EP0640211A1 - Verfahren zum herstellen eines diagnostikums zum nachweis von entzündungen - Google Patents

Verfahren zum herstellen eines diagnostikums zum nachweis von entzündungen

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Publication number
EP0640211A1
EP0640211A1 EP93912276A EP93912276A EP0640211A1 EP 0640211 A1 EP0640211 A1 EP 0640211A1 EP 93912276 A EP93912276 A EP 93912276A EP 93912276 A EP93912276 A EP 93912276A EP 0640211 A1 EP0640211 A1 EP 0640211A1
Authority
EP
European Patent Office
Prior art keywords
protein
kit
substance
purified
preparing
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP93912276A
Other languages
English (en)
French (fr)
Inventor
Ernest K. J. Pauwels
R. I. J. Feitsam
Mick W. Welling
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mallinckrodt Inc
Original Assignee
Mallinckrodt Medical Inc
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 Mallinckrodt Medical Inc filed Critical Mallinckrodt Medical Inc
Priority to EP93912276A priority Critical patent/EP0640211A1/de
Publication of EP0640211A1 publication Critical patent/EP0640211A1/de
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1093—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody conjugates with carriers being antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
    • 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
    • G01N33/532—Production of labelled immunochemicals
    • 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
    • G01N33/532—Production of labelled immunochemicals
    • G01N33/534—Production of labelled immunochemicals with radioactive label
    • 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
    • G01N33/58—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
    • 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
    • G01N33/60—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances involving radioactive labelled substances

