin retains catalytic activity in heart failure", THE JOURNAL OF HEART AND LUNG TRANSPLANTATION : THE OFFICIAL PUBLICATION OF THE INTERNATIONAL SOCIETY FOR HEART TRANSPLANTATION, vol. 35, 2016, pages 684 - 5, XP029539404, DOI: 10.1016/j.healun.2015.12.015
EVGENIYA E FEYGINA ET AL: "CONCLUSIONS", CLINICAL CHEMISTRY, vol. 65, no. 10, 1 October 2019 (2019-10-01), pages 1239 - 1247, XP055677326, ISSN: 0009-9147, DOI: 10.1373/clinchem.2019.303438 *
FEYGINA E E ET AL: "Neutral Endopeptidase (Neprilysin) in Therapy and Diagnostics: Yin and Yang", BIOCHEMISTRY, MAIK NAUKA - INTERPERIODICA, RU, vol. 84, no. 11, 1 November 2019 (2019-11-01), pages 1346 - 1358, XP036940980, ISSN: 0006-2979, [retrieved on 20191114], DOI: 10.1134/S0006297919110105 *
KURUPPU SRAJAPAKSE NWMINOND DSMITH AL: "Production of soluble neprilysin by endothelial cells", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 446, 2014, pages 423 - 7, XP028843410, DOI: 10.1016/j.bbrc.2014.01.158
MCMURRAY JJPACKER MDESAI ASGONG JLEFKOWITZ MPRIZKALA AR ET AL.: "Angiotensin-neprilysin inhibition versus enalapril in heart failure", THE NEW ENGLAND JOURNAL OF MEDICINE, vol. 371, 2014, pages 993 - 1004, XP055175908, DOI: 10.1056/NEJMoa1409077
SPILLANTINI MGSICUTERI FSALMON SMALFROY B.: "Characterization of endopeptidase 3.4.24.11 (enkephalinase) activity in human plasma and cerebrospinal-fluid", BIOCHEM PHARMACOL, vol. 39, 1990, pages 1353 - 6, XP025811773, DOI: 10.1016/0006-2952(90)90012-A
TAKAHASHI GTABATA MTAGUCHI KCHIKUMA T: "Fluorimetric assay for measuring neprilysin activity using hplc", CHROMATOGRAPHIA, vol. 78, 2015, pages 593 - 7, XP035474323, DOI: 10.1007/s10337-015-2856-4
TAMM N N ET AL: "Recombinant Proform of Brain Natriuretic Peptide (proBNP), Expressed in Eukaryotic Cells as a Stable Standard fro mBNP Immunoassay", AACC MANUAL MEETING, SAN DIEGO, CA,, 17 July 2007 (2007-07-17), pages 1, XP003020785 *
VELAZQUEZ EJMORROW DADEVORE ADDUFFY CIAMBROSY APMCCAGUE K ET AL.: "Angiotensin-neprilysin inhibition in acute decompensated heart failure", THE NEW ENGLAND JOURNAL OF MEDICINE, vol. 380, 2019, pages 539 - 48
YANDLE TRICHARDS MSMITH MCHARLES CLIVESEY JESPINER E.: "Assay of endopeptidase-24.11 activity in plasma applied to in vivo studies of endopeptidase inhibitors", CLINICAL CHEMISTRY, vol. 38, 1992, pages 1785 - 91

Similar Documents

Publication Publication Date Title
US9977013B2 (en) Assays for B-type natriuretic peptide analogues resistant to prolyl-specific dipeptidyl degradation
Danser et al. Prorenin, renin, angiotensinogen, and angiotensin-converting enzyme in normal and failing human hearts: evidence for renin binding
Semenov et al. Different susceptibility of B-type natriuretic peptide (BNP) and BNP precursor (proBNP) to cleavage by neprilysin: the N-terminal part does matter
EP2356450B1 (fr) Pronostic et évaluation des risques chez les patients frappés par une crise cardiaque par détermination du niveau de peptides marqueurs
EP2084544B1 (fr) Standards stables pour des immunodosages de bnp
Siriwardena et al. B-type natriuretic peptide signal peptide circulates in human blood: evaluation as a potential biomarker of cardiac ischemia
US20090163415A1 (en) NT-proBNP, proBNP AND BNP IMMUNOASSAYS, ANTIBODIES AND STABLE STANDARD
Toscana Circulating forms of the b-type natriuretic peptide prohormone: pathophysiologic and clinical considerations
JP2009538288A (ja) ＮＴ−ｐｒｏＢＮＰおよびｐｒｏＢＮＰの免疫アッセイに用いるための抗体と標準物質
US20120129187A1 (en) Diagnostical use of peroxiredoxin 4
WO2010049178A1 (fr) Procédé in vitro pour le diagnostic, le pronostic, la surveillance et le suivi thérapeutique des troubles liés au syndrome métabolique, à une maladie cardiovasculaire et/ou à une résistance à l'insuline
US10613101B2 (en) Non-oxidized, biological active parathyroid hormone determines mortality in hemodialysis patients
WO2020141157A1 (fr) Procédés et biomarqueurs pour prédire l'efficacité d'un traitement avec des médicaments modulant l'activité de la néprilysine et pour l'évaluer
US20120021431A1 (en) Diagnostic methods using bnp
US20070212729A1 (en) Prognostic Methods for Congestive Heart Failure
JP2007502991A (ja) 生物活性ナトリウム利尿ペプチドを測定するための、およびその治療可能性を向上させるための方法および組成物
DK2006688T3 (en) Determination of the effective parathyroid hormone activity in a sample
Bhandari et al. The midregional portion of proadrenomedullin is an independent predictor of left ventricular mass index in hypertension
US20150299283A1 (en) Novel peptide and application thereof
US20230127487A1 (en) Assessing and treating acute decompensated heart failure
CN100543471C (zh) 组织缺氧的体液指标
JP2023515981A (ja) ペプチジルグリシンαアミド化モノオキシゲナーゼ（ＰＡＭ）を決定する方法および診断目的でのその使用
Heublein et al. Natriuretic Peptides and Heart Failure
Berezin Pattern of apoptotic endothelial cell-derived micro vesicles in patients with different phenotypes of chronic heart failure

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19831766

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19831766

Country of ref document: EP

Kind code of ref document: A1