WO2003107000A2 - Procede de criblage a haut debit (hts) et systeme d'essai permettant de determiner l'interaction entre la proteine c-reactive et des composants se liant a la proteine c-reactive - Google Patents

Procede de criblage a haut debit (hts) et systeme d'essai permettant de determiner l'interaction entre la proteine c-reactive et des composants se liant a la proteine c-reactive Download PDF

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Publication number
WO2003107000A2
WO2003107000A2 PCT/EP2003/006038 EP0306038W WO03107000A2 WO 2003107000 A2 WO2003107000 A2 WO 2003107000A2 EP 0306038 W EP0306038 W EP 0306038W WO 03107000 A2 WO03107000 A2 WO 03107000A2
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WO
WIPO (PCT)
Prior art keywords
group
component
components
donor
compound
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PCT/EP2003/006038
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German (de)
English (en)
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WO2003107000A3 (fr
Inventor
Aimo Kannt
Antje Pommereau
Original Assignee
Aventis Pharma Deutschland 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
Application filed by Aventis Pharma Deutschland Gmbh filed Critical Aventis Pharma Deutschland Gmbh
Priority to BR0311709-0A priority Critical patent/BR0311709A/pt
Priority to CA002489021A priority patent/CA2489021A1/fr
Priority to MXPA04012232A priority patent/MXPA04012232A/es
Priority to JP2004513768A priority patent/JP2005529348A/ja
Priority to AU2003250344A priority patent/AU2003250344A1/en
Priority to EP03759923A priority patent/EP1516187A2/fr
Publication of WO2003107000A2 publication Critical patent/WO2003107000A2/fr
Publication of WO2003107000A3 publication Critical patent/WO2003107000A3/fr
Priority to NO20050037A priority patent/NO20050037L/no

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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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/566—Immunoassay; Biospecific binding assay; Materials therefor using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/536—Immunoassay; Biospecific binding assay; Materials therefor with immune complex formed in liquid phase
    • G01N33/542—Immunoassay; Biospecific binding assay; Materials therefor with immune complex formed in liquid phase with steric inhibition or signal modification, e.g. fluorescent quenching
    • 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
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4737—C-reactive protein
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value