Definitions

  • the invention relates to a method of preparing a diagnostic agent for detecting and locating inflammations in a warm-blooded living being by attaching a detectable label to an immunospecific protein or proteinaceous substance.
  • the invention further relates to a diagnostic agent obtained by using said method, to a pharmaceutical composition comprising said diagnostic agent, to the use of said composition and to a kit for preparing said pharmaceutical composition.
  • Inflammations in the body of a warm-blooded living being cause many diseases and disorders, and may even turn out to be life-threatening.
  • the detection and location of the inflammation site(s) in an early stage is of the utmost importance.
  • a good diagnostic agent is also indispensable for supporting the therapy used.
  • Various requirements have to be imposed on such a diagnostic agent, for example, non-toxic, no adverse influence on the host resistance and/or therapeutic treatment, well detectable and selective.
  • the required high selectivity means that the diagnostic agent, after having been introduced into the body, must accumulate selectively at the site of the inflammation to be detected.
  • the diagnostic agent In order to be detectable from outside the body, the diagnostic agent should be labelled, preferably with a radionuclide or with a paramagnetic metal isotope. In the former case, the radioactive radiation can be detected by using a suitable detector (scanning). Modern techniques in this field use emission tomography; when gamma radiating isotopes are used, the so-called single photon emission computerized tomography (SPECT) may be applied.
  • SPECT single photon emission computerized tomography
  • the use of paramagnetic diagnostic agents enables a detection by means of imaging by magnetic resonance (magnetic resonance imaging).
  • European Patent Application 241 106 describes the use of labelled immunoglobulins or fragments thereof for diagnosing inflammations.
  • immunoglobulins tend to accumulate more strongly in the inflamed sites than in the non-inflamed sites.
  • labelled immunoglobulins may be used for diagnostic imaging. From the examples of said patent specification a notable preference of radioactive-labelled immunoglobulins indeed appears for accumulation in inflamed sites over uptake in non-inflamed sites of the body.
  • the selectivity i.e. the specific accumulation of the above-described labelled immunoglobulins in the inflamed sites
  • Selectivity is to be understood to mean the target-to-non- target ratio.
  • the locating of inflammations is disturbed in case these are present in certain sites of the body.
  • a good imaging in particular in an early stage of the inflammation, is disturbed so that a correct diagnosis is impeded. Therefore there exists a need for agents for diagnosing inflammations with a better selectivity than the above-described labelled immunoglobulins known for this purpose-
  • the present invention relates to a method of preparing a diagnostic agent as defined in the opening paragraph, and is characterized in that prior to the labelling procedure the protein or proteinaceous substance is purified by using a system comprising an anion exchange separating substance.
  • Suitable anion exchange separating substances which can be used for the method of the invention are, in particular, anion exchange resins.
  • anion exchange resins instead of bacterial proteins such as protein-A is advantageous in that no detrimental bacterial endotoxins or other pyrogens are applied by intravenous administration in a human being.
  • an example of a suitable system comprising an anion exchange resin is Mono- .
  • the purification is carried out by subjecting a solution of the protein or proteinaceous substance to be purified, preferably in a suitable aqueous buffer solution, to anion exchange chromatography.
  • said system comprising an anion exchange resin, is used as the immobile phase and the solution of the protein or proteinaceous substance as the mobile phase.
  • the purified protein or proteinaceous substance can be isolated and then be labelled at each desired instant.
  • the protein or proteinaceous substance should be labelled by attaching a detectable label thereto.
  • the detectable label may be a radionuclide, preferably selected from the group consisting of 1-123, 1-131 , Br-
  • Direct labelling of the protein with radioactive halogen can be carried out by reacting the protein with a suitable compound of the radionuclide in a preferably aqueous solution, if desired in the presence of an oxidant.
  • Suitable radioactive halogen compounds are radioactive alkali halogenides or radioactive halo-substituted aromates, such as tyrosine.
  • the direct labelling of the protein with a metal radionuclide has two disadvantages, via (i) that the biologically active site of the protein needed for a good selectivity can easily be blocked by said reaction so that the normal behaviour of the biologic macromolecule is disturbed, and (ii) that the affinity between metal isotope and macromolecule is often insufficient as a result of which the formed bond is insufficiently stable to remain intact under physiological conditions. Therefore in that case a reductive treatment of the protein, as suggested e.g. in European patent applications 237150 and 271806, is preferred. In such a pretreatment the disulphide bonds in the protein are reduced with a suitable agent, e.g.
  • dithiothreitol, dithioerythritol, 2-mercaptoethanol or 2-mercaptoeth ⁇ lamine after which the reduced protein, now comprising free mercapto groups, may be reacted with a salt or chelate of the desired metal isotope. Stabilization of the reduced protein or the final complex may be desired. It is generally recognized, however, that the reductive pretreatment of the protein may exert an unfavourable influence on the biological behaviour of the protein.
  • the protein or proteinaceous substance to be labelled is then first modified by treating with a coupling agent, after which the resulting protein conjugate is brought into a complexing reaction with a salt or chelate of the desired metal isotopes.
