WO1999056126A2 - Matrice d'immuno-adsorption, ses procedes de production et son utilisation - Google Patents

Matrice d'immuno-adsorption, ses procedes de production et son utilisation Download PDF

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Publication number
WO1999056126A2
WO1999056126A2 PCT/DE1999/001228 DE9901228W WO9956126A2 WO 1999056126 A2 WO1999056126 A2 WO 1999056126A2 DE 9901228 W DE9901228 W DE 9901228W WO 9956126 A2 WO9956126 A2 WO 9956126A2
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Prior art keywords
antigen
fragments
matrix
binding
immunoadsorption
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PCT/DE1999/001228
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German (de)
English (en)
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WO1999056126A3 (fr
Inventor
Wolfgang RÖNSPECK
Frank Gebauer
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Affina Immuntechnik Gmbh
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Application filed by Affina Immuntechnik Gmbh filed Critical Affina Immuntechnik Gmbh
Priority to AU46000/99A priority Critical patent/AU4600099A/en
Publication of WO1999056126A2 publication Critical patent/WO1999056126A2/fr
Publication of WO1999056126A3 publication Critical patent/WO1999056126A3/fr

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
    • B01J20/3202—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the carrier, support or substrate used for impregnation or coating
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
    • B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
    • B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
    • B01J20/3268—Macromolecular compounds
    • B01J20/3272—Polymers obtained by reactions otherwise than involving only carbon to carbon unsaturated bonds
    • B01J20/3274—Proteins, nucleic acids, polysaccharides, antibodies or antigens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/14—Extraction; Separation; Purification
    • C07K1/16—Extraction; Separation; Purification by chromatography
    • C07K1/22—Affinity chromatography or related techniques based upon selective absorption processes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/42—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins
    • C07K16/4283—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an allotypic or isotypic determinant on Ig
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K17/00—Carrier-bound or immobilised peptides; Preparation thereof
    • 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
    • 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
    • G01N33/563—Immunoassay; Biospecific binding assay; Materials therefor involving antibody fragments
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
    • B01D15/08—Selective adsorption, e.g. chromatography
    • B01D15/26—Selective adsorption, e.g. chromatography characterised by the separation mechanism
    • B01D15/38—Selective adsorption, e.g. chromatography characterised by the separation mechanism involving specific interaction not covered by one or more of groups B01D15/265 - B01D15/36
    • B01D15/3804—Affinity chromatography
    • B01D15/3809—Affinity chromatography of the antigen-antibody type, e.g. protein A, G, L chromatography
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/23—Immunoglobulins specific features characterized by taxonomic origin from birds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/55—Fab or Fab'

