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WO2015185391A1 - Procédé de mesure de forces de liaison entre des cellules et des ligands dans des solutions troubles - Google Patents

Procédé de mesure de forces de liaison entre des cellules et des ligands dans des solutions troubles Download PDF

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Publication number
WO2015185391A1
WO2015185391A1 PCT/EP2015/061588 EP2015061588W WO2015185391A1 WO 2015185391 A1 WO2015185391 A1 WO 2015185391A1 EP 2015061588 W EP2015061588 W EP 2015061588W WO 2015185391 A1 WO2015185391 A1 WO 2015185391A1
Authority
WO
WIPO (PCT)
Prior art keywords
cell
ligand
channel
sensor elements
ligands
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
PCT/EP2015/061588
Other languages
German (de)
English (en)
Inventor
Oliver Hayden
Lukas RICHTER
Michael Johannes HELOU
Mathias Reisbeck
Benjamin Krafft
Andreas Wiemhöfer
Marina KROELL
Tibor WLADIMIR
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.)
Siemens AG
Siemens Corp
Original Assignee
Siemens AG
Siemens Corp
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 Siemens AG, Siemens Corp filed Critical Siemens AG
Publication of WO2015185391A1 publication Critical patent/WO2015185391A1/fr
Anticipated expiration legal-status Critical
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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • 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
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54313—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form
    • G01N33/54326—Magnetic particles
    • G01N33/54333—Modification of conditions of immunological binding reaction, e.g. use of more than one type of particle, use of chemical agents to improve binding, choice of incubation time or application of magnetic field during binding reaction

