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WO1991001368A1 - Liaison d'affinite d'haptene/antihaptene dans la separation des cellules - Google Patents

Liaison d'affinite d'haptene/antihaptene dans la separation des cellules Download PDF

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Publication number
WO1991001368A1
WO1991001368A1 PCT/EP1990/001171 EP9001171W WO9101368A1 WO 1991001368 A1 WO1991001368 A1 WO 1991001368A1 EP 9001171 W EP9001171 W EP 9001171W WO 9101368 A1 WO9101368 A1 WO 9101368A1
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WIPO (PCT)
Prior art keywords
hapten
target cell
cells
cell
insoluble support
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Application number
PCT/EP1990/001171
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English (en)
Inventor
Terje Michaelsen
Original Assignee
Dynal A.S.
Holmes, Michael, John
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 Dynal A.S., Holmes, Michael, John filed Critical Dynal A.S.
Publication of WO1991001368A1 publication Critical patent/WO1991001368A1/fr

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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
    • 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
    • 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
    • G01N33/56966—Animal cells

Definitions

  • This invention relates to a method of linking target substances in a manner which can be reversed with minimal destructive effect, and in particular to a method of linking a target cell to a support, in a manner which permits a desired cell-type to be positively selected.
  • hapten/anti-hapten binding pairs provide a particularly appropriate reversible linkage system in that reaction of substances linked by such a system with an excess of the hapten, a small molecule providing efficient and rapid reaction kinetics, or with an analogue of the hapten having a greater affinity for the anti-hapten, readily breaks the linkage under mild conditions avoiding destruction of proteins or other sensitive species present.
  • the bound substances is a molecule on a cell surface
  • the cell can be bound, for example to a reporter substance or a solid support and subsequently liberated with its reproductive potential undiminished.
  • hapten/anti-hapten linkage system enables cells in a positive selection procedure to be easily liberated from the particles or other solid support.
  • a method of positively isolating a target cell type from a mixed population of cells wherein, sequentially or simultaneously, a hapten is bound to either an insoluble support or said target cell and an anti-hapten is bound to said hapten and to the other of said support and said target cell, whereby said support and said target cell are reversibly linked, the support and bound target cell are isolated from the mixed population of cells and the target cell is released from said support by the addition of hapten or hapten analogue.
  • cell is intended to encompass both prokaryotic and eukaryotic cells and viruses.
  • the method according to the invention may be used to isolate sub-cellular components such as mitochondria and nuclei, and macromolecules, such as proteins and nucleic acids.
  • the anti-hapten may be a complete anti-hapten antibody or a hapten-binding fragment, e.g. an F(ab) 2 or Fv fragment, thereof.
  • the insoluble support or the target cell may be covalently bound to the hapten by a preliminary chemical reaction.
  • the hapten 4-hydroxy-3- nitro-phenylacetic acid (NP) can be activated, e.g. by forming an activated ester such as NP-caproyl-O- succimidyl ester (NP-CAP-0-Su) and reacted with an insoluble support or target substance cell carrying free NH 2 groups.
  • the anti-hapten may then, in one embodiment of the method, be reacted with the hapten carrying support to provide a reagent capable of binding to target cells via other binding interactions.
  • a reagent capable of binding to target cells via other binding interactions.
  • the anti-hapten may be bound to the target cell initially and then reacted with the hapten-carrying support.
  • the anti-hapten may be attached to the insoluble support, advantageously via the Fc region of the intact antibody, leaving the hapten- binding portions free.
  • the support may carry anti-Fc antibody, i.e. antibody produced in an animal of a species different from that producing the anti-hapten antibody.
  • the anti-hapten antibody is a mouse antibody or mouse-human chimeric antibody
  • the support may carry sheep-antimouse antibody to bind the anti-hapten antibody to the support while the hapten may be bound to the target cell directly or indirectly via free NH 2 or other appropriate functional groups.
  • insoluble support and target cell normally may be reacted simultaneously with the anti-hapten antibody instead of in separate stages.
  • the target cell, once bound to the support may be released by a mild change in conditions caused by the addition of excess hapten or by the addition of a hapten analogue.
  • the target cell/support complex is first washed to remove contaminants before it is released from the support by excess hapten or by addition of hapten analogue.
  • the anti-hapten antibody may be, for example, of polyclonal or monoclonal origin. Monoclonal antibodies are preferred because of their homogeneity.
  • the hapten may be linked directly, normally covalently, to the insoluble support or the target cell or it may be linked indirectly, for example by being covalently coupled to an antibody which binds to the insoluble support or the target cell.
  • the anti-hapten may be attached directly to the insoluble support or target cell or it too may be linked indirectly, for example by being coupled to an antibody which binds to the insoluble support or the cell.