Definitions

  • the invention relates to a new immunoadsorption matrix, processes for its preparation and its use for therapeutic, diagnostic, preparative, analytical and medical purposes.
  • An immuno-chromatographic method is referred to as immunoadsorption, in which the specific bond between the antibody and antigen is used to isolate one of the reactants from complex mixtures of biogenic origin (Carlsson, J. et al. 1989).
  • Affinity chromatography has the ability to produce molecules with the help of
  • Carrier material fixed antibodies made prior art (Goding, J.W.
  • immunapheresis In a treatment method called immunapheresis, the patient's plasma circulates in a closed circuit through columns with specific carrier-fixed antibodies, with the aid of which the concentration of the harmful component in the plasma is reduced (Stoffel, W. 1981, Ulbricht, CJ 1991). Lowering serum cholesterol with the help of LDL immunoadsorption is now recognized as a treatment method for patients with familial hypercholesterolemia (Richter, WO and Schwandt, P. 1995, Jansen, M. et al. 1996).
  • the antibodies are usually covalently bound via their primary amino groups.
  • This type of coupling requires chemical activation of the matrix with correspondingly reactive groups.
  • a preferred activation method is the formation of cyanate esters or imidocarbonates after the action of cyanogen bromide on a matrix with vicinal hydroxyl groups (Axen, R. and Ernback, p. 1971, Jacoby, WV and Wilchek, M. 1975).
  • Other common reactive groups are N-hydroxysuccinimide esters (Cuatrecasas, P. and Parikh, I. 1972) or also N-hydroxysuccinimide and imidazoyl carbonates (Wilchek, M. and Miron, T.
  • Hyperdiffusion resins are available, which are up to 50 times higher in chromatography
  • this carrier material can be activated in the same way as conventional material.
  • these antigen-binding structures must be coupled to a carrier material via a covalent bond.
  • the aim of the coupling is a high yield of coupled antigen-binding structures in relation to the amount used, coupled with the highest possible activity retention in relation to the specific binding for the antigen.
  • the problem is that covalent bonds can also occur in the region of the antigen-binding region, thereby impairing the antigen-binding properties and reducing the activity.
  • a problem with many applications is an unsatisfactory binding capacity of the immunoadsorption matrix.
  • a high binding capacity enables the use of smaller column volumes and thus saves time and material in routine use
  • the binding capacity is usually given in mg bound antigen per ml adsorption matrix, or per mg coupled antigen-binding structure. It is dependent on the affinity of the antigen-binding structure for the antigen and on the loading density, ie the amount of functionally intact antigen-binding structures which can be coupled to a certain amount of the immunoadsorption material.
  • the loading density is usually given in mmol or mg coupled antigen-binding structure per ml column matrix.
  • a high loading density is usually achieved by using a carrier material with a large available matrix surface and a high concentration of functional or reactive groups on the matrix surface, to which the antigen-binding structures can be coupled under suitable conditions.
  • a maximum binding capacity higher by a factor of 1.7 can be expected if, with the same quantitative loading, given in mg antigen-binding structure per ml carrier matrix, their F (ab) fragments are coupled instead of complete immunoglobulins. Due to the smaller molecular weight, the percentage of binding sites for the antigen is higher. The F (ab) fragment has only 1 antigen binding site. Similar increases should also apply to the coupling of single chain antibodies or peptides (with an antigen binding site) compared to complete immunoglobulins.
  • the object was achieved in that additional functional Groups are introduced into the antigen-binding structure, while the binding site for the antigen was protected.
  • antigen-binding structure All molecules that contain an antigen-binding region and can react in the sense of an antigen-antibody binding are referred to below as the antigen-binding structure.
  • Antigen-binding structures can be polyclonal or monoclonal antibodies (e.g. single chain antibodies) or fragments thereof. However, they can also be recombinant or synthetically produced peptides or proteins.
