EP0538266A1 - PROCEDE DE DETECTION ET DE PREPARATION D'AUTOANTICORPS ANTI-IgE, ET UTILISATION DE CES ANTICORPS COMME AGENTS ACTIFS DANS DES COMPOSITIONS A USAGE THERAPEUTIQUE ET DIAGNOSTIQUE - Google Patents

PROCEDE DE DETECTION ET DE PREPARATION D'AUTOANTICORPS ANTI-IgE, ET UTILISATION DE CES ANTICORPS COMME AGENTS ACTIFS DANS DES COMPOSITIONS A USAGE THERAPEUTIQUE ET DIAGNOSTIQUE

Info

Publication number
EP0538266A1
EP0538266A1 EP91909250A EP91909250A EP0538266A1 EP 0538266 A1 EP0538266 A1 EP 0538266A1 EP 91909250 A EP91909250 A EP 91909250A EP 91909250 A EP91909250 A EP 91909250A EP 0538266 A1 EP0538266 A1 EP 0538266A1
Authority
EP
European Patent Office
Prior art keywords
ige
antibodies
autoantibodies
recombinant
carrier
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Withdrawn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
EP91909250A
Other languages
German (de)
English (en)
Inventor
Alain Ladislas De Weck
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.)
Individual
Original Assignee
Individual
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 Individual filed Critical Individual
Publication of EP0538266A1 publication Critical patent/EP0538266A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • C07K16/4291—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an allotypic or isotypic determinant on Ig against IgE
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • 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
    • G01N33/548—Carbohydrates, e.g. dextran
    • 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
    • G01N33/564—Immunoassay; Biospecific binding assay; Materials therefor for pre-existing immune complex or autoimmune disease, i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9
    • 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
    • G01N33/6854—Immunoglobulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/24—Immunology or allergic disorders