Definitions

  • the present invention relates to a HTS-capable method and test system for determining the interaction between C-reactive protein (CRP) or C1q and components binding to CRP or C1 q, for determining the concentration of a solution containing CRP or C1q and for determining of substances that influence the interaction of CRP or C1 q and components that bind to it.
  • CRP C-reactive protein
  • CRP C-reactive protein
  • PCh phosphocholine
  • the complement is part of the immune system and mainly involved in the antibody-mediated immune system.
  • the three physiological functions of the complement are the defense against bacterial infections, the connection of innate and acquired immunity and the elimination of immune complexes and apoptical cells.
  • the classic complement cascade leads to the lysis of bacterial cells and begins with the association of C1q with an antibody binding to the cell surface or CRP bound to PCh.
  • C-reactive protein is used as a marker and also as a predictor of coronary artery disease, the leading cause of death in industrialized countries (Rifai and Ridker (2001), Clinical Chemistry 47, 403-411). Based on new studies (Jialal et al (2001), Circulation 103, 1933-1935) it is believed that lowering the CRPr level or blocking the CRP-mediated effector functions, for example complement activation by binding to C1q, is useful for prevention and treatment which can be coronary artery disease.
  • the object is achieved by a method for determining a binding event of two components which bind directly or via one or more components to CRP or C1 q, comprising the following steps: (a) presentation of a CRP or C1q-containing solution, (b) Addition of at least one donor component or a group of
  • Component which comprises at least one compound or group of compounds which can receive the signal emitted by the compound or group of compounds according to (b) and emit it in the form of electromagnetic radiation (acceptor group), and wherein the acceptor component is capable of this to bind directly or via one or more components from the group of components mentioned to CRP or C1q,
  • the electromagnetic radiation emitted by the at least one compound or group of compounds according to (c) is preferably fluorescence radiation.
  • the light source according to (d) can be, for example, a laser or a lamp, for example a helium or halogen lamp.
  • the detection of the electromagnetic radiation according to (e) can take place, for example, with the aid of a photomultiplier.
  • the components to be used according to the invention are or preferably comprise polypeptides.
  • at least one of the components is an antibody.
  • the antibody can be a monoclonal or polyclonal antibody.
  • a group of components are preferably able to bind spatially in succession to CRP or C1 q or to one another.
  • the binding takes place in the form of a binding cascade, such as is achieved, for example, by the sequential binding of antibodies (primary antibodies, secondary antibodies, etc.).
  • the components which bind directly to CRP or C1 q according to (b) and (c) are preferably components which each bind to a specific binding region or to a specific epitope of CRP or C1 q, the component bound to CRP or C1q according to (b) binds to a different binding site than the component binding to CRP or C1q according to (c).
  • one of the components binding directly to CRP or C1q is a naturally occurring binding partner of CRP or C1q.
  • this is particularly preferably C1 q and vice versa.
  • the donor or acceptor component is bound directly to CRP or C1 q, then in this case it is accordingly either the donor or the acceptor component that is C1 q or CRP, comprising a donor or
  • a group of components that can form a binding cascade, it is C1q or CRP correspondingly around the first component binding to CRP or C1q, via which either the donor or the acceptor component can be bound to CRP or C1q.
  • the other components of the group of components are particularly preferably antibody molecules.
  • either the donor or acceptor component itself preferably comprises C1 q or the donor or acceptor component is bound to CRP via C1 q.
  • the donor or acceptor component can then comprise an anti-C1 q antibody or a secondary antibody attached to the anti-C1 q
  • the respective other component then comprises an anti-CRP antibody or an antibody which can bind to the anti-CRP antibody or a tertiary antibody directed against the latter.
  • the at least one compound or group of compounds according to (b) (donor group) and / or according to (c) (acceptor group) are localized on particles, the average diameter of the particles preferably being between 150 and 250 nm, particularly preferably at is about 200 nm. The particles are then removed from the donor or
  • the particles can be made of a polymeric material.
  • the method according to the invention is an HTS (high throughput screening) -capable method which can be carried out homogeneously in the form of a one-step method.
  • the method according to the invention is carried out according to the “mix and measure” principle, which leads to considerable time savings and greater accuracy of the measured values.
  • the method according to the invention allows the measurement of the binding of CRP to C1q, and thus the identification of substances that influence this binding, and the measurement of the concentration of CRP or C1q in complex media in less than 10 percent of the time using the previously described , inhomogeneous methods had to be used.
  • a special characteristic of the new process is that the binding between the two proteins can be followed in solution, since none of the reactants has to be immobilized on a solid phase.
  • the measurement can also be carried out directly with the proteins obtained from biological sources, without having to modify CRP or C1q, for example by binding a fluorophore.
  • a particular advantage of the method is therefore that the protein can be subjected to the test in its native state and the risk of denaturation, which would exist if the protein was immobilized and / or modified, is eliminated.
  • sample volume of the method according to the invention is considerably reduced compared to conventional methods. In this way, volumes of less than 10 ⁇ l can be used, which minimizes the material expenditure. Highly dilute solutions can also be used
  • Concentrations of CRP or C1q of less than 1 nM, even less than 100 pM can be used. It is also a very sensitive process. Furthermore, because of the foregoing, it is the first method that enables high-throughput screening for substances that influence complement activation by binding CRP to C1q.
  • the signal transmission from the at least one compound or group of compounds according to (a) (donor group) to the at least one compound or group of compounds according to (b) (acceptor group) takes place by singlet oxygen.
  • the donor group preferably comprises a compound which can convert triplet oxygen into singlet oxygen after excitation by a laser
  • the acceptor group comprises at least a first compound which can be excited by singlet oxygen and a second compound which is that of the can absorb energy absorbed by singlet oxygen excitable group without emissions and emit it in the form of fluorescent radiation.
  • the singlet oxygen formed can diffuse from the donor group to the acceptor group and react with the chemiluminescent substances located there.
  • the energy released in the process is transferred to the fluorophores, which ultimately emit the energy in the form of fluorescent radiation, which can be detected with a photomultiplier.
  • the prerequisite for a detectable signal is the spatial proximity of donor and acceptor beads, since the singlet oxygen is unstable and decays in aqueous solution.