  • the antigen-binding structures can be directed against a wide variety of antigens or haptens, whereby haptens are understood to mean compounds which alone do not produce antibodies in the organism, but only after coupling to a polymeric carrier. However, they can still be bound very efficiently by antigen-binding structures.
  • Support materials to which the antigen-binding structures are covalently bound are preferably used.
  • these are matrices as carrier material, which consist of organic, inorganic, synthetic polymers or of mixed polymers and which may be chemically activated.
  • the functional groups introduced can either be suitable for coupling to a chemically activated matrix or can themselves represent an activated group which can couple to a suitable functional group of a matrix.
  • the amino groups of the antigen binding structures can e.g. reacted with succinic anhydride and the carboxyl groups introduced after activation with e.g. l-Ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) can be coupled to an amino-containing matrix.
  • EDC l-Ethyl-3- (3-dimethylaminopropyl) carbodiimide
  • carboxyl groups of the antigen-binding structures can also be reacted with EDC and a suitable diamine and coupled to, for example, an N-hydroxysuccinimide or cyanogen bromide-activated matrix via the introduced amino group.
  • EDC succinimidyl 3 (2-pyridyldithio) propionate
  • DTT dithiothreitol
  • SH groups can be introduced, for example to a maleimido group. supporting matrix can be coupled.
  • SH groups Another possibility for the introduction of SH groups is the reaction with N-succinimidyl-S-acetylthioacetate (SATA) and aftertreatment with hydroxylamine. SPDP and SATA have the advantage over the Traut see reagent that the SH group is only released after separation from the antigen.
  • SATA N-succinimidyl-S-acetylthioacetate
  • Antigens of interest for immunapheresis are e.g. Autoantikö ⁇ er, Low density lipoprotein (LDL), ß2-microglobulin, fibrinogen, antibodies to factor VIII or endotoxin.
  • LDL Low density lipoprotein
  • ß2-microglobulin ß2-microglobulin
  • fibrinogen antibodies to factor VIII or endotoxin.
  • the Fc fragments of mouse immunoglobulins can be suitable antigens.
  • the binding region of the antigen-binding structure is protected according to the invention during the derivatization by temporary, reversible binding to the antigen and, after separation from the antigen, is bound to a suitable, appropriately derivatized matrix via the newly introduced functional groups.
  • the matrices produced according to the invention surprisingly show significantly increased binding capacities. So they show an unexpected increase up to a factor of 3.69.
  • the matrices according to the invention are therefore outstandingly suitable for use for therapeutic, diagnostic, preparative, analytical and medical technology purposes.
  • F (ab) fragments are derived from chicken antibodies (immunoglobulin Y), the specificity of which is directed against human immunoglobulin.
  • Immunology adsorbents - 1. Isolation of antibody by means of a cellulose-protein antigen,
  • SCA Single chain antibody
  • Plasmapheresis and immunoadsorption in the treatment of a patient with thrombotic thrombocytopenic Pu ⁇ urea TTP
  • Wiener Klinische Wienschrift 108 suppl 1, 27 TTP
  • the matrix m-maleimidobenzoyl-Sepharose 4B which is preferably used for coupling immunoglobulin Y (IgY) or its F (ab) fragments (IgY-F (ab)), is prepared as described below.
  • Dried bromine-activated Sepharose 4B is suspended in 1 mM HCl and washed with 70 times the volume of 1 mM HCl.
  • the bromocyan-activated Sepharose 4B is then mixed with twice the volume of 0.5 M diaminoethane, adjusted to pH 8.2 with 1 M HCl, and shaken for 18 h at room temperature.
  • the amino-Sepharose 4B thus produced is washed with physiological phosphate-buffered saline (PBS) and can be stored in PBS with the addition of 0.05% sodium azide at 2-8 ° C.
  • PBS physiological phosphate-buffered saline
  • the amino-Sepharose 4B is washed with 50 times the volume of 0.1 M sodium phosphate pH 8.0 and with twice the volume of a mixture of 50% (v / v) dimethyl sulfoxide and 50% (v / v ) 0.1 M sodium phosphate pH 8.0 resuspended. If necessary, the pH is adjusted by adding 1 M NaOH. A solution of 10 mg of m-maleimidobenzoyl-N-hydroxysuccinimide in 0.2 ml of dimethyl sulfoxide is then added to each 1 ml of Amino-Sepharose 4B and the reaction mixture is shaken at room temperature for 18 h.