Definitions

  • the present invention concerns a method for detecting anti-Ige autoantibodies in bodyfluids, a method for preparing auto-anti-IgE antibodies and the use of these antibodies for diagnostic and therapeutic purposes.
  • anti-IgE autoantibodies have been described as rheumatoid factors and have been associated with disease ( Magnusson C.G.M., Vaerman J.P., Int.Arch.Allergy appl. Immunol. 79(1986), 149, Stevens W. J., Bridts CH., J.
  • Anti-IgE-autoantibodies were first described in 1972 (Williams R.C., Griffith R.W., Emmons J.D., Field R.C., J. Clin. Invest: 51(1972), 955-1003). Later such specific anti-IgE autoantibodies were reported in 1972 (Williams R.C., Griffith R.W., Emmons J.D., Field R.C., J. Clin. Invest: 51(1972), 955-1003). Later such specific anti-IgE autoantibodies were reported in 1972 (Williams R.C., Griffith R.W., Emmons J.D., Field R.C., J. Clin. Invest: 51(1972), 955-1003). Later such specific anti-IgE autoantibodies were reported in 1972 (Williams R.C., Griffith R.W., Emmons J.D., Field R.C., J. Clin. Invest: 51(1972), 955-1003
  • anti-IgE autoantibodies failed to trigger histamine release from blood basophils (Nakajima K., de Week A.L., Stadler B.M., Allergy
  • the object of the present invention is thus to provide a simple and reliable method for a quantitative detection of anti-IgE-autoantibodies.
  • An object of the present invention is also a method for distinction of functional categories of human anti-IgE-autoantibodies for an assessment of their function in allergic and other diseases associated with anti-IgE-autoantibodies.
  • Another object of the present invention is a method for the selection of human plasmas comprising anti-IgE-autoantibodies being useful for preparing therapeutic agents against allergic and other IgE
  • Another object of the present invention consists in providing a method for purification of anti-IgE autoantibodies having specific properties.
  • Another object of the present invention is the in-vivo production of selected anti-IgE-autoantibodies of desired properties by active immunisation by using selected recombinant IgE fragments.
  • the present invention comprises the subjects according to the definition in the appended claims.
  • auto-anti-IgE antibodies can be detected either in free form or in the form of IgE-IgG complexes. Their fine specifity can be located with the use of recombinant IgE fragments
  • Fig. 1a shows the principle of a direct assay for detection of anti-IgE antibodies.
  • Fig. 1b shows the principle of a sandwich assay for the detection of IgE/anti-IgE autoantibody immune complexes.
  • Fig. 1c shows the principle of a competitive assay for determining the specifity of anti-IgE
  • Fig 2. is a diagram corresponding to Table 4 which shows the intradermal reaction of Rh monkey to anti-IgE antibodies.
  • Fig. 3 is a diagram corresponding to Table 5 showing the effect of various human sera containing various amounts of anti-IgE antibodies on histamine release induced by Le27 moAb anti-IgE on "stripped" human basophils resensitized by rIgE (CH 1-4).
  • Fig. 4 is a diagram showing the effect of various sera containing various amounts of anti-IgE antibodies on Rhesus skin reaction to Le 27 moAb anti-IgE.
  • Fig. 5 is a diagram showing the effect of human anti-IgE antibodies (pool) purified by passage on
  • immunosorbent columns made of various rlgE (CH 1-4 or CH 3-4) on Le 27 induced skin reaction in Rhesus monkeys.
  • Fig. 6 is a diagramm showing the effect of human serum after treatment with mixtures of allergen/IgG anti- allergen (postr.) versus pretreatment serum (pretr,) and serum of a classically desensitized patient on histamine release induced by allergen.
  • Fig. 7 is a diagram showing the effect of serum of Rhesus immunized with rlgE (Immun.) versus
  • pretreatment serum and serum of Rhesus immunized with allergen on the histamine release induced by
  • IgE materials are deposited on the solid phase material, usually in the form of a 1 to 2 ⁇ l dot, at a concentration varying between 100 to 1000 ⁇ g/ml.
  • the strip (consisting preferably from PVC coated with
  • nitrocellulose is incubated with the serum sample to be investigated at a dilution of 1:1 to 1:10 for a period of 1 - 18 h. After suitable washings, the strip is
  • HRP horse radish peroxidase
  • monoclonal antibodies against IgG subclasses e.g. IgG1, 2, 3, 4
  • immunoglobulin classes e.g. A, M
  • This second incubation is usually for a period of 1 to 2 h and is followed by incubation with chromogen.
  • the preferred chromogen is a mixture of 2-4 chloronaphtol and hydrogen peroxide.
  • the ensuing blue dots may be measured quantitatively by a suitable refractometer.
  • the materials dotted are well defined monoclonal anti-IgE antibodies specific for various epitopes on the IgE molecule.
  • IgE peptides are first dotted on the solid phase. Following incubation with the serum sample to be investigated for 2 to 18 h and suitable washings, a second incubation occurs with selected HRP-labelled Anti-IgE monoclonal antibodies. If the serum sample comprises IgE antibodies of the same epitope specifity as the HRP labelled anti-IgE antibody, the reaction will be
  • auto-anti-IgE antibodies can also be used.
  • lymphocytes the killing effect on IgE bearing B
  • lymphocytes and the effect on IgE synthesis.
  • immunochemical assays provide a rational and efficient basis for different therapeutic approaches and development of corresponding therapeutic products, as illustrated below.
  • plasmas obtained by blood donation or plasmapheresis are screened for their content in anti-IgE free or complexed antibodies by the above-described immunochemical tests: According to their content in such antibodies and their specifity, they are pooled and tested also for some functional properties (e.g. histamine release).
  • the selected plasmas are then processed for preparing of immunoglobulin fractions by classical techniques in the art (e.g. alcohol fraction or ion exchange chromatography).
  • Example 4 Human plasmas obtained by plasmapheresis are submitted to the Immunodot test for detection of anti-IgE antibodies (Table 3) and/or sulfido leukotrienes. The plasmas are also investigated for their capacity to induce histamine release from human basophils (Table 3). The plasmas possessing no, low or high levels of anti- IgE-antibodies and no or high histamine releasing