  • Indirect linkage of the hapten or anti-hapten to the target cell by means of a cell-specific antibody or fragment thereof is a particularly preferred embodiment of the invention, since the use of specific anti-cell antibodies or antibody fragments enables a desired cell population to be positively selected from a mixed population of cells.
  • the hapten or anti-hapten is linked to the cell by the smallest effective anti-cell antibody fragment, e.g. an F(ab) 2 or Fv fragment.
  • hapten is intended to encompass any small molecule which by itself cannot stimulate antibody synthesis but will combine with an antibody formed by immunising an animal with an antigenic conjugate of the hapten and some other substance e.g. a protein such as keyhole limpet haemocyanin.
  • Hapten analogues are analogues of such molecules which will also combine with the anti-hapten antibody. Ideally, when the method is used to isolate living cells, the hapten (and, if used, its analogue) is non-toxic.
  • haptens examples include aminobenzene sulphonates and corresponding arsenates and carbocylates (Landsteiner, J.Exp.Med. 1936 63: 325) and molecules containing nitrophenyl and dinitrophenyl groups such as nitrophenylacetic acid and dinitrophenyl acetic acid, in particular 4-hydroxy-3-nitrophenyl acetic acid. (J. Klein, Immunology, "The science of self-non-self” John Wiley & Son 1982) . Derivatives of these compounds preferably have linker groups to enable attachment of hapten to the antigenic protein used to produce the anti-hapten e.g. capryl-OH groups.
  • Analogues of such haptens which have higher binding affinities to anti- hapten include 5-iodo derivatives of such phenolic haptens e.g. 4-hydroxy-5-iodo-3-nitro-phenylacetic acid or its cap-OH derivative. It is, of course, desirable that the hapten and hapten analogue should be water- soluble since, in general, the coupling and uncoupling reactions will be effected in aqueous media.
  • the affinity of the hapten or a hapten analogue for the binding partner can be tailored so that the excess hapten or hapten analogue added to the mixture containing immobilised target cell will have a greater affinity for the binding partner than the hapten or hapten analogue used to link the cell to the insoluble support. Even without this sort of tailoring of affinity, an excess of hapten or hapten analogue pushes the equilibrium of bound and free cell towards a higher proportion of free target cell.
  • haptens are small molecules allows an unbound excess of hapten or hapten analogue to readily compete with the hapten or analogue attached to the target cell or insoluble support and effect displacement.
  • the insoluble support may be a surface on a plate or tube such as a microtitre well although more preferably it is provided by a particulate material.
  • the particulate material may be, for example, beads of agarose gel or finely divided apatite. It is preferred that the particles are monodisperse and, advantageously superparamagnetic; Dynabeads M-450 being an example of such beads. The manufacture of monodisperse superparamagnetic beads is described in EP 83901406.5 (Sintef) .
  • a second aspect of the invention therefore provides an insoluble support, preferably particles and more particularly magnetic particles, coated with hapten.
  • the invention also provides, in a third aspect thereof, an insoluble support, preferably particles and more particularly magnetic particles, coated with anti- hapten.
  • a fourth aspect of the invention provides an insoluble support, preferably particles and more particularly magnetic particles, coated with anti-hapten bound to hapten which is bonded to anti-cell antibodies or fragments thereof.
  • the invention provides, in a fifth aspect thereof a kit comprising; (i) an insoluble support according to the second aspect of the invention, (ii) anti-hapten capable of being bound to a target cell, and (iii) an effective amount of hapten or hapten analogue.
  • a sixth aspect of the invention provides a kit comprising; (i) an insoluble support according to the third aspect of the invention, (ii) hapten capable of being bound to a target cell, and (iii) an effective amount of hapten or hapten analogue.
  • a seventh aspect of the invention provides a kit comprising; (i) an insoluble support according to the fourth aspect of the invention, and (ii) an effective amount of hapten or hapten analogue.
  • the method of the invention has many uses in the field of cell isolation.
  • the method may be used to isolate infectious agents such as bacteria or viruses in order to quantitate them or characterise their infectivity, toxi ⁇ ity or susceptibility to drug treatment.
  • the method can also be used for isolation of malignant cells or cell populations specific for different diseases and to characterise these cells further without interference from other contaminating cells.
  • the method may be used to isolate protective cell populations from an individual or form a group of individuals; the isolated population can then be expanded and/or potentiated before being returned to the patient under treatment.
  • Such protective cell populations can for example be monocytes/macrophages, lymphocytes or bone marrow stem cells.
  • lymphocytes one can use the method to isolate antigen- specific cells which may have antitumor activity and use said cells for cancer treatment. Infectious agents and malignant cells can also be isolated and studied for drug susceptibility in order to choose the most effective treatment strategy.
