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WO1988008981A1 - Immobilization of receptor molecules to hydrophobic water soluble polymer in separation methods on assays - Google Patents

Immobilization of receptor molecules to hydrophobic water soluble polymer in separation methods on assays Download PDF

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Publication number
WO1988008981A1
WO1988008981A1 PCT/SE1988/000243 SE8800243W WO8808981A1 WO 1988008981 A1 WO1988008981 A1 WO 1988008981A1 SE 8800243 W SE8800243 W SE 8800243W WO 8808981 A1 WO8808981 A1 WO 8808981A1
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WO
WIPO (PCT)
Prior art keywords
polymer
hydrophobized
ligand
receptor
water soluble
Prior art date
Application number
PCT/SE1988/000243
Other languages
French (fr)
Inventor
Bo Håkan NYGREN
Johan Emanuel Stenberg
Original Assignee
Capsula Lab Aktiebolag
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 Capsula Lab Aktiebolag filed Critical Capsula Lab Aktiebolag
Publication of WO1988008981A1 publication Critical patent/WO1988008981A1/en

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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
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/544—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being organic
    • 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
    • G01N33/54353—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals with ligand attached to the carrier via a chemical coupling agent

Definitions

  • the present invention relates to ways of isolation or measurement of the amount of an organic substance, hereafter called the ligand, in liquids such as blood, urine, culture media etc by covalent coupling of a ligand specific counter reactant, hereafter called the receptor, to a surface adsorbed hydrophobized water soluble polymer. More particularly the invention relates to ways of isolation or measurement of the ligand by its reaction with the polymer receptor conjugate.
  • the surface immobilized complex can then be detected and quantified by prior art techniques with enzyme labeled or radioactive labeled antibodies which are specific for the ligand to be detected ("Enzyme-linked immunosorbent assay", Engvall and Perlmann J. Immunology vol.109 p.129, 1972. "Radioimmunoassay", Catt and Tregear Science vol.158 p.1570, 1967).
  • Isolation of the surface immobilized ligand can be performed by rinsing the surrounding liquid and subsequentely break the binding between ligand and receptor by treatment with acid or chaotropic ions (Jaton et al in "Immunological Methods” Academic Press 1979 vol.l p.55).
  • Prior art techniques to provide surface immobilized receptors comprises coupling of the receptor molecule to large molecular weight proteins. These carrier proteins are subsequently adsorbed to a solid phase.
  • Another prior art technique relates to the use of inherently surface active receptor molecules, as proteins adsorbed to a hydrophobic solid phase (Campbell et al, Proc. Nat. Acad. Sci. vol. 37 p. 575, 1951, Catt and Tregear, Science vol.158 p.1570, 1967). With this technique it is essential that the adsorbed receptor is firmly attached to the surface and that no exchange reactions occur during the exposure to the sample solution. Such exchange reactions may occur when the adsorbed receptor is of lower molecular weight than protein present in the sample solution.
  • This technique has several disadvantages. One is that most proteins are composed of similar amino-acid sequencies, which allows the ligand to react with the carrier rather than with the receptor. Another disadvantage is that the isolation and purification of carrier proteins is an expensive process.
  • the object of the present invention is to provide a process for isolation or measurement of the amount of a ligand by covalent coupling of a ligand-specific receptor to a surface-adsorbed hydrophobized water soluble polymer.
  • the present invention is based on the fact that certain water-soluble polymers can be chemically modified in a way that makes them adsorb strongly to hydrophobic surfaces.
  • the process according to the invention is characterized in that a ligand-specific counter reactant, the receptor, is covalently coupled to a hydrophobized water-soluble polymer and that this polymer is allowed to adsorb to a substrate with a hydrophobic surface which af er adsorption of the polymer is brought into contact with the sample solution.