  • the m-maleimidobenzoyl-Sepharose 4B is washed immediately before further processing with 10 times the volume of dimethyl sulfoxide and resuspended in 0.1 M sodium phosphate pH 6.5.
  • additional sulfhydryl groups are preferably introduced in IgY-F (ab) (specifically against human immunoglobulin) as described below.
  • human immunoglobulin coupled to Sepharose 4B is incubated in a solution of IgY-F (ab) up to the maximum load.
  • the matrix loaded with IgY-F (ab ') is washed with PBS, buffered in an alkaline buffer such as triethylamine-HCl buffer pH 8.0 (50 mM triethylamine, 150 mM NaCl, 1 mM EDTA-Naj) and in 2- times the volume of the same buffer resuspended.
  • the suspension is, under N 2 atmosphere with 2-iminothiolane-HCl (Traut's reagent, Jue R. et al. 1978), the molar amount of which preferably corresponds to 8 times the amount of bound IgY-F (ab) present.
  • the matrix loaded with IgY-F (ab) is rinsed with 0.1 M sodium phosphate pH 6.5, pre-gassed with N 2 .
  • the IgY-F (ab) (IgY-F (ab) -SH) derivatized with 2-iminothiolane are then eluted from the matrix with 0.1 M sodium phosphate-HCl pH 2.5 (pre-gassed with N 2 ).
  • the eluate is brought to pH 6.5 with 0.5 M sodium phosphate pH 9.1, pre-gassed with N 2 , and immediately used for coupling to the m-maleimidobenzoyl-Sepharose 4B.
  • a defined volume of the prepared IgY-F (ab ') - SH solution is mixed with a defined volume of the prepared m-maleimidobenzoyl-Sepharose 4B.
  • the mixture is shaken at 2-8 ° C for 18 h.
  • Unbound IgY-F (ab) -SH is then eluted with 0.1 M sodium phosphate pH 6.5. From the quantification of the remaining amount of IgY-F (ab) -SH, the amount of coupled IgY-F (ab ') - SH and thus the loading of m-maleimidobenzoyl-Sepharose 4B (mg protein / ml gel) can be concluded.
  • the amount of the eluted protein is determined spectrophotometrically and its identity (> 90% human immunoglobulin) in the
  • ELISA enzyme linked immunosorbent assay
  • steps 1 to 4 The procedure described in steps 1 to 4 is also applied to the coupling of IgY to Sepharose 4B (coupling product IgY-SH / S 4B).
  • IgY is coupled to bromocyan-activated Sepharose 4B without prior derivatization.
  • the coupling product is mixed with twice the volume of 0.1 M ethanolamine-HCl pH 8.0 and shaken for 2 hours at room temperature. After a subsequent wash with 50 times the volume of 0.1 M sodium bicarbonate pH 8.2 / 0.5 M NaCl and 50 times the volume of 0.1 M glycine-HCl pH 2.5, it becomes 0.05 in PBS % Sodium azide buffered and stored at 2-8 ° C. 1 ml of the coupling product (IgY / S 4B) is tested as described in step 4.
  • IgY anti-human IgG achieved binding capacities of 0.23 to 0.27 mg human IgG per mg bound IgY.
  • a comparison of experiments 9 and 7 or 8 and 6 in Table 1 shows an increase of approximately 1.7 in each case in the binding of human IgG per mg IgY-F (ab) fragment compared to the value of the coupled complete immunoglobulin (IgY ).
  • the binding capacity of the immunoadsorption material could already be increased to 0.30 mg to 0.38 mg human IgG.
  • immunosorbent materials can be produced on the basis of the exemplary embodiment presented, which have binding capacities of more than 19 mg human IgG per ml Sepharose 4B. (See Experiment 3 in Table 1). This capacity could not be achieved with conventional coupling methods, even when using far higher concentrations of antigen-binding structures. (See Experiment 7 in Table 1)
  • This increase in binding capacity enables the volume of an immunoadsorption column to be reduced for a given capacity and thus allows shorter times for loading with the antigen, for rinsing, for eluting the antigen and for regeneration of the column. Sensitive antigens are protected by the shorter residence time in the mostly harmful elution buffer. On the other hand, larger yields can be achieved at the same time for a given column volume.
  • the method used here to couple antigen-binding structures can be easily transferred from Sepharose to other substrates.
  • the treatment times can be shortened or the concentrations of the substance to be removed can be significantly reduced with the same treatment time.
  • Antigen binding site derivatizes IgY-SH complete IgY, with thiol groups (SH) under the protection of
  • Antigen binding site derivatizes IgY-F (ab) IgY-F (ab) fragments, not derivatized and without protection of the
  • Antigen binding site coupled IgY complete IgY, not derivatized and without protection of the