  • the binding components to be used in this process are therefore chosen such that when the binding event occurs, the distance between the donor and acceptor groups is preferably less than 200 nm, since at a greater distance effective energy transfer by means of singlet oxygen, due to the disintegration time of the singlet Oxygen, is not possible.
  • the donor group and acceptor group are particularly preferably located on particles, the particles preferably having an average diameter of between 150 and 250 nm, particularly preferably of about 200 nm.
  • the particles are preferably used in such a way that there is a final concentration of particles bearing donor groups of 1-40 ⁇ g / ml and a final concentration of particles bearing acceptor groups of 1-80 ⁇ g / ml.
  • the binding capacity of the particles can be, for example, about 0.1 nM to 1 nM per ⁇ g / ml particle.
  • Alpha screen beads from Perkin-Elmer Life Sciences are particularly preferably used as particles for the method.
  • the donor group is excited by irradiation with a laser at a wavelength of 680 nm and the radiation emitted by the acceptor group can be detected at a wavelength between 520 and 600 nm.
  • the process can then be carried out accordingly in such a way that donor and acceptor beads which carry donor and acceptor groups are introduced.
  • Donor and acceptor beads are now bound to components that are able to bind to CRP or C1q either themselves or via additional components.
  • these components can either be C1q or CRP or an anti-CRP or anti-C1 q antibody or an anti-CRP or anti-C1 q antibody Act secondary antibodies.
  • the signal transmission from the at least one compound or group of compounds according to (b) (donor group) to the at least one compound or group of compounds according to (b) (acceptor group) takes place by emission-free energy transfer, particularly preferably by fluorescence resonance energy transfer.
  • the method can be carried out, for example, such that the at least one compound or group of compounds according to (a) (donor group) is one
  • Europium salt-containing compound and the at least one compound or group of compounds according to (b) (acceptor group) comprises allophycocyanin (Grepin et al. (2000), Drug Discovery Today 5, 212).
  • the donor and acceptor groups can be dyes that are suitable for emission-free energy transfer.
  • all compounds known to the person skilled in the art can be used which are suitable for emission-free energy transfer, in particular for fluorescence resonance energy transfer (see, for example, Pope et al. (1999), Drug Discovery Today 4, 350).
  • the binding components to be used are preferably chosen so that the distance between the donor and Acceptor groups after binding is less than 10 nm, since effective emission-free energy transfer is not possible at a greater distance.
  • the method according to the invention is used to determine the concentration of a CRP or C1 q-containing solution of unknown CRP or C1 q content, this solution preferably being blood plasma or blood serum or by means of a suitable physiological Buffer or blood plasma or blood serum diluted with water.
  • This method can be used, for example, for diagnostic purposes, in particular to determine the inflammatory state of an organism and / or to determine the risk of a heart attack and / or a stroke.
  • the present invention therefore also relates to an HTS-capable diagnostic test system for determining a binding event between CRP or C1q and a component binding to CRP or C1q, comprising the following components:
  • the HTS-capable test system preferably comprises the following additional components:
  • test substance added at least one test substance to observe whether this has an influence on the binding event.
  • substances can be determined which have a modulating, inhibiting or activating effect on the interaction between CRP or C1 q and a binder, in particular on the interaction between CRP and C1q.
  • a library of test substances is preferably screened in the HTS method in order to determine a substance with the desired properties.
  • the present invention therefore also relates to an HTS-capable device
  • Test system for determining active substances that have a modulating effect on the interaction between CRP or C1 q and a component that binds to CRP or C1q, comprising the following components:
  • the donor component being a component which comprises at least one compound or group of compounds which, after excitation by a light source, can emit a signal ( Donor group), and wherein the donor component is able to bind directly or via one or more components from the group of components mentioned to CRP or C1q,
  • the Acceptor component is a component which comprises at least one compound or group of compounds which can receive the signal emitted by the compound or group of compounds according to (b) and emit it in the form of electromagnetic radiation, and which the acceptor component is capable of to bind directly or via one or more components from the group of components mentioned to CRP or C1q,
  • This HTS-capable test system preferably comprises the following additional components:
  • HTS-capable test systems are preferably used here to carry out the previously described methods according to the invention.
  • Special embodiments of the components and components of the test systems therefore correspond to the aforementioned special embodiments which are used in the methods according to the invention.
  • an anti-C1 q antibody was used as the donor component, the donor group being located on particles which are bound to the anti-C1 q antibody.
  • the donor component can bind to the CRP via C1 q.
  • the acceptor component is an anti-rabbit secondary antibody, the acceptor group being located on particles which are bound to the anti-rabbit secondary antibody.
  • the acceptor component can bind to the CRP via an anti-CRP antibody from rabbits.
  • Exemplary embodiment binding assay for determining the binding of CRP to C1 q
  • the Alphascreen Detection Kit from Packard Bioscience was used to carry out the experiment. This includes donor and acceptor beads, the donor beads comprising compounds which, after excitation at a defined one
  • Wavelength can convert triplet oxygen to singlet oxygen
  • the acceptor leads include compounds that can be excited by singlet oxygen, as well as compounds that take energy from the excited compounds in the form of an emission-free energy transfer and can then emit in the form of fluorescent radiation
  • the compounds mentioned are each embedded in a hydrogel matrix.
  • the beads used had already been pre-coated by the manufacturer, namely the donor beads with streptavidin and the acceptor beads with anti-rabbit antibody.
  • the following reaction buffer was used in the alpha screen system: 20 mM Tris-HCl, pH 7.2, 150 mM NaCl, 5 mM CaCl 2 , 1 mM phosphorylcholine, 0.1% BSA.
  • Tris-NaCl buffer 3.15 g of Tris-HCl and 8.77 g of NaCl were dissolved in H 2 0, a pH of 7.2 was set using 1 M NaOH and then made up to 1 l with H 2 0.
  • the buffer is kept at room temperature.
  • the reaction buffer was prepared by adding 36.7 mg CaCl 2 , 12.9 mg phosphorylcholine and 50 mg BSA to 50 ml Tris-NaCl buffer.
  • the anti-C1q antibody In order to allow the anti-C1q antibody to bind to the streptavidin-coated donor bead, it first had to be biotinylated. For this purpose, 100 ⁇ l of anti-C1 q polyclonal serum were dialyzed twice against 200 ml of PBS for one hour at room temperature. After adding 20 ⁇ l of 1.5 mM sulfo-NHS solution (in Milli-Q water), the solution was left to stand at room temperature for 30 minutes and then dialyzed again against PBS twice in order to remove excess biotinylation reagent.
  • the negative controls do not give a positive result, while a strong signal can be seen when a solution containing C1 q and CRP is combined.