  • the invention will now be described by way of non- limiting examples in which the method is used to isolate cells, but as mentioned earlier, the method is equally applicable for the isolation of bacteria and viruses or other substances. Below is described a rapid and generally applicable method for the positive isolation of cells by means of monodisperse superparamagnetic particles.
  • the method of isolation has two main steps, one in which particles and the desired cell are linked or complexed to each other by hapten/antihapten antibodies optionally covalently bonded to anti-cell antibodies or fragments thereof such as F(ab) 2 or Fv fragments, and another where the isolated cell/particle rosettes are gently disrupted by incubation for a short time with a competing hapten or hapten analogue solution.
  • Noncomplexed cells are separated from the corresponding complexed ones by use of a magnet when the particles are magnetized or by other physio-chemical means when they are not.
  • the isolated completed cells are stripped from the particles by incubation with excess of hapten which will break the hapten/antibody bonds present in the cell/particle complexes.
  • the particles are then separated from the free cells by the same method used to isolate the complexes of cell particles i.e. magnet or other physio-chemical means.
  • the affinity between anti-hapten antibody and hapten can be tailored by suitable selection systems or by empirical trials. Such antibodies can also cross react with chemically related hapten analogues which have either lower or higher affinity towards the antibody compared to the hapten used for immunization (in which case the antibodies are "heteroclitic") .
  • the hapten-binding antibodies should preferably be of hybridoma origin, but polyclonal antibodies may also be used. For optimal separation, the hapten used in linking the cells and particles should have lower affinity for the hapten-antibody than the hapten used to competitively liberate the cells from the cell/particle complex.
  • This example describes the isolation of cells which each have Fc receptors on their membranes. Such Fc receptors can react with the Fc part of immunoglobulins of different species. This specificity is taken into account when the anti-hapten antibody is chosen. Hapten is coupled to particles and then reacted with anti- hapten antibody. The Fc-part of this antibody will then react with the Fc-receptor on the cells to be isolated and the cell/particle complex can be disrupted by incubation with a solution of free hapten.
  • hapten Activated haptens such as NP-Cap-O-Su (4-hydroxy-3-nitro-phenacetyl- caproyl-O-succimidyl ester, e.g. supplied by Cambridge Research Biochemicals Cat. No. PA18040) OR nip-Cap-OSu (4-hydroxy-5-iodo-3-nitro-phenacetyl-caproyl-0- succimidylester, Cat. No. PA18140 were used to attach the NP groups to the particles. Paramagnetic hapten coated particles were reacted with chimeric antibodies, i.e.
  • the anti-hapten antibodies can be chosen from other species to isolate Fc-receptor positive cells reacting with immunoglobulins from that species.
  • Immunoglobulin class and subclass specificity of the Fc-receptor positive cells can also be selected for by employing anti-hapten antibodies of one class or subclass only.
  • Dynabeads M-450 which can be coated by standard methods with, for example, BSA-NIP or BSA-NP were used. The rest of the procedure was as described in Example l.
  • Example 3
  • Cells were separated by coupling anti-hapten antibodies either to secondary antibodies such as sheep anti-mouse antibodies or directly to monoclonal antibodies.
  • the monoclonal antibody is specific for the type of cell to be isolated.
  • the particles, which in this Examples were paramagnetic Dynobeads were haptenised as in Example 1. The particles were loaded with hapten/anti-hapten/sheep anti-mouse and the cell- preparation reacted with monoclonal antibodies which specifically reacted with the cell type to be isolated. Complexes (rosettes) formed between the cells to be isolated and the particles. As the particles were paramagnetic, the complexes were isolated by the use of a magnet. The cells were then separated from the particles by incubation with an excess of free hapten.
  • Example 4 Compared to Example 3 the coupling was turned round in this Example by coating the particles with anti- hapten antibodies and haptenising either the secondary antibody (i.e. sheep anti-mouse) or the monoclonal anti- cell antibody.
  • the anti-hapten antibody and the anti-cell antibody are both mouse antibodies
  • the anti- hapten antibodies would preferentially be applied in the form of F(ab') 2 fragments prepared by standard pepsin digestion at pH 4.0-4.8
  • the sheep anti-mouse antibody should be specific for the Fc-part of mouse IgG prepared by immunizing with Fc-frag ents made by papain digestion or trypsin digestion of mouse IgG.
  • the sheep anti-mouse antibodies will only react with the cell/bacteria/virus specific antibodies and not with mouse F(ab') 2 anti-hapten fragments.
  • the particles were loaded with anti-hapten antibodies/haptenised secondary antibodies or with anti- hapten antibodies/haptenised secondary antibodies/monoclonal anti-cell antibodies.
  • the cells were first reacted with the specific antibody and then reacted with the sensitized particles.
  • the sensitized particles are reacted directly with the cells.
  • the cells can be stripped off the particles by incubation with excess of free hapten. The method which leaves the lowest number of linking materials on the finally isolated cells will be most favourable for further biological use.
  • the cells are relatively free of linking materials where the cell specific antibody is haptenised (for example in the NP/NIP-system with NP/NIP-Cap-O-Su supplied from C R B) .