  • a coupling agent for example, N 2 S 2 -, N 3 S- or N 4 - T/US93/03586
  • N-containing di- or polyacetic acids or their derivatives such as EDTA, DTPA, NTA, etc.
  • amino-containing compounds such as the maleimide derivatives disclosed in the above EP 178125, peptide-derivatives, and compounds comprising chelating groups such as isocyanate, formyl, diazonium, isoth ⁇ ocyanate, alkoxycarbimidoyl groups and the like.
  • a coupling agent is preferred which is described in the above WO 89/07456 and which may generally be represented by the formula , - R - ⁇ ' ⁇ -_ s- Y-'' wherein
  • R is a branched or non-branched, optionally substituted hydrocarbyl radical, which may be interrupted by one or more hetero-atoms selected from N, 0 and S and/or by one or more NH groups
  • Y is a group which is capable of reacting with a functional group of the protein and which is preferably selected from the group consisting of carbonyl, carbimidoyl, N-CC,-C ⁇ ) alkylcarbimidoyl, N-hydroxycarbimido ⁇ l and
  • N-(C t -C ⁇ ) alkoxycarbimidoyl, or a water-soluble salt of this ring compound are substituted or unsubstituted 2-iminothiolanes and 2-iminothiac ⁇ clohexanes.
  • the modification of the protein or proteinaceous substance i.e. the reaction with the coupling agent resulting in the protein conjugate
  • the metal isotope is presented to the protein conjugate in the form of a salt or chelate.
  • relatively weak chelators are used, e.g. a phosphonate or polyphosphonate, an oxinate, a carboxylate, a hydroxycarboxylate, an aminocarboxylate or an enolate.
  • the desired complex is formed by ligand exchange.
  • the complex forming reactions can generally be carried out in a simple manner and under conditions which spare the protein or proteinaceous substance.
  • the above-mentioned labelling with Tc-99m in the presence of a borohydride can equally be carried out in a simple manner and under very moderate conditions, e.g. at room temperature.
  • the method of the invention relates more in particular to the preparation of a diagnostic agent for detecting and locating inflammations, by labelling human immunoglobulin, a subclass of human im unoglobulin or a suitable fragment of human immunoglobulin, said immunoglobulin (fragment) being purified by using a system comprising an anion exchange separating substance.
  • the invention further relates to a diagnostic agent obtained by using the method as defined above and to a pharmaceutical composition which comprises, in addition to a pharmaceutically acceptable carrier, a diagnostic agent obtained as defined above.
  • a pharmaceutical composition is intended for diagnostic application.
  • the composition so obtained can be brought into a form more suitable for intravenous or subcutaneous application, e.g. by adding a pharmaceutically acceptable liquid carrier material.
  • the solution should of course be in a sterile condition.
  • the composition for performing a diagnostic examination the composition, as described above, if desired after dilution with a pharmaceutically acceptable liquid, preferably a physiological saline solution, can be administered to a warm-blooded living being in a quantity sufficient for externally imaging said being to detect and locate an inflammation in said being.
  • a pharmaceutically acceptable liquid preferably a physiological saline solution
  • the radioactive material is generally administered to the living being in a quantity from 1 to 2000 MBq, preferably from 1 to 2000 MBq, preferably from 1 to 2000 MBq, preferably from
  • sterile and asterile inflammations can be detected by using the above compositions.
  • An example of the former is rheumascintigraphy; bacterial inflammations and abscesses are examples of asterile inflammations.
  • the invention also relates to a kit for preparing a radiopharmaceutical composition.
  • kit may comprise (i) an immunospecific protein or proteinaceous substance purified as described above, to which substance, if desired, an inert pharmaceutically acceptable carrier and/or formulating agents and/or auxiliary substances is/are added, (ii) a solution of a compound of a radionuclide, and (iii) instructions for use with a prescription for
  • the radionuclide is radioactive halogen, preferably a halogen compound as defined hereinbefore is used as an ingredient of the kit.
  • such a kit according to the present invention may comprise (i) a substance obtained by treating a human immuno-specific protein or proteinaceous substance purified as described above, with a suitable disulphide-reducing agent as defined hereinbefore, to which substance, if desired, an inert pharmaceutically acceptablecarrier and/or formulation agents and/or auxiliary substances is/are added, (ii) a solution of a salt or chelate of a metal-radionuclide, and (iii) instruction for use with a prescription for reacting the ingredients present in the kit.
  • a suitable carrier is a physiological saline solution.
  • auxiliary substances are stabilizers, antioxidants and filling agents. Suitable metal-radionuclides have been mentioned hereinbefore.
  • the desired radionuclide for this complex forming reaction prescribed may be presented to the reduced protein in the form of a chelate, bound to a comparatively weak chelator, in which the reaction may take place in a neutral environment, e.g. a buffered substantially aqueous solution.
  • the kit to be supplied to the user may also comprise the ingredient(s) defined sub (i) above, together with instructions for use, whereas the solution of the salt or chelate of the radionuclide, defined sub (ii) above, which solution has a limited shelf life, may be put to the disposal of the user separately.
  • kits may comprise, in addition to the ingredient(s) defined sub (i) above, (ii) a pertechnetate-reducing agent and, if desired, a chelator, and (iii) instructions for use with a prescription for reacting the ingredients of the kit with technetium-99m in the form of a pertechnetate solution.