  • These adsorbed hydrophobized polymers are not subject to exchange reactions with proteins upon exposure to blood (table 1).
  • Organic substances of medical interest such as enzymes, antibodies and hormones can easily be coupled to hydrophobized water-soluble polymers and reactants such as substrates for enzymes, antigens and antibodies will spontaneously bind to the polymer-receptor conjugate.
  • One advantage with this process is that the coupling of the receptor can be carried out in solution in a large scale and that the immobilization to the solid phase is performed by spontaneous adsorption of the hydrophobized polymer to a hydrophobic surface.
  • the adsorbing solid phase matrix which is to be exposed to the water soluble polymer exhibits at least one hydrophobic surface.
  • suitable hydrophobic materials are polystyrene, polyethene, polytetra- fluoroethylene (PTFE), polyurethane, polyvinylchloride (PVC) or other solid hydrophobic polymers.
  • PTFE polytetra- fluoroethylene
  • PVC polyvinylchloride
  • the adsorbing solid phase matrix can also be made of glass or aluminium provided that the surface has been modified to hydrophobi ⁇ ty by methylization.
  • the hydrophobized polymer in the present invention is a water soluble polymer that has been partially hydrophobic by binding hydrophobic radicals such as hydrocarbons to the polymer backbone.
  • suitable hydrophobized polymers are hydrophobized polysaccharides such as nonionic ethers of cellulose (USP 3,926,951), alkylated dextran or corresponding derivatives of starches.
  • the coupling of receptor molecules to the water soluble hydrophobized polymer can for example be made by bifunctional coupling reagents such as diisothiocyanate or diglycidylethers but can also be performed by the creation of reactive groups in the polymer backbone by for example oxidation of hydroxyl groups, present in polysaccharides, to aldehydes. Such oxidation can be performed by periodate, bromine or bromo- sucdnimide. The aldehydes created by the oxidation can then react with with aminogroups present on the receptor molecule in the presence of a catalysator e.g cyanoborohydride.
  • a catalysator e.g cyanoborohydride.
  • the binding of the ligand to the receptor occurs spontaneously upon exposure of the receptor coated surface to the sample solution.
  • the surface immobilized complex can be detected by use of specific antibodies directed against the ligand and labeled with for example enzymes, radioactive isotopes or fluorochromes.
  • the labeled antibody binds spontaneously to the ligand and the amount of bound antibody is proportional to the amount of surface bound ligand.
  • the process according to the present invention can be used in various fields.
  • surface bound antigens are used for measurement of antibodies present in samples of serum.
  • antigens of medical interest are small molecules that do not spontaneously adsorb to solid phases. These molecules can be coupled to partially hydrophobic water soluble polymers which are stably adsorbed to solid phases.
  • the invention may also be applied for coupling of receptor molecules to filters that can be used for separation of certain ligands from complex mixtures of organic substances such as cell cultures.
  • filters that can be used for separation of certain ligands from complex mixtures of organic substances such as cell cultures.
  • Ethyl-hydroxyethyl-cellulose is dissolved in water at a concentration of 10 g/1.
  • Sodiumperiodate is added at a concentration of 0.1 g/1.
  • the solution is heated to 60° C, at which temperature the cellulose ether precipitates.
  • the solution is centrifugalized and the precipitate is washed in hot water. This washing procedure is repeated three times.
  • the oxidized cellulose is dissolved in cold phosphate buffer ( 0.01 M, pH 7. ) and insulin is added at a concentration of 10 g/1 together with sodium-cyano-borohydride.
  • the amino groups present at the insulin molecules reacts with the aldehyde groups at the oxidized cellulose by reductive ⁇ unination. Excess of insulin is removed by repeated heat precipitation as described above.
  • the cellulose-insulin conjugate is diluted to a concentration of 0.1 g/1 in phosphate buffer and poured into basins of a polyester micro titer plate. The plate is rinsed in buffer and serum samples with or without antibodies against insulin are incubated in different basins for 1 hour. The plates are then repeatedly rinsed in r- .

