WO1989008261A1 - Composition de detection et/ou de quantification simple de substances antigeniques dans des liquides corporels - Google Patents

Composition de detection et/ou de quantification simple de substances antigeniques dans des liquides corporels Download PDF

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Publication number
WO1989008261A1
WO1989008261A1 PCT/NO1989/000021 NO8900021W WO8908261A1 WO 1989008261 A1 WO1989008261 A1 WO 1989008261A1 NO 8900021 W NO8900021 W NO 8900021W WO 8908261 A1 WO8908261 A1 WO 8908261A1
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Prior art keywords
erythrocytes
antibodies
reactive
protein
compositions according
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PCT/NO1989/000021
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English (en)
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Erling Sundrehagen
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Erling Sundrehagen
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Filing date
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Priority claimed from GB888804933A external-priority patent/GB8804933D0/en
Application filed by Erling Sundrehagen filed Critical Erling Sundrehagen
Publication of WO1989008261A1 publication Critical patent/WO1989008261A1/fr

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    • 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
    • G01N33/80—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood groups or blood types or red blood cells
    • 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
    • G01N33/531—Production of immunochemical test materials
    • 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
    • G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
    • G01N33/585—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances with a particulate label, e.g. coloured latex
    • G01N33/586—Liposomes, microcapsules or cells
    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • 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
    • G01N33/86—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood coagulating time or factors, or their receptors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/745—Assays involving non-enzymic blood coagulation factors
    • G01N2333/75—Fibrin; Fibrinogen
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/795—Porphyrin- or corrin-ring-containing peptides
    • G01N2333/805—Haemoglobins; Myoglobins