  • the ingredients of the kit may be combined, provided they are compatible.
  • the kit should comprise a reducing agent to reduce the pertechnetate, for example, a dithionite, a metallic reducing agent or a complex- stabilizing reducing agent, e.g.
  • Sn(II)-tartrate,Sn(ll)-phosphonate or -pyrophosphate, or Sn(ll)-glucohe ⁇ tonate can simply be obtained by the user from a suitable generator. Examples of suitable chelators have been described hereinbefore.
  • the kit according to the present invention and intended for the preparation of a Tc-99m labelled composition comprises in addition a borohydride in a quantity effective for the labelling procedure.
  • the kit according to the present invention comprises, instead of a reduced protein or proteinaceous substance, a protein
  • SUBSTITUTE SHEET conjugate obtained by modifying an immunospecific protein or proteinaceous substance, purified as described hereinbefore, by a treatment with a coupling agent. Suitable coupling agents have been described hereinbefore. The use of a compound of the general formula . ⁇ -R- - .
  • the complex forming reaction with the protein conjugate can simply be produced by combining the components in a neutral medium and causing them to react.
  • the radionuclide is preferably presented to the protein conjugate in the form of a chelate bonded to a comparatively weak chelator.
  • Suitable chelators for the radionuclide are 8-h ⁇ droxquinoline or derivatives hereof; dicarboxylic acids, pol ⁇ carbox ⁇ lic acids or hydroxycarboxylic acids, for example, oxalic acid, malonic acid, succinic acid, maleic acid, orthophtalic acid, malic acid, lactic acid, tartaric acid, citric acid, ascorbic acid, salicylic acid or derivatives of these acids; pyrophosphates; phosphonates or polyphosphonates, for example, methylene diphosphonate, hydroxyethylene disphosph ⁇ nate or hydroxymethylene diphosphonate; or enolates, for example, with a ⁇ -diketone, for example, acetyl acetone, furoyl acetone, thenoyl acetone, benzoyl acetone, dibenzoyl methane, tropolone or derivatives of these diketones.
  • a chelate of a radionuclide for example, indium- 1 1 1 or lead-203, with one of these chelators in a suitable medium, preferably a buffered aqueous solution, easily reacts at a physiological pH with a protein conjugate as defined hereinbefore, the desired radionuclide complex being formed in a high yield and purity by ligand exchange.
  • a buffered aqueous indium-1 1 1- tropolonate solution which may be used for the desired complex formation and is suitable for this purpose is described in European patent application no.
  • the supplied kit may also consist of the constituent defined sub (1 ) with instructions for use, while the solution mentioned sub (2), which is bound to an expiration date, can be placed at the user's disposal separately.
  • the kit in addition comprises a borohydride
  • said borohydride is preferably NaBH 4 or NaBH 3 CN.
  • a quantity of 0.01-1 ug of borohydride is generally sufficient for labelling 0.1 mg of the protein or proteinaceous substance.
  • a pertechnetate-reducing agent is present in such a kit, e.g. Sn(ll).
  • the kit comprises a protein conjugate as defined hereinbefore and is intended for the preparation of a radiopharmaceutical composition, labelled with technetium-99m, the radionuclide will preferably be added separately in the form of a pertechnetate solution.
  • the kit will comprise a pertechnetate-reducing agent and, if desired, a chelator, the former to reduce the pertechnetate.
  • a pertechnetate-reducing agent may be used, for example, a dithionite or a metallic reducing agent.
  • the ingredients may optionally be combined, provided they are compatible.
  • Such a monocomponent kit, in which the combined ingredients are preferably freeze-dried, is excellently suitable for being reacted, by the user, with the radionuclide solution.
  • a metallic reducing agent for example, Sn(ll), Fe(ll), Cud), Ti(lll) or Sb(lll); Sn(ll) is excellently suitable.
  • the protein constituent of the above-mentioned kits may be supplied as a solution, for example, in the form of a physiological saline solution, or in some buffer solution, but is preferably present in a dry state, for example, in the freeze-dried state.
  • a physiological saline solution or in some buffer solution, but is preferably present in a dry state, for example, in the freeze-dried state.
  • sterile in which, when the constituent is in the dry state, the user should preferably use a sterile physiological saline solution as a solvent.
  • the above-mentioned constituent may be stabilized in the conventional manner with suitable stabilizers, for example, ascorbic acid, gentisic acid or salts of these acids, or it may comprise other auxiliary agents, for example, fillers, such as glucose, lactose, mannitol, an the like.
  • suitable stabilizers for example, ascorbic acid, gentisic acid or salts of these acids, or it may comprise other auxiliary agents, for example, fillers, such as glucose, lactose, mannitol, an the like.
  • This product is prepared from a lyophil ⁇ zed kit containing 1 mg 2- ⁇ minothiolane-mod ⁇ f ⁇ ed polyclonal human immunoglobulin and stannous tartrate, marketed by Mallinckrodt Medical B.V. under the registered :rade nameTechnescan HIG, and technetium-99m in the form of a pertechnetate solution, obtained from a molybdenum-technetium generator. ,
  • the above labelled human immunoglobulin (Ig) is purified by anion exchange chromatography by using a Mono C column. This column is regenerated with 100
  • the labelled protein is brought on the regenerated Mono CP* column and the protein is fixed on the column with a 20 mM TRIS solution.
  • the protein fractions are eluted from the column using mixtures of 25/75%, 50/50% and 0/100% of 20 mM TRIS and 1 M NaCI, resp.
  • the fractions obtained are injected in mice, infected with 2x10 7 CFU of St. Aureus 25923 in one thigh 18 hours before. After 15 minutes, 1 hour, 4 houri, and 24 hours, via a region of interest (ROD method, the ratios of injected-to- normal thigh are determined.
  • ROI method region of interest