Definitions

  • the invention relates to a method for measuring binding strengths between cells and ligands in turbid solutions.
  • the binding strength between cells with receptors and ligands, or cells with antigens and antibodies can be measured by a variety of different methods.
  • Commercial methods used in the pharmaceutical industry include, for example, the
  • the surface ⁇ plasmon resonance is an optical method in which refractive indices are measured to a depth of 100 nm on a Me ⁇ tallfilm in the presence of an analyte.
  • the ELISA is based on an enzymatic color reaction in which an antibody is labeled with an enzyme which triggers the color reaction when bound to an antigen.
  • Flow cytometry allows the analysis of cells or artificial beads, also referred to as "beads", which, whenever possible, individually flow past an electrical voltage, a light beam or a magnetic sensor, as is well known in the literature. that binding strengths can be measured by means of flow cytometry by means of fluorescence-labeled ligands.
  • the object is achieved by the method mentioned in claim 1.
  • the subclaims relate to advantageous Ausgestal ⁇ tions of the invention.
  • the inventive method for measuring a bonding strength of at least one cell with a ligand comprising Be ⁇ riding provide a magnetic flow cytometer with we ⁇ iquess wherein the sensor elements comprise a first pair of magnetoresistive sensor elements, a first distance of at least 1 times the cell diameter.
  • a receptor of the cell is at least bonded to at least one ligand to form a first complex, wherein the cell and / or the ligand having superparamagnetic properties.
  • This first complex which thus also has paramagnetic properties, is then passed over the sensor elements in a channel.
  • the bond strength is calculated.
  • analytes with superparamagnetic properties are transported in a flow chamber near the surface, in particular by rolling, via a magnetoresistive sensor.
  • the cell detection in complex media, such as whole blood can be made.
  • the stray field of the cell When repainting the Magnetoresistive sensor through a cell, the stray field of the cell generates a change in resistance, which can be detected as elekt ⁇ cal signal.
  • two resistors, the measuring resistors, of a Wheatstone bridge arrangement with a total of four magnetoresistive resistors are preferably used for a propagation time measurement of the analytes, ie the cells or beads (beads.)
  • the results of the running time measurement it is advantageously possible to determine the bond strength the more ligands are closed between the cell and the ligand. bind to the cell, the greater is the magnetic moment of the cell and the less rapidly flowing ⁇ SEN the labeled cells, that is, the longer the running time between the two sensor elements.
  • the binding strength depends on the following two factors: firstly, the ratio of receptors on the cell to ligands and, secondly, the incubation time of the cell with the ligand
  • the receptor is advantageously an antigen which binds to an antibody of the ligand Receptors, in particular lipids, Zu cker, proteins, and DNA strands.
  • the binding of the ligand to the cell takes place in the channel.
  • a sample is then passed to the cell without a dilution or preparation step in the Ka ⁇ nal and marking takes place in the magnetic flow cytometer.
  • whole blood can then be analyzed without dilution with buffer or without sample preparation.
  • a superparamagnetic ligand is held by means of an external magnetic field at the channel inner wall.
  • the ligands can then be attached in a planar manner over the channel inner wall.
  • the marking of the cell is carried out by rolling on the channel inner wall in a uniform manner.
  • the ligand is arranged on the same channel inner wall as the sensor elements. Before ⁇ geous enough, the cell rolls then first on the WE iquess one, but preferably several ligands to the Ka ⁇ nalinnenwand, so that the first complex. Subsequently ⁇ hd this first complex continues to roll over the two sensor elements, so that a sensor signal is produced, from which the duration of the first complex is determined.
  • the cell and the ligand in an incubation chamber, which in
  • the incubation can be carried out in particular with stirring.
  • the incubation chamber typically has a volume of 10 to 1000 ⁇ .
  • the ratio of receptor number on the cell to ligand ranges from 1:10 to 1: 1000 for weak bonds and is only sterically limited by the size of the magnetic nanoparticles.
  • the ratio of receptor number on the cell to ligand for strong bonds, especially avidin and biotin, is in a range of 1: 1 to 1:10.
  • the amount of ligands that bind to the cell also depends in particular on the incubation time. After a theoretically infinite incubation period, the equilibrium of the ligands on the cell is established. In order to shorten the incubation time a measurement is typically reproduction ⁇ ible carried out as a kinetic measurement after a fixed incubation time.
  • the cell is a first biological cell h ⁇ le.
  • it is a tumor cell, a blood cell or a stem cell.
  • the typical ligands include, in particular, monoclonal antibodies, polyclonal antibodies, proteins of the complement system.
  • synthetic substances whose interaction one wishes to investigate, in particular with blood, can be used as ligands.
  • Biosimilars or “bio-similar” may crave as ligands fun ⁇ .
  • This "Bio-like" substances are typically pharmaceuticals comprising antibodies or Antikör ⁇ perfragmente.
  • the respective cell types are typically dissolved in their native environment, especially in full ⁇ blood, urine or cerebrospinal fluid.
  • the cell is an artificial pearl, or English, "bead".
  • Pa ⁇ parameters such as size, shape and magnetic properties can be produced defi ned ⁇ here. This makes it possible to investigate the influence of these parameters on the runtime.
  • these artificial pearls can be added as standard, in particular size standard, in particular to natural biological samples such as whole blood.
  • the channel inner wall comprises a layer having at least the first and / or a second biological cell. In particular, this makes it possible to investigate the rolling behavior of the first cell over natural surfaces, in particular vascular surfaces.
  • the second cell in the layer is in particular a tumor cell or a tumor cell
  • FIG. 2 schematically shows the sensor signal over time for magnetically marked cells and their transit time
  • FIG. 3 schematically shows a magnetic flow cytometer with an incubation chamber in which the ligands and cells are present.
  • FIG. 4 schematically shows a magnetic flow cytometer with a cell layer on a channel inner wall.
  • FIG. 5 schematically shows a typical measurement signal via
  • Figure 6 shows schematically the structure of a magnetic
  • the magnetic flow cytometer 1 comprises a channel 5 with a channel inner wall 6.
  • the channel inner wall 6 comprises a first sensor element 7 and a second sensor element 8 of a sensor pair. In this example, these are GMR sensors.
  • the channel inner wall 6 is formed by a substrate 10.
  • the substrate 10 also constitutes the substrate 10 for the sensor elements 7 and 8 ⁇ . Beneath the substrate 10 is a Per ⁇ manentmagnet 11.
  • a sample flows with a biological first cell 2 and a first artificial bead 3. These are magnetically marked in the channel 5, so that the sensor elements 7,8 perceive the over ⁇ rolling of the cells (2,3) can.
  • To mark the ligands 4 are stapled to the channel inner wall 6. This attachment or fixing takes place magnetically. This is possible because the ligands 4 comprise supermagnetic properties.
  • the ligands 4 are distributed over the area of the first channel inner wall 6. During the rolling of the cells 2,3 in Flow direction 9 roll it along the channel inner wall 6 along and take on ligands 4.
  • First receptors 12 are located on the surface of the first cell 2. These first receptors 12 bind specifically to the ligands 4.