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  • Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Chemical & Material Sciences (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Cell Biology (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Investigating Or Analyzing Non-Biological Materials By The Use Of Chemical Means (AREA)

Abstract

Process for isolation and/or measurement of the amount of an organic substance present in a sample solution. The process is characterized in that a ligand specific counter reactant is covalently coupled to a hydrophobized water soluble polymer and that this polymer is allowed to adsorb to a substrate with a hydrophobic surface which after adsorption of the polymer is brought into contact with the sample solution.

Description

IMMOBILIZATION OF RECEPTOR MOLECULES TO HYDROPHOBIC WATER SOLU¬ BLE POLYMER IN SEPARATION METHODS ON ASSAYS
Field of the invention
The present invention relates to ways of isolation or measurement of the amount of an organic substance, hereafter called the ligand, in liquids such as blood, urine, culture media etc by covalent coupling of a ligand specific counter reactant, hereafter called the receptor, to a surface adsorbed hydrophobized water soluble polymer. More particularly the invention relates to ways of isolation or measurement of the ligand by its reaction with the polymer receptor conjugate. The surface immobilized complex can then be detected and quantified by prior art techniques with enzyme labeled or radioactive labeled antibodies which are specific for the ligand to be detected ("Enzyme-linked immunosorbent assay", Engvall and Perlmann J. Immunology vol.109 p.129, 1972. "Radioimmunoassay", Catt and Tregear Science vol.158 p.1570, 1967).
Isolation of the surface immobilized ligand can be performed by rinsing the surrounding liquid and subsequentely break the binding between ligand and receptor by treatment with acid or chaotropic ions (Jaton et al in "Immunological Methods" Academic Press 1979 vol.l p.55).
Background of the invention
Prior art techniques to provide surface immobilized receptors comprises coupling of the receptor molecule to large molecular weight proteins. These carrier proteins are subsequently adsorbed to a solid phase.
Another prior art technique relates to the use of inherently surface active receptor molecules, as proteins adsorbed to a hydrophobic solid phase (Campbell et al, Proc. Nat. Acad. Sci. vol. 37 p. 575, 1951, Catt and Tregear, Science vol.158 p.1570, 1967). With this technique it is essential that the adsorbed receptor is firmly attached to the surface and that no exchange reactions occur during the exposure to the sample solution. Such exchange reactions may occur when the adsorbed receptor is of lower molecular weight than protein present in the sample solution. This technique has several disadvantages. One is that most proteins are composed of similar amino-acid sequencies, which allows the ligand to react with the carrier rather than with the receptor. Another disadvantage is that the isolation and purification of carrier proteins is an expensive process.
Other prior art techniques comprises direct covalent coupling of the receptor to a surface (Axen et al, Nature vol.214 p.1302, 1967), covalent coupling of an intermediary layer followed by covalent coupling of the receptor to this layer (EP 0 103 184 A2) or the adsorption of an intermediary layer of lipids followed by covalent coupling of the receptor to this layer (DE 31 26551 C2). The disadvantages with these techniques are that covalent coupling of reagents at a surface often results in low yield and that it can be necessary to use coupling procedures that partly destroys the reactivity of the recptor molecules. Furthermore, procedures for covalent coupling of receptor molecules are not available for all kinds of surfaces.
Disclosure of the invention
The object of the present invention is to provide a process for isolation or measurement of the amount of a ligand by covalent coupling of a ligand-specific receptor to a surface-adsorbed hydrophobized water soluble polymer. The present invention is based on the fact that certain water-soluble polymers can be chemically modified in a way that makes them adsorb strongly to hydrophobic surfaces. The process according to the invention is characterized in that a ligand-specific counter reactant, the receptor, is covalently coupled to a hydrophobized water-soluble polymer and that this polymer is allowed to adsorb to a substrate with a hydrophobic surface which af er adsorption of the polymer is brought into contact with the sample solution. These adsorbed hydrophobized polymers are not subject to exchange reactions with proteins upon exposure to blood (table 1).