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Physics & Mathematics (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Microbiology (AREA)
  • Cell Biology (AREA)
  • Food Science & Technology (AREA)
  • Biotechnology (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Optics & Photonics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Virology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
EP93912276A 1992-05-15 1993-04-15 Verfahren zum herstellen eines diagnostikums zum nachweis von entzündungen Withdrawn EP0640211A1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP93912276A EP0640211A1 (de) 1992-05-15 1993-04-15 Verfahren zum herstellen eines diagnostikums zum nachweis von entzündungen

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP92201390 1992-05-15
EP92201390 1992-05-15
PCT/US1993/003586 WO1993023743A1 (en) 1992-05-15 1993-04-15 Method of preparing a diagnostic agent for detecting inflammations
EP93912276A EP0640211A1 (de) 1992-05-15 1993-04-15 Verfahren zum herstellen eines diagnostikums zum nachweis von entzündungen

Publications (1)

Publication Number Publication Date
EP0640211A1 true EP0640211A1 (de) 1995-03-01

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EP93912276A Withdrawn EP0640211A1 (de) 1992-05-15 1993-04-15 Verfahren zum herstellen eines diagnostikums zum nachweis von entzündungen

Country Status (5)

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EP (1) EP0640211A1 (de)
JP (1) JPH07506830A (de)
AU (1) AU4288493A (de)
CA (1) CA2135882A1 (de)
WO (1) WO1993023743A1 (de)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19514088A1 (de) 1995-04-13 1996-10-17 Deutsches Krebsforsch Konjugat zur Behandlung von Entzünduns-, Infektions- und/oder Hauterkrankungen
RU2571486C1 (ru) * 2014-11-05 2015-12-20 Общество с ограниченной ответственностью "ДИАМЕД" Способ визуализации воспалений

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4323546A (en) * 1978-05-22 1982-04-06 Nuc Med Inc. Method and composition for cancer detection in humans
US4311688A (en) * 1979-10-29 1982-01-19 Serono Laboratories Inc. Composition and method for cancer detection in humans
US4472371A (en) * 1979-10-29 1984-09-18 Summa Medical Corporation Radiolabeled antibody to anti-tumor associated antigen and process
US4639513A (en) * 1984-02-02 1987-01-27 Cuno Inc. Intravenously injectable immunoglobulin G (IGG) and method for producing same
US5037630A (en) * 1985-01-14 1991-08-06 Neorx Corporation Metal radionuclide labeled proteins for diagnosis and therapy
US4859449A (en) * 1987-09-14 1989-08-22 Center For Molecular Medicine And Immunology Modified antibodies for enhanced hepatocyte clearance

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9323743A1 *

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JPH07506830A (ja) 1995-07-27
WO1993023743A1 (en) 1993-11-25
CA2135882A1 (en) 1993-11-25
AU4288493A (en) 1993-12-13

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