  • the artificial bead 3 also comprises second receptors 13 which bind to the ligands 4.
  • the ligand 4 are constructed such that they 19 umfas ⁇ sen, which can bind to the respective receptors 12 and 13, an antibody. Furthermore, they comprise a superparamagnetic nanopearl 18, which can be detected by the sensor elements 7 and 8.
  • a sensor signal 27 is generated.
  • the sensor elements preferably have a distance of at least 1.5 times the cell diameter.
  • the sensor signal 27 is shown in FIG. 2.
  • a measurement signal 20 is plotted over time t.
  • the first artificial pearl 3 rolls over the first sensor element 7. If half the distance of the sensor element 7 in the flow direction 9 is reached, this is shown in the sensor signal 27 at the time t 2.
  • the first artificially ⁇ Liche bead 3 runs over the second sensor element, crosses the ⁇ 8. After ren half the distance along the sensor element 8 is reached at time t4.
  • the distance between the two maxima between the times t1 and t2 and the times t3 and t4 is the so-called time of flight or "time-of-flight.” Based on this time, it is possible to draw conclusions as to the size of the first artificial pearl 3.
  • the RESIZE ⁇ SSER is the magnetic moment of the cell, which rolls over the sensor elements 7.8, at a constant size of the cell, and the greater the Binding strength between ligand 4 and zeptor 12,13 after a defined incubation.
  • the RESIZE ⁇ SSER is the magnetic moment of the cell, which rolls over the sensor elements 7.8, at a constant size of the cell, and the greater the Binding strength between ligand 4 and zeptor 12,13 after a defined incubation.
  • large cells move faster through the channel as small cells, ie size ⁇ re cells have in this case the shorter term.
  • the interaction, in particular the binding strength, between receptor 12, 13 and ligand 4 can be investigated as a function of different parameters.
  • These parameters include the ligand concentration on the inner channel wall 6 which receptor concentration on an artificial bead 3 or on a biological cell 2, the laminar flow conditions, particularly shear stress, shear rate and Flussra ⁇ te, the strength of the external magnetic field, the diameter of the cell, the temperature of the sample and the viscosity of the sample, in particular a biological sample.
  • FIG. 1 it can be seen that, seen in terms of time, the first cell 2 rolls over the sensor elements 7, 8 after the first artificial bead 3. It is possible to compare the sensor signal 27 of this first cell 2 with that of the artificial pearl 3.
  • the first cell 2 can comprise a different receptor than the artificial pearl 3. Thus can be investigated with the ligand in a measurement of the same sample Bindungsstär ⁇ ken different receptors.
  • the amplitude of the sensor signal 27 and the integral of the sensor signal 27 between times t1 and t2 and t3 and t4 can be used to determine the bond strength.
  • Figure 3 shows schematically a magnetic
  • This magnetic flow cytometer 1 comprises a channel 5, a channel inner wall 6, a substrate 10, and a permanent magnet 11.
  • the sample comprises a first cell 2 and a first artificial bead 3.
  • the magnetic Marking of the first cell 2 and the first artificial bead 3 takes place in this example in an incubation chamber 14, which in front of the channel 5 of the magnetic
  • Flow cytometer 1 is arranged.
  • Incubations ⁇ chamber 14 are the first cells to be marked 2 or artificial beads 3 and the ligands 4.
  • the incubation with stirring is typically for an incubation period of 30 s to 1 h.
  • the incubation chamber is typically operated at temperatures in the range between 4 ° C and 95 ° C.
  • Particularly advantageous for biological systems is a Tempe ⁇ ratur Scheme of 20 ° C to 40 ° C.
  • the concentration ratio of receptor (several per cell) to ligand varies in the
  • Incubation chamber from 1:10 to 1: 1000 for weak bonds and from 1: 1 to 1:10 for strong bonds.
  • a ligand comprises multiple antibodies
  • multiple linkages to a receptor are possible. As a result, the bond appears disproportionately strengthened.
  • the bond strength in this example can again be examined in dependence on numerous parameters. These include the ligand-to-cell ratio in the incubation chamber, the concentration of receptor on the cell surface, the lamina ⁇ ren flow conditions, the external magnetic field, the Zellengrö ⁇ SSE, the temperature and the viscosity of the sample.
  • FIG. 4 shows, by way of example, a magnetic flow cytometer 1, on the first channel inner wall 6 of which there is a first flow channel
  • the first cell layer 16 is located.
  • the first cell layer 16 comprises ty ⁇ pisch legally tumor cells or endothelial cells.
  • the first artificial pearl 15 is itself superparamagnetic in this case.
  • To ligands are on the surface 4.
  • the magnetic artificial pearl 15 rolls in the direction of flow 9 through the sensor elements 7 and 8. From the thus resulting run ⁇ time 21, the bonding strength of the ligand 4 are determined at the anhef ⁇ Tenden first cell layer sixteenth
  • These cell ⁇ layer 16 serves as a model for vascular surfaces In both example play biological vessels.
  • the first cell 2 has been marked to ⁇ present in an incubation chamber 14 with superparamagnetic ligand 17th Also from this period 21, the binding strength of the first cell 2 to the first cell layer 16 determine.
  • the binding strength can be measured as a function of the following parameters: the strength of the external magnetic field, the flow rate, the receptor density on the surface of the first cell layer and the
  • FIG. 5 shows a typical result function 28 of several binding tests.
  • the measurement signal 20 is plotted against the ligand concentration 22.
  • Ligand concentration is in particular the heatnbele ⁇ tion of the cell or bead with ligands.
  • An artificial bead 3 typically has a diameter in the range of 200nm.
  • the measurement signal 20 is typically the running time 21 the measurement signal 20 may alternatively or in a parallel initial evaluation, the amplitude or the integral of the Sensorsig ⁇ Nals 27 represent.
  • the incubation time can also be plotted on the X-axis instead of the ligand concentration 22.
  • the result function 28 is similar to a titration curve. The longer the cell 2, 3 was incubated with the ligand 4, or the higher the ligand concentration 22 per cell, the higher is the measurement signal 20, in particular the transit time 21.
  • FIG. 6 schematically shows the plan view of a magnetic flow cytometer 1.
  • channel 5 the channel inner wall 6 can be seen from above.
  • guide elements 24 which focus the cells 2,3 in the middle of the channel 5.
  • the sensor elements 7 and 8 are arranged after this enrichment path.
  • the cells 2, 3 collected in a waste 23.
  • the magnetic flow cytometer 1 includes a Perma ⁇ nentmagnet 11 and the substrate 10.
  • an incubation chamber 14 which is filled, from two syringes 25, 26 out.
  • the biological sample is especially whole blood.
  • this syringe may also contain a standard mixture, for example of artificial pearls with receptors to be examined.
  • curve 28 the manner of a titration curve ⁇ , as shown in Figure 5 to obtain, that behaves ⁇ nis of biological sample is added to magnetic markers vari- ated.
  • the incubation time is varied. The longer the incubation time and the higher the ratio of ligand to cell, the sooner the measured value 20 is in the range of the saturation range of large incubation times in FIG. 5.
  • the incubation chamber 14 can in particular be equipped with a magnet, around the magnetic markings in this chamber to hold back and only to release the cells in the channel.
  • the magnetic holding force must be coordinated by the stirrer with respect to the centrifugal forces occurring due to the rotation.
  • the nanoparticles in this case require a much RESIZE ⁇ ßere centrifugal force, ie a faster rotation of the stirring bar, as the much larger cell with magnetic particles to exit the incubation 14th