Organic substances of medical interest such as enzymes, antibodies and hormones can easily be coupled to hydrophobized water-soluble polymers and reactants such as substrates for enzymes, antigens and antibodies will spontaneously bind to the polymer-receptor conjugate. One advantage with this process is that the coupling of the receptor can be carried out in solution in a large scale and that the immobilization to the solid phase is performed by spontaneous adsorption of the hydrophobized polymer to a hydrophobic surface.
The adsorbing solid phase matrix which is to be exposed to the water soluble polymer exhibits at least one hydrophobic surface. Examples of suitable hydrophobic materials are polystyrene, polyethene, polytetra- fluoroethylene (PTFE), polyurethane, polyvinylchloride (PVC) or other solid hydrophobic polymers. The adsorbing solid phase matrix can also be made of glass or aluminium provided that the surface has been modified to hydrophobiάty by methylization.
The hydrophobized polymer in the present invention is a water soluble polymer that has been partially hydrophobic by binding hydrophobic radicals such as hydrocarbons to the polymer backbone. Examples of suitable hydrophobized polymers are hydrophobized polysaccharides such as nonionic ethers of cellulose (USP 3,926,951), alkylated dextran or corresponding derivatives of starches.
The coupling of receptor molecules to the water soluble hydrophobized polymer can for example be made by bifunctional coupling reagents such as diisothiocyanate or diglycidylethers but can also be performed by the creation of reactive groups in the polymer backbone by for example oxidation of hydroxyl groups, present in polysaccharides, to aldehydes. Such oxidation can be performed by periodate, bromine or bromo- sucdnimide. The aldehydes created by the oxidation can then react with with aminogroups present on the receptor molecule in the presence of a catalysator e.g cyanoborohydride.
The binding of the ligand to the receptor occurs spontaneously upon exposure of the receptor coated surface to the sample solution. The surface immobilized complex can be detected by use of specific antibodies directed against the ligand and labeled with for example enzymes, radioactive isotopes or fluorochromes. The labeled antibody binds spontaneously to the ligand and the amount of bound antibody is proportional to the amount of surface bound ligand. The process according to the present invention can be used in various fields. In medical diagnostics surface bound antigens are used for measurement of antibodies present in samples of serum. Several antigens of medical interest are small molecules that do not spontaneously adsorb to solid phases. These molecules can be coupled to partially hydrophobic water soluble polymers which are stably adsorbed to solid phases.
The invention may also be applied for coupling of receptor molecules to filters that can be used for separation of certain ligands from complex mixtures of organic substances such as cell cultures. The invention will in the following be illustrated by a working example but is not limited thereto and hence modifications are of course conceivable within the limits of the claims.
Working example
Measurement of antibodies against insulin in serum by insulin coupled to surface adsorbed cellulose ether.
Ethyl-hydroxyethyl-cellulose is dissolved in water at a concentration of 10 g/1. Sodiumperiodate is added at a concentration of 0.1 g/1. After 1 hour the solution is heated to 60° C, at which temperature the cellulose ether precipitates. The solution is centrifugalized and the precipitate is washed in hot water. This washing procedure is repeated three times.
The oxidized cellulose is dissolved in cold phosphate buffer ( 0.01 M, pH 7. ) and insulin is added at a concentration of 10 g/1 together with sodium-cyano-borohydride. The amino groups present at the insulin molecules reacts with the aldehyde groups at the oxidized cellulose by reductive εunination. Excess of insulin is removed by repeated heat precipitation as described above. The cellulose-insulin conjugate is diluted to a concentration of 0.1 g/1 in phosphate buffer and poured into basins of a polyester micro titer plate. The plate is rinsed in buffer and serum samples with or without antibodies against insulin are incubated in different basins for 1 hour. The plates are then repeatedly rinsed in r- .
buffer and enzyme-labeled anti-immunoglobulin antibodies are added to the basins and incubated for 30 minutes. A careful final rinse is followed by the addition of a substrate for detection of peroxidase activity. The result of the experiment described above is shown in table 1.
Table 1. ELISA- measurement of antibodies against insulin by covalent binding of insulin to ethyl-hydroxyethyl-cellulose (EHEC), and subsequent adsorption of the insulin polymer conjugate to micro titer plates. The binding of antibodies to microtiter plates coated with adsorbed insulin and adsorbed unmodified EHEC are also shown for comparison.
A450 ra: n
Insulin-EHEC EHEC Insulin
Anti-insulin diluted in buffer 3,148 0 0,090
Anti-insulin diluted in blood 2,558 0 0