Definitions

  • This is invention relates to compositions useful in the detection and quantification of antigenic substances in body liquids.
  • Antigenic substances are molecules with structures to which specific antibodies of polyclonal and monoclonal origin can bind.
  • General immunological literature describes the formation and production of antibodies and antibody fragments reactive to antigens of different origins.
  • fibrin from fibrinogen is a part of the thrombotic process in vivo.
  • both thrombosis and fibrinolysis simultaneously take place.
  • fibrin degradation products appear in circulating blood as signs of thromboembolic processes in the body, and may be detected and quantified as antigens reactive to antibodies in immunoassays (Devine & al: Blood 68, 317-319, 1986. Elms & al.: Thrombosis & Haemostasis 50, 591-594, 1983. Mirshaj & al.: Thrombosis res. 44, 715-728, 1986.
  • the acute phase proteins constitute a group of individual proteins which share, one common characteristics: Their plasma concentrations are altered when an organism, i.e. a patient, undergoes a disease involving inflammation and/or infection. Also neoplastic diseases may induce inflammatory reactions causing acute phase reactions. (Chambers RE & al: "Akute-Phase-Proteine bei entzuriumen preparationen", Diagnose und Labor 36: 124-132, 1986).
  • C-reactive protein was first reported in 1930 as a human serum protein that binds to the C-polysaccharide of the pneumococcus cell membrane (Tillet W.S. and Francis T: "Seriological reaction in pneumonia with a non-protein somatic fraction of pneumococcus", J.Exp. Med.52:561-571, 1930). Later it was demonstrated that C- reactive protein binds to phosphoryl choline residues and to aminoethyldihydrogen phosphate residues of this fraction, and these bindings have been utilized for the purification of C-reactive protein and serum. (Volanakais J.E. & al: J. Immunol. Methods 23, 285-295, 1978), (Potent M.
  • CRP C-reactive-protein 50 years on; Lancet 1:653-657, 1981).
  • the CRP molecule consists of 5 identical subunits held together by non-covalent bonds (Pepys MB: se above).
  • Pepys MB se above.
  • Several methods for CRP detection and quantification are available, including immunoprecipitation (Andersen HC, and McCarty M: "Determination of C-reactive protein in blood as measure of the activity of the disease process in acute rheumatic fever", Am.J. Med. 8: 445-445, 1950);(Wadsworth C: "A rapid spot immuno-precipitate assay method applied to quantitating C-reactive protein in pediatric sera”. Scand. J. Immunol.
  • Serum amyloid A consists of a single polypeptide chain of molecular weight 11 000 - 14 000. This subunit is associated with high density lipoprotein, then to a molecular weight of 85 000 - 200 000 (Anders, RF., Natvig, J., Michalsen TE & Huseby G. Isolation and characterisation of amyloid related SAA as a small molecular weight protein. Scandinavian Journal of Immunology 4, 397-640, 1977). (Rosenthal CJ. et Franklin, EC; "Variation with age and disease of an amyloid A protein related serum component". Journal of Clinical Investigation, 55, 746-753, 1975). The function of SAA is not known, but it behaves as an acute phase reactant.
  • SAA seems to be an apolipoprotein of a fraction of high density lipoprotein molecules.
  • the LI protein is a highly immunogenic protein of about 36500 daltons that can be purified from granulocytes with good yield. It is present in the cytoplasm of ' virtually all resting peripheral neutrophiles and monocytes.
  • CRP, and SAA and LI are presently the plasma proteins known to have the most prominent concentration differences between the normal plasma concentrations and the plasma concentrations in acute inflammatory and infectious phase reactions. Since the increase in blood concentration of CRP, SAA and LI is a very rapid response to infections and tissue damage, their determination are especially valuable in acute medical situations. A large number of acute medical incidents take place in general medical practice far from advanced medical laboratories. Most of the known methods for the detection and/or quantification of increased CRP, SAA and LI concentrations utilize laboratory equipment like spectrophotometers, radioactivity counters, nephelometric equipment, and a time consuming isolation of serum or plasma from whole blood is necessary.
  • Antibodies with specific affinity for body liquid antigens are obtained by immuniza ⁇ tion of animals with purified antigens. Monoclonal antibodies reactive to the said antigens may be obtained by fusion of spleen cells from animals immunized with antigen or fragments thereof with suitable cancer cell lines (K ⁇ hler and Milstein. "Continous cultures of fused cells secreting antibodies of predefined specificity", Nature 286, 495-497, 1975). In vivo immunization techniques may also be applied. Several of the immunological techniques utilize modified antibodies, i.e. antibodies conjugated to enzymes or fluorescent moieties or radioactive labels.
  • This invention relates to the use of conjugates or hybrids of different antibodies for detection and/or quantification of antigenic substances in samples of body liquids, especially in whole blood samples. Contrary to other methods using signal • forming molecules like enzymes or radioactive or fluoroscent moities or advanced equipment or latex agglutination, the present invention utilizes a constituent of the blood itself to indicate the presence of elevated concentration of the relevant antigenic substances.
  • conjugation or hybridization of antibodies or ligands reactive to the relevant antigenic substances with antibodies reactive to ery- throcyte antigens a chemical composition is obtained which is able to aggregate erythrocytes in presence of the relevant antigenic substances.