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Abstract

L'invention concerne un procédé de mesure de la force de liaison d'au moins une cellule à un ligand. Tout d'abord, on prend un cytomètre en flux magnétique pourvu au moins d'une première paire d'éléments sensibles magnétorésistifs. Puis au moins un ligand se lie à la cellule pour former un complexe, la cellule et/ou le ligand présentant des propriétés superparamagnétiques. Ce premier complexe est guidé par l'intermédiaire des éléments sensibles. Le temps de vol du premier complexe est mesuré par les éléments sensibles et une force de liaison est calculée sur la base du temps de vol.
PCT/EP2015/061588 2014-06-04 2015-05-26 Procédé de mesure de forces de liaison entre des cellules et des ligands dans des solutions troubles Ceased WO2015185391A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102014210590.0A DE102014210590A1 (de) 2014-06-04 2014-06-04 Verfahren zum Messen von Bindungsstärken zwischen Zellen und Liganden in trüben Lösungen
DE102014210590.0 2014-06-04

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WO2015185391A1 true WO2015185391A1 (fr) 2015-12-10

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000052474A1 (fr) * 1999-03-01 2000-09-08 Idec Pharmaceuticals Corporation Dosages par electrochimiluminescence pour cellules eucaryotes
WO2011038982A1 (fr) * 2009-09-30 2011-04-07 Siemens Aktiengesellschaft Chambre d'écoulement équipée d'un dispositif de guidage de cellules
WO2013000853A1 (fr) * 2011-06-29 2013-01-03 Siemens Aktiengesellschaft Procédé et appareil pour cytométrie à flux magnétique

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102011077905A1 (de) * 2011-06-21 2012-12-27 Siemens Aktiengesellschaft Hintergrundfreie magnetische Durchflusszytometrie
DE102012210457B4 (de) * 2012-06-21 2015-08-27 Siemens Aktiengesellschaft Verfahren und Anordnung zur partiellen Markierung und anschließenden Quantifizierung von Zellen einer Zellsuspension

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000052474A1 (fr) * 1999-03-01 2000-09-08 Idec Pharmaceuticals Corporation Dosages par electrochimiluminescence pour cellules eucaryotes
WO2011038982A1 (fr) * 2009-09-30 2011-04-07 Siemens Aktiengesellschaft Chambre d'écoulement équipée d'un dispositif de guidage de cellules
WO2013000853A1 (fr) * 2011-06-29 2013-01-03 Siemens Aktiengesellschaft Procédé et appareil pour cytométrie à flux magnétique

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