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Abstract

L'invention concerne un procédé d'isolation positive d'un type de cellule cible à partir d'une population cellulaire mixte, dans lequel, séquentiellement ou simultanément, un haptène est lié à un support insoluble ou bien à ladite cellule cible et un antihaptène est lié audit haptène et audit autre support et à la cellule cible, ledit support et ladite cellule cible étant isolés de la population cellulaire mixte et la cellule cible étant relâchée par ledit support par l'addition d'haptène ou d'un analogue d'haptène. Ce procédé est particulièrement utile à l'isolation d'agents infectieux, de cellules malignes ou de populations cellulaires de protection.
PCT/EP1990/001171 1989-07-24 1990-07-17 Liaison d'affinite d'haptene/antihaptene dans la separation des cellules WO1991001368A1 (fr)

Applications Claiming Priority (2)

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GB8916859.5 1989-07-24
GB898916859A GB8916859D0 (en) 1989-07-24 1989-07-24 Hapten linking

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WO1991001368A1 true WO1991001368A1 (fr) 1991-02-07

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Cited By (11)

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WO1994007139A1 (fr) * 1992-09-14 1994-03-31 Fodstad Oystein Procede ameliore de detection de cellules cibles specifiques dans une population de cellules specialisees ou mixtes et solutions contenant une population de cellules mixtes
WO1995024648A1 (fr) * 1994-03-10 1995-09-14 Fodstad Oeystein Methode et dispositif de depistage de certaines cellules cibles dans des populations de cellules specialisees ou mixtes et des solutions contenant des populations de cellules mixtes
US5500348A (en) * 1992-11-04 1996-03-19 Shionogi & Co., Ltd. Basophil-binding monoclonal antibody, method for separation of basophils, method for chemical mediator release from basophils, and method for testing release of basophil-derived chemical mediators
EP0652703A4 (fr) * 1992-07-28 1996-05-29 Steven Kessler Methodes d'immunoselection positive de cellules souches.
WO1997044666A1 (fr) * 1996-05-17 1997-11-27 Cytovax Biotechnologies Inc. Procedes immunologiques de selection et d'extraction de composants
US5968753A (en) * 1994-06-14 1999-10-19 Nexell Therapeutics, Inc. Positive and positive/negative cell selection mediated by peptide release
US6348318B1 (en) 1997-04-04 2002-02-19 Biosite Diagnostics Methods for concentrating ligands using magnetic particles
WO2001090153A3 (fr) * 2000-05-23 2003-03-20 Nexell Therapeutics Inc Reactifs pour selection de cellules et modes d'utilisation
US6680301B2 (en) 1994-09-08 2004-01-20 Photocure As Transfer of molecules into the cytosol of cells
US7198787B2 (en) 1996-03-13 2007-04-03 Oystein Fodstad Method of killing target cells in harvested cell populations with one or more immuno-toxins
WO2008038022A1 (fr) * 2006-09-28 2008-04-03 Ucl Business Plc Test concernant une infection à h. pylori