  • two or more identical conjugates or hybrides may bind to the antigenic substance and at the same time bind to the erythrocytes present in the sample or added to the sample if necessary, thus inducing an aggregation of the said erythrocytes.
  • the relevant antigenic substances are not constituted by two or more identical subunits, mixtures of different antibody conjugates or hybrids may be used, characterized by at one hand all being reactive to the erythrocytes, present in the sample or if necessary added to the sample, and on the other hand reactive to different epitopes on the relevant antigenic substances.
  • CRP consist of five identical subunits, thus several conjugates may bind to the same CRP molecule. In this way the conjugates and CRP build bridges between erythrocytes, forming aggregates of the said erythrocytes. Mixtures of different antibodies binding to different epitopes of e.g. LI, myoglobin, CRP or SAA may be used.
  • fibrinogen degradation products When fibrinogen and fibrin are degraded in vivo, fibrinogen degradation products of variable molecular weight are formed.
  • Several antigens and epitopes of these degradation products have been investigated, and several of these antigenic determinants and epitopes are not expressed in fibrinogen. Conjugates of antibodies reactive to such determinants and epitopes, with antibodies, reactive to erythrocytes induce aggregation of the erythrocytes in presence of such determinants and epitopes, thus whole blood testing for fibrinogen degradation products is made possible.
  • Erythrocytes of a particular species contain numerous different antigenic deter ⁇ minants, several of these antigens being common to all members of the species, and several antigens are common only to a limited number of the members of the species (i.e. blood group antigens) (Van Bennet: "The membrane skeleton of human erythrocytes and its implications for more complex cells", Ann. Rev. Biochem. 1985, 54: 273-304).
  • This invention is favourably applied with conjugates or hybrids of antibodies reactive to erythrocyte antigens common to all members of the species.
  • Peripheral erythrocyte proteins like spectrin, ankyrin and Band 3 proteins may favourably serve as determinants.
  • This invention may also utilize antibodies reactive to all human cells, then all the cellular constituents of the blood will take part in the aggregation reaction.
  • Monoclonal or polyclonal antibodies to erythrocyte antigens may be obtained by immunization with erythrocyte antigens. Monoclonal antibodies reactive to all human cells have been produced by the inventor. Conjugates between antibodies or ligands reactive to the relevant antigenic substances and antibodies reactive to erythrocyte antigens or common human cell antigens may be formed by several different methods. A glutaraldehyde activation followed by conjugation is easily performed, but is not optimal from a biochemical functional point of view. Bifunctional linkers such as - but not limited to - bifunctional diimidates, bifunctional dimaleimides, bifunctional maleimido-imides, and other bifunctional . linkers may be used. Also linkages between the carbohydrate moities of immunglobulins or between sulphydryl moities may be formed.
  • Immunoglobulins consist of different polypeptides which are held together by disulfide linkages. These disulfide linkages may undergo reductive cleavage and the fragments formed may be separated under acid conditions. By neutralization, such fragments will reunite. If the fragments formed from antibodies reactive to eryth ⁇ rocyte antigens are mixed and then allowed to reunite with fragments formed from antibodies reactive to the relevant antigenic substances, hybrids of antibodies which are reactive both to the relevant antigenic substances and reactive to erythrocytes may be formed.
  • the protein conjugates described may be replaced by conjugates between antibodies, reactive to erythrocytes or to all blood cells, and ligands containing phosphorylcholine residues or aminoethyldihydrogen phosphate residues, because _ these ligand residues bind to C-reactive protein in presence of Ca (II).
  • Immunological purification of the hybrids or the conjugates may be purified by affinity chromatography.
  • conjugates or hybrids When such conjugates or hybrids have been isolated, they may be kept in solution, if necessary with preservatives, or lyophilized, for later use. In the actual clinical situation, these conjugates or hybrids can be combined with whole blood from the patient, most practically with capillary blood obtained by microsampling.
  • the solution of conjugates or hybrids, or the redissolved lyophilized dry solid obtained may contain anticoagulants prohibiting coagulation of the blood added. After a short incubation time, aggregation of the erythrocytes is observed if the relevant antigen is present in an appropriate concentration in the blood added. The sensitivity of the aggregation reaction is adjusted by adjustment of the amount of conjugate or hybrid present.
  • Aggregation of the blood cells may be observed visually in tubes, on slides from glass or plastics or by other techniques found practical.
  • a more precise quantifi ⁇ cation of the relevant antigenic substance present may be obtained by particle counting, i.e. by counting the number of aggregated and/or non- aggregated erythrocytes, turbidimetric quantification, optotermic spectroscopy, thin layer chromatographic separation of aggregates from free non-aggregated erythrocytes, and other measuring techniques.
  • Antibodies to different antigenic determinants, epitopes, on relevant antigenic substances and to different antigenic determinants on erythrocytes are available.