  • anaphylactogenic anti-IgE antibodies will block the effect of anaphylactogenic anti-IgE antibodies (Table 5 and the corresponding Fig. 3 ). A similar inhibiting effect of Ig preparations can be observed on the
  • sheep anti-IgE antibodies directed against human IgE have also the property to kill IgE-bearing cells which express the IgE receptor (CD 23).
  • some human anti-IgE antibodies possess similar potential in vitro, presumably exerting thereby an inhibiting effect on IgE synthesis in vivo.
  • Plasmas containing anti-IgE antibodies selected by the Immunodot test described above are passed over chromatography columns prepared with recombinant IgE-fragments.
  • the Ig preparations are then processed according to techniques well known in the art.
  • Ig preparations show in functional tests in humans and monkeys (Fig. 5) the desired protective properties, in preventing allergic reactions.
  • the preparation of purified auto-anti-IgE antibodies obtained from selected plasmapheresis and passed over appropriate IgE recombinant peptide columns is able to block histamine release from leukocytes of allergic patients challenged by allergen or anti-IgE. It is also capable of blocking the histamine release from leukocytes first "stripped" of their own IgE by acid treatment, reloaded with with recombinant IgE fragment and
  • IgG antibodies specific for allergen such as encountered spontaneously in some highly allergic patients or raised by repeated injections of allergen during hyposensitization therapy are
  • IgG anti-IgE complexed to allergen-specific IgE and allergen induces in allergic patients the beneficial immunological changes associated with immunotherapy. Since, as seen above, the functional effects of IgG auto anti-IgE may be very different according to their fine specifity, it became imperative to evaluate these therapeutic methods in terms of specific anti-IgE-antibodies.
  • Plasmas from hypersensitized patients are selected on the basis of their apparent IgG specifity for allergens (e.g. such as grass pollen), on the basis of allergen-specific IgG tests and analyzed for the presence of auto-anti-IgE antibodies.
  • allergens e.g. such as grass pollen
  • Plasma pools rich or devoid of auto-anti-IgE antibodies are used as source of immunoglobulin
  • This technique can in principle be used also for fostering other immune responses which may rest upon IgE activities, such as the immune defense against some parasites.
  • the presence of blocking antibodies for IgE has been for example described in filiarosis.
  • IgE-vaccine recombinant fragments, in order to raise beneficial anti- IgE antibodies in allergic patients
  • Anti-IgE antibodies of the desired specifity having the desired blocking anti-allergic activity can be produced actively.
  • Example 7 Recombinant IgE peptides of various sizes and encompassing various domains of the IgE heavy chain are produced according to combinations of procedures known in the art.
  • the antibodies raised have the functional properties required, based on the previous analysis of similar but naturally occurring human auto- anti-IgE antibodies. In particular, these antibodies are able to recognize IgE and IgE fragments. These antibodies have also the capacity to block histamine release induced by anaphylactogenic anti-IgE monoclonal antibodies or allergen (Fig. 7).
  • Table 7 Schedule and amounts of allergen and antibody to be used as complexes for hyposensitization therapy
  • allergen-specific "IgG antibodies” which contain as well antiallergen IgE complexed with IgG anti-IgE autoantibodies.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Biomedical Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Food Science & Technology (AREA)
  • General Physics & Mathematics (AREA)
  • Cell Biology (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biotechnology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Microbiology (AREA)
  • Pathology (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Rheumatology (AREA)
  • Rehabilitation Therapy (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Selon un procédé de détection d'autoanticorps libres ou complexes dirigés contre l'IgE, des échantillons, en particulier de sang humain, sont mis en contact et incubés avec du matériau contenant de l'IgE sous la forme d'anticorps d'IgE, de peptides d'IgE ou de fragments d'IgE recombinés fixés sur un véhicule solide. Le procédé peut être effectué sous forme d'un dosage direct, d'un dosage en sandwich ou d'un dosage compétitif. Le procédé peut être utilisé pour préparer des anticorps humains antiallergiques dirigés contre l'IgE et faisant preuve d'une activité de blocage thérapeutique en ce qui concerne les affections allergiques. Selon ce procédé, un fluide corporel humain contenant des autoanticorps anti-IgE est choisi selon le processus décrit ci-dessus, et l'immunoglobuline contenue dans le fluide est concentrée, de préférence par fractionnement à l'alcool ou par chromatographie par échange d'ions. Afin d'obtenir des autoanticorps anti-IgE purs, l'on isole ceux-ci à partir du produit concentré par chromatographie par affinité. Les anticorps anti-IgE et des complexes de ceux-ci sont utilisés comme principes actifs dans des compositions pharmaceutiques destinées au traitement d'affections allergiques. La formation d'autoanticorps anti-IgE peut être induite in vivo par des peptides d'IgE ou des fragments d'IgE recombinés.
EP91909250A 1991-05-10 1991-05-10 PROCEDE DE DETECTION ET DE PREPARATION D'AUTOANTICORPS ANTI-IgE, ET UTILISATION DE CES ANTICORPS COMME AGENTS ACTIFS DANS DES COMPOSITIONS A USAGE THERAPEUTIQUE ET DIAGNOSTIQUE Withdrawn EP0538266A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PCT/EP1991/000881 WO1992021031A1 (fr) 1991-05-10 1991-05-10 PROCEDE DE DETECTION ET DE PREPARATION D'AUTOANTICORPS ANTI-IgE, ET UTILISATION DE CES ANTICORPS COMME AGENTS ACTIFS DANS DES COMPOSITIONS A USAGE THERAPEUTIQUE ET DIAGNOSTIQUE
CA002086605A CA2086605A1 (fr) 1991-05-10 1991-05-10 Methodes de detection et de preparation des auto-anticorps anti-ige et utilisation de ces anticorps comme agents actifs dans des compositions diagnostiques et therapeutiques