Claims

1. Process for isolation and/or measurement of the amount of an organic substance, the ligand, present in a sample solution characterized in that a ligand specific counter reactant, the receptor, is covalently coupled to a hydrophobized water soluble polymer and that this polymer is allowed to adsorb to a substrate with a hydrophobic surface which after adsorption of the polymer is brought into contact with the sample solution.
2. Process according to claim 1 in which the polymer is a hydrophobized uncharged polysacchaiide.
3. Process according to claim 1-2 in which the polymer is a hydrophobized cellulose.
4. Process according to claim 1-3 in which the polymer is an alkylated cellulose.
5. Process according to claim 1-4 in which the polymer is ethyl-hydroxy- ethyl-cellulose.
6. Article exhibiting at least one hydrophobic surface of glass, metal or hydrophobic polymer coated with a surface layer characterized in that the surface layer consists of an adsorbed hydrophobized water-soluble polymer which polymer before adsorption has been equipped with a covalently coupled ligand-specific counter reactant.
PCT/SE1988/000243 1987-05-13 1988-05-11 Immobilization of receptor molecules to hydrophobic water soluble polymer in separation methods on assays WO1988008981A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE8701962-6 1987-05-13
SE8701962A SE8701962D0 (en) 1987-05-13 1987-05-13 SET TO INSULATE AND / OR DETERMINE THE CONTENT OF AN ORGANIC SUBSTANCE THROUGH COVALENT COUPLING OF A FOR-SPECIFICALLY SPECIFIC MOTOR REACTANT TO SURFACE PREPARED, HYDROPHOBATED WATER SOLUBLE POLYMER

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WO1988008981A1 true WO1988008981A1 (en) 1988-11-17

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991008482A1 (en) * 1989-12-01 1991-06-13 Unilever Plc Antibody variable domain conjugates

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0438534A4 (en) * 1988-10-11 1991-09-11 Coulter Corporation Immunoreactant carriers having a novel biocompatible intermediate coating and process of making same

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3126551A1 (en) * 1981-07-04 1983-01-20 Rolf Dr. 8700 Würzburg Siegel Process for the preparation of materials for the immobilisation of proteins and carbohydrate groups
US4530900A (en) * 1982-09-13 1985-07-23 Seragen Diagnostics Inc. Soluble insoluble polymers in enzymeimmunoassay
US4579661A (en) * 1983-05-02 1986-04-01 Pharmacia Ab Process in the purification of biologically active substances
EP0230768A1 (en) * 1985-12-20 1987-08-05 Syntex (U.S.A.) Inc. Particle separation method

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3126551A1 (en) * 1981-07-04 1983-01-20 Rolf Dr. 8700 Würzburg Siegel Process for the preparation of materials for the immobilisation of proteins and carbohydrate groups
US4530900A (en) * 1982-09-13 1985-07-23 Seragen Diagnostics Inc. Soluble insoluble polymers in enzymeimmunoassay
US4579661A (en) * 1983-05-02 1986-04-01 Pharmacia Ab Process in the purification of biologically active substances
EP0230768A1 (en) * 1985-12-20 1987-08-05 Syntex (U.S.A.) Inc. Particle separation method

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF BIOTECHNOLOGY, Vol. 1, (1984), pages 3-12, (C.R. LOWE), "New Developments in Downstream Processing". *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991008482A1 (en) * 1989-12-01 1991-06-13 Unilever Plc Antibody variable domain conjugates

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AU1797188A (en) 1988-12-06
SE8701962D0 (en) 1987-05-13

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