  • hybrids or conjugates reactive to on one hand erythrocytes and on the other hand different epitopes on the relevant antigenic substance may be formed.
  • These type of conjugates or hybrids may be used in combination to streng ⁇ then the aggregation reactions and to increase the sensitivity of the test: In this way more than one single (type of) conjugate or hybrid may serve as linker between the relevant antigenic substance and the erythrocytes, thus facilitating the aggregation reaction.
  • compositions comprising mixtures of different conjugates or hybrids may favourably be in the very same buffer solution or in the same lyophylized solid, thus a simple mixing of the claimed composition and the blood from the invidial to be tested may be the only technical handling necessary, optionally followed by instrumental handling for quantitative measurement of the aggregation reaction.
  • erythrocytes from any individual may be added to form the necessary aggregates.
  • Tests may also, by additon of erythrocytes, be performed on samples of urin or cerebrospinal fluid.
  • compositions for detection and/or quantification of antigenic substances present in a sample of body liquid will have a certain measuring range.
  • the amount of ligand or immunoglobulin conjugate or hybrid present must be adjusted.
  • the sensitivity for antigenic substance detection and/or quantification at the optimized conjugate/hybrid concentration may be adjusted or decreased by addition of antibodies reactive to the relevant antigen, which have not been conjugated or hybridized with antibodies reactive to erythrocytes. These adjustments must be performed according to the actual clinical application, i.e. how much blood should be combined with the composition, and how sensitive to elevated antigenic substance concentrations the test should be.
  • Both antibodies of monoclonal and polyclonal origin may be used in the present invention. However, monoclonal antibodies are easier to standardize, conjugate and hybridize and will give higher yields after immunological purification. If available, non-immunoglobulin ligands that bind to the relevant antigenic substance may replace the antibodies. E.g. phosphorylcholine residues or aminoethyldihydrogen phosphate residues may replace anti-CRP-antibodies, since such ligands binds to CRP.
  • compositions according to this invention may be formed to aggregate eryth ⁇ rocytes of the human species or of other species in presence of the relevant antigenic substance in a clinically significant concentrations in samples of body liquids.
  • Mouse IgG monoclonal antihuman C-reactive antibodies were formed by conventional hybridoma technique and isolated from mouse ascites. Similarly mouse monoclonal IgG reactive to human erythrocyte membranes was produced by conventional hybridoma technique. Both the anti CRP antibodies and the antieryth- rocyte antibodies were dissolved in sodium phosphate buffer at neutral pH. N- succinimidyl 3 - (2-pyridyldithio) propionate (abbreviated SPDP) was dissolved in ethanol to 20 mM concentration. The SPDP solution was added to both immunoglo ⁇ bulins solutions in 3-4 molar excess to the immunoglobulins. The solution was left to react for 30 minutes at 23 °C with occasional stirring.
  • SPDP N- succinimidyl 3 - (2-pyridyldithio) propionate
  • Monoclonal mouse IgG reactive to all human cells was produced and purified by conventional hybridoma technique from a cell line available in the laboratory.
  • P-aminophenylphosphoryl choline acid was conjugated to the antibodies in a one step reaction by means of bis-(sulfosuccinimidyl)-suberate, where the p-aminophenylphosphoryl choline acid was present in 15 molar excess to the antibodies, and bis-(suIfosuccinimidyl)suberat was present In 20 fold molar excess to the antibodies.
  • the conjugate was purified by gel chromatography. Immunological purification of conjugates reactive on one hand to C-reactive protein and on the other hand to erythrocytes was performed by affinity chromatography.
  • Example 1 Equivalent to Example 1, though antibodies reactive to CRP was replaced by antibodies reactive to myoglobin. 4.
  • the conjugate described in Example 1 was demonstrated to have the ability to aggregate the erythrocytes in presence of human C-reactive protein.
  • the conjugate described in example 1 required higher concentration of CRP to be present when non- conjugated antibodies reactive to CRP had been added, demonstrating that non- conjugated antibodies reactive to the same epitopes on CRP as the conjugate described in example 1 could be used to reduce the sensitivity of the aggregation reaction.
  • a test system could be adjusted to induce aggregation of erythrocytes when a clinically significant concentration of CRP is present.
  • Monoclonal antibodies reactive to human fibrin degradation products - but not to fibrinogen - and mouse monoclonal anti-human erythrocyte antibodies were produced by conventional hybridoma technique.
  • the anti-erythrocyte monoclonal antibodies and the anti-human fibrin degradation products monoclonal antibodies were conjugated by SPDP as described in example 1.
  • the conjugates were isolated, and the conjugates reactive on one hand to the erythrocytes and on the other hand to fibrin degradation products were purified with affinity chromatography techni ⁇ ques.
  • erythrocytes were made to aggregate in presence of CRP or myoglobin or fibrin degradation products. The aggregation could be visually observed on transparent slides and in tubes. Further more, it was demonstrated that the aggregation reaction reduced the absorption of light passing through a cuvette where the erythrocytes were suspended. Furthermore, it was demonstrated that, while erythrocytes migrated in chromatography paper, aggregates were withheld to a reduced travelling distance.