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Abstract

L'invention concerne une nouvelle matrice d'immuno-adsorption, ses procédés de production et son utilisation pour la thérapie, le diagnostic, la réalisation de préparations, l'analyse, et dans la technique médicale. Par couplage avec un matériau support, des structures de liaison d'antigène sont dérivatisées et/ou activées, les sites de liaison d'antigène étant protégés, avec des groupes fonctionnels qui conviennent pour un couplage à une matrice chimiquement activée ou constituent eux-mêmes un groupe activé.
PCT/DE1999/001228 1998-04-27 1999-04-24 Matrice d'immuno-adsorption, ses procedes de production et son utilisation WO1999056126A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU46000/99A AU4600099A (en) 1998-04-27 1999-04-24 Immuno-adsorption matrix, a method for the production thereof, and the utilization thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19818790.4 1998-04-27
DE1998118790 DE19818790A1 (de) 1998-04-27 1998-04-27 Immunadsorptionsmatrix, Verfahren zu ihrer Herstellung und ihre Verwendung

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WO1999056126A2 true WO1999056126A2 (fr) 1999-11-04
WO1999056126A3 WO1999056126A3 (fr) 2000-01-13

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WO2007101732A1 (fr) 2006-03-09 2007-09-13 Max-Delbrück-Centrum für Molekulare Medizin Peptides dirigés contre des auto-anticorps associés au glaucome et utilisation de ces peptides
EP1950222A1 (fr) 2007-01-26 2008-07-30 GA Generic Assays GmbH Procédé à la vérification d'anticorps dans des liquides corporels par une réaction immunitaire avec les glycoprotéines 2 (GP2) à partir de granulés zymogènes du pancréas pour le diagnostic différentiel de maladies inflammatoires de l'intestin et de pancréatites chroniques
DE102007004909A1 (de) 2007-01-26 2008-07-31 Ga Generic Assays Gmbh Verfahren zum Nachweis von Antikörpern aus Körperflüssigkeiten durch eine Immunreaktion mit Glykoprotein 2(GP2) aus zymogenen Granula des Pankreas zur Differentialdiagnose von entzündlichen Darmerkrankungen und chronischer Pankreatitis
EP2199305A1 (fr) 2008-12-18 2010-06-23 Max-Delbrück-Centrum Peptides contre les anticorps associés au CRPS et utilisation de ces peptides
WO2013023852A1 (fr) 2011-08-12 2013-02-21 E.R.D.E.-Aak-Diagnostik Gmbh Auto-anticorps agonistes contre le récepteur adrénergique alpha1 et le récepteur adrénergique bêta2 dans la démence d'alzheimer et vasculaire
EP2913675A2 (fr) 2014-02-28 2015-09-02 GA Generic Assays GmbH Isoformes GP2 et leur utilisation dans la capture d'auto-anticorps
WO2016109872A1 (fr) 2015-01-09 2016-07-14 Adalta Pty Ltd Molécules de liaison cxcr4
EP3299818A1 (fr) 2016-09-26 2018-03-28 GA Generic Assays GmbH Procédé de diagnostic de pancréatite aigüe (ap) par détection de glycoprotéine 2 alpha isoforme (gp2a)
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US10584175B2 (en) 2014-10-23 2020-03-10 La Trobe University FN14-binding proteins and uses thereof
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WO2021239949A1 (fr) 2020-05-29 2021-12-02 Deutsches Zentrum Für Neurodegenerative Erkrankungen E. V. (Dzne) Anticorps monoclonal recombinant humain dirigé contre la glycoprotéine de spicule de sars-cov-2
WO2022195120A1 (fr) 2021-03-19 2022-09-22 Charité - Universitätsmedizin Berlin Procédé d'analyse directe de l'avidité fonctionnelle de lymphocytes t
EP4183409A1 (fr) 2021-11-17 2023-05-24 Charité - Universitätsmedizin Berlin Vaccin contre les coronavirus mutants présentant une meilleure immunogénicité

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ES2433280T3 (es) * 2004-10-20 2013-12-10 Hans-Werner Prof. Dr. Heinrich Adsorbente inmunológico para el tratamiento de inflamaciones

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CHEMICAL ABSTRACTS, vol. 115, no. 21, 25. November 1991 (1991-11-25) Columbus, Ohio, US; abstract no. 223755, XP002121981 & L.I. SURVILO ET AL.: "Production of immunoaffinity sorbent with biospecific protected antigen - binding centers and its use for separation of human thyrotropin" VESTSI AKAD. NAVUK BSSR, SER. KHIM. NAVUK, Bd. 4, 1991, Seiten 79-83, Minsk USSR *

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007101732A1 (fr) 2006-03-09 2007-09-13 Max-Delbrück-Centrum für Molekulare Medizin Peptides dirigés contre des auto-anticorps associés au glaucome et utilisation de ces peptides
EP1950222A1 (fr) 2007-01-26 2008-07-30 GA Generic Assays GmbH Procédé à la vérification d'anticorps dans des liquides corporels par une réaction immunitaire avec les glycoprotéines 2 (GP2) à partir de granulés zymogènes du pancréas pour le diagnostic différentiel de maladies inflammatoires de l'intestin et de pancréatites chroniques
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AU4600099A (en) 1999-11-16
WO1999056126A3 (fr) 2000-01-13
DE19818790A1 (de) 1999-10-28

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