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Abstract

L'invention concerne un procédé de criblage à haut débit (HTS) ainsi qu'un système d'essai permettant de déterminer l'interaction entre la protéine C-réactive (CRP) ou la C1q et des composants se liant à la CRP ou à la C1q, de déterminer la concentration d'une solution en CRP ou en C1q, ainsi que de déterminer des substances qui influent sur l'interaction entre la CRP ou la C1q et des composants se liant à la CRP ou à la C1q, en particulier sur l'interaction entre la CRP et la C1q.
PCT/EP2003/006038 2002-06-12 2003-06-10 Procede de criblage a haut debit (hts) et systeme d'essai permettant de determiner l'interaction entre la proteine c-reactive et des composants se liant a la proteine c-reactive WO2003107000A2 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
BR0311709-0A BR0311709A (pt) 2002-06-12 2003-06-10 Processo capaz de hts e sistema de teste para a determinação da interação entre proteìna reativa com relação ao c e componentes que se ligam à proteìna reativa com relação ao c
CA002489021A CA2489021A1 (fr) 2002-06-12 2003-06-10 Procede de criblage a haut debit (hts) et systeme d'essai permettant de determiner l'interaction entre la proteine c-reactive et des composants se liant a la proteine c-reactive
MXPA04012232A MXPA04012232A (es) 2002-06-12 2003-06-10 Metodo con capacidad hts y sistema de ensayo para la determinacion de la interaccion entre la proteina c-reactiva y los componentes unidos a la proteina c-reactiva.
JP2004513768A JP2005529348A (ja) 2002-06-12 2003-06-10 Ｃ−反応性タンパク質と、ｃ−反応性タンパク質に結合する成分との相互作用を測定するための、ｈｔｓ可能な方法および試験システム
AU2003250344A AU2003250344A1 (en) 2002-06-12 2003-06-10 Determining the interaction between a C-reactive protein and constituents that bind to a C-reactive protein
EP03759923A EP1516187A2 (fr) 2002-06-12 2003-06-10 Procede de criblage a haut debit (hts) et systeme d'essai permettant de determiner l'interaction entre la proteine c-reactive et des composants se liant a la proteine c-reactive
NO20050037A NO20050037L (no) 2002-06-12 2005-01-04 Fremgangsmate som er i stand til HTS og testsystem for a bestemme interaksjonen mellom et C-reaktivt protein og komponenter som binder til et C-reaktivt protein

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10226011.7 2002-06-12
DE10226011A DE10226011A1 (de) 2002-06-12 2002-06-12 HTS-fähiges Verfahren und Testsystem zur Ermittlung der Wechselwirkung zwischen c-reaktivem Protein und an C-reaktives Protein bindenden Komponenten

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WO2003107000A2 true WO2003107000A2 (fr) 2003-12-24
WO2003107000A3 WO2003107000A3 (fr) 2004-05-27

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PCT/EP2003/006038 WO2003107000A2 (fr) 2002-06-12 2003-06-10 Procede de criblage a haut debit (hts) et systeme d'essai permettant de determiner l'interaction entre la proteine c-reactive et des composants se liant a la proteine c-reactive

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EP (1) EP1516187A2 (fr)
JP (1) JP2005529348A (fr)
CN (1) CN1745300A (fr)
AR (1) AR040259A1 (fr)
AU (1) AU2003250344A1 (fr)
BR (1) BR0311709A (fr)
CA (1) CA2489021A1 (fr)
DE (1) DE10226011A1 (fr)
MX (1) MXPA04012232A (fr)
NO (1) NO20050037L (fr)
RU (1) RU2005100042A (fr)
TW (1) TW200411179A (fr)
WO (1) WO2003107000A2 (fr)
ZA (1) ZA200409199B (fr)

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AU2003250344A1 (en) 2003-12-31
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CN1745300A (zh) 2006-03-08
TW200411179A (en) 2004-07-01
CA2489021A1 (fr) 2003-12-24
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MXPA04012232A (es) 2005-02-25
WO2003107000A3 (fr) 2004-05-27
AR040259A1 (es) 2005-03-23

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