Abstract

On a mis au point des compositions de diagnostic comprenant des conjugués de ligands ou d'anticorps, ou d'hybrides d'anticorps réactifs à la fois à des substances spécifiques (par exemple des antigènes) d'une part et à des érythrocytes d'autre part. Ils provoquent une agrégation d'érythrocytes en présence de ladite substance spécifique dans une quantité cliniquement significative permettant la détection et/ou la quantification de ladite substance spécifiée dans le sang, le plasma, le sérum ou d'autres liquides corporels. L'invention concerne également l'utilisation de compositions comprenant des mélanges de conjugués ou d'hybrides d'anticorps réactifs aux différents déterminants antigéniques, sur des érythrocytes et/ou différents déterminants antigéniques se trouvant sur ladite substance spécifique, afin d'augmenter la sensibilité des compositions pour détecter et/ou quantifier ladite substance spécifique dans le sang, le plasma, le sérum ou d'autres liquides corporels. L'invention concerne en outre l'utilisation de telles compositions dans des combinaisons avec des anticorps réactifs auxdites substances spécifiques, mais pas aux érythrocytes, afin d'ajuster la sensibilité de la détection et/ou de la quantification de ladite substance antigénique spécifiée dans le sang, le plasma, le sérum ou d'autres liquides corporels. De tels anticorps, conjugués et/ou hybrides peuvent être d'origine monoclonale ou polyclonale. On peut employer cette invention en médecine vétérinaire et humaine à des fins de diagnostic.
PCT/NO1989/000021 1988-03-02 1989-03-01 Composition de detection et/ou de quantification simple de substances antigeniques dans des liquides corporels WO1989008261A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB888804933A GB8804933D0 (en) 1988-03-02 1988-03-02 Compositions for simple detection &/quantification of acute phase proteins in body liquids
GB8804933 1988-03-02
GB8903820.2 1989-02-20
GB8903820A GB2218100A (en) 1988-03-02 1989-02-20 Conjugates for the detection and/or quantification of antigenic substances in body fluids

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WO1989008261A1 true WO1989008261A1 (fr) 1989-09-08

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GB (1) GB2218100A (fr)
WO (1) WO1989008261A1 (fr)

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EP0602290A1 (fr) * 1992-12-04 1994-06-22 Philippe Pouletty Médicaments cellulaires à ancres
EP0431171B1 (fr) * 1989-04-25 1995-06-21 Iatron Laboratories, Inc. Anticorps monoclonal contre proteine c-reactive
US5500345A (en) * 1989-04-25 1996-03-19 Iatron Laboratories, Inc. Hybridomas producing monoclonal antibodies specific for C-reactive protein and methods for detection of C-reactive protein
EP1739430A2 (fr) * 2002-12-20 2007-01-03 Axis-Shield Asa Analyse CVD
CN105929173A (zh) * 2016-04-27 2016-09-07 深圳市国赛生物技术有限公司 一种血清淀粉样蛋白a的检测试剂盒及检测方法
CN106198993A (zh) * 2016-06-22 2016-12-07 浙江达美生物技术有限公司 一种降钙素原蛋白的测定试剂及其制备方法
CN106290907A (zh) * 2016-08-03 2017-01-04 宁波普瑞柏生物技术有限公司 全血中血清淀粉样蛋白a定量检测试剂以及检测方法

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US5474893A (en) * 1994-04-11 1995-12-12 Fang; Ta-Yun Spectrophotometry of amyloid degrading activity in serum or tissue

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0431171B1 (fr) * 1989-04-25 1995-06-21 Iatron Laboratories, Inc. Anticorps monoclonal contre proteine c-reactive
US5500345A (en) * 1989-04-25 1996-03-19 Iatron Laboratories, Inc. Hybridomas producing monoclonal antibodies specific for C-reactive protein and methods for detection of C-reactive protein
EP0602290A1 (fr) * 1992-12-04 1994-06-22 Philippe Pouletty Médicaments cellulaires à ancres
EP1739430A2 (fr) * 2002-12-20 2007-01-03 Axis-Shield Asa Analyse CVD
EP1739430A3 (fr) * 2002-12-20 2007-01-17 Axis-Shield Asa Analyse CVD
EP1573335B1 (fr) * 2002-12-20 2007-12-05 Axis-Shield Asa Dosage permettant d'indiquer un risque de maladie cardiovasculaire
US10101325B2 (en) 2002-12-20 2018-10-16 Sundrehagen, Erling, Dr. Determination method for calprotectin and the use of calprotectin as a predictive marker for cardiovascular disease
CN105929173A (zh) * 2016-04-27 2016-09-07 深圳市国赛生物技术有限公司 一种血清淀粉样蛋白a的检测试剂盒及检测方法
CN106198993A (zh) * 2016-06-22 2016-12-07 浙江达美生物技术有限公司 一种降钙素原蛋白的测定试剂及其制备方法
CN106290907A (zh) * 2016-08-03 2017-01-04 宁波普瑞柏生物技术有限公司 全血中血清淀粉样蛋白a定量检测试剂以及检测方法
CN106290907B (zh) * 2016-08-03 2018-07-06 宁波普瑞柏生物技术股份有限公司 全血中血清淀粉样蛋白a定量检测试剂以及检测方法

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GB2218100A (en) 1989-11-08
GB8903820D0 (en) 1989-04-05

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