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0652703A4 (fr) * 1992-07-28 1996-05-29 Steven Kessler Methodes d'immunoselection positive de cellules souches.
US6184043B1 (en) 1992-09-14 2001-02-06 FODSTAD øYSTEIN Method for detection of specific target cells in specialized or mixed cell population and solutions containing mixed cell populations
USRE43979E1 (en) 1992-09-14 2013-02-05 Abbott Laboratories Method for detection of specific target cells in specialized or mixed cell population and solutions containing mixed cell populations
JP3417563B2 (ja) 1992-09-14 2003-06-16 フーツタ，オイスタイン 特殊細胞集団もしくは混合細胞集団および混合細胞集団を含有する溶液中の特異標的細胞の検出方法
WO1994007139A1 (fr) * 1992-09-14 1994-03-31 Fodstad Oystein Procede ameliore de detection de cellules cibles specifiques dans une population de cellules specialisees ou mixtes et solutions contenant une population de cellules mixtes
AU686569B2 (en) * 1992-09-14 1998-02-12 Oystein Fodstad Improved method for detection of specific target cells in specialized or mixed cell population and solutions containing mixed cell populations
US6893881B1 (en) 1992-09-14 2005-05-17 Abbott Laboratories, Inc. Method for detection of specific target cells in specialized or mixed cell population and solutions containing mixed cell populations
US5500348A (en) * 1992-11-04 1996-03-19 Shionogi & Co., Ltd. Basophil-binding monoclonal antibody, method for separation of basophils, method for chemical mediator release from basophils, and method for testing release of basophil-derived chemical mediators
AU690244B2 (en) * 1994-03-10 1998-04-23 Oystein Fodstad Method and device for detection of specific target cells in specialized or mixed cell populations and solutions containing mixed cell populations
US6265229B1 (en) 1994-03-10 2001-07-24 Oystein Fodstad Method and device for detection of specific target cells in specialized or mixed cell populations and solutions containing mixed cell populations
WO1995024648A1 (fr) * 1994-03-10 1995-09-14 Fodstad Oeystein Methode et dispositif de depistage de certaines cellules cibles dans des populations de cellules specialisees ou mixtes et des solutions contenant des populations de cellules mixtes
US5968753A (en) * 1994-06-14 1999-10-19 Nexell Therapeutics, Inc. Positive and positive/negative cell selection mediated by peptide release
US6017719A (en) * 1994-06-14 2000-01-25 Nexell Therapeutics, Inc. Positive and positive/negative cell selection mediated by peptide release
US6680301B2 (en) 1994-09-08 2004-01-20 Photocure As Transfer of molecules into the cytosol of cells
US7198787B2 (en) 1996-03-13 2007-04-03 Oystein Fodstad Method of killing target cells in harvested cell populations with one or more immuno-toxins
WO1997044666A1 (fr) * 1996-05-17 1997-11-27 Cytovax Biotechnologies Inc. Procedes immunologiques de selection et d'extraction de composants
US6348318B1 (en) 1997-04-04 2002-02-19 Biosite Diagnostics Methods for concentrating ligands using magnetic particles
WO2001090153A3 (fr) * 2000-05-23 2003-03-20 Nexell Therapeutics Inc Reactifs pour selection de cellules et modes d'utilisation
WO2008038022A1 (fr) * 2006-09-28 2008-04-03 Ucl Business Plc Test concernant une infection à h. pylori

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