Publications (1)

Publication Number Publication Date
EP0538266A1 true EP0538266A1 (fr) 1993-04-28

Family

ID=4150928

Family Applications (1)

Application Number Title Priority Date Filing Date
EP91909250A Withdrawn EP0538266A1 (fr) 1991-05-10 1991-05-10 PROCEDE DE DETECTION ET DE PREPARATION D'AUTOANTICORPS ANTI-IgE, ET UTILISATION DE CES ANTICORPS COMME AGENTS ACTIFS DANS DES COMPOSITIONS A USAGE THERAPEUTIQUE ET DIAGNOSTIQUE

Country Status (4)

Country Link
EP (1) EP0538266A1 (fr)
JP (1) JPH05508220A (fr)
CA (1) CA2086605A1 (fr)
WO (1) WO1992021031A1 (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19505266C1 (de) * 1995-02-16 1996-10-02 Brahms Diagnostica Gmbh Verwendung von polyklonalen humanen anti-hTg-Autoantikörpern als Reagenz für die klinische Diagnostik von Schilddrüsen-Autoimmunerkrankungen sowie Reagenziensatz für eine Bestimmung von anti-hTg-Autoantikörpern in Patientenseren
EP1671646A3 (fr) * 1998-09-18 2007-08-29 Dynavax Technologies Corporation Procédés de traitement de troubles associés à IgE et compositions pouvant être utilisées à cet effet.
ES2259478T3 (es) * 1998-09-18 2006-10-01 Dynavax Technologies Corporation Metodos para tratar trastornos asociados con la ige y composiciones para este uso.
US6787524B2 (en) 2000-09-22 2004-09-07 Tanox, Inc. CpG oligonucleotides and related compounds for enhancing ADCC induced by anti-IgE antibodies
JP2007524096A (ja) * 2004-02-26 2007-08-23 アルカベロ アクチェセルスカプ 粘膜投与用ワクチンの治療可能性の評価方法
EP1902320B1 (fr) * 2005-05-20 2010-03-10 Genentech, Inc. Préparation d'échantillon biologique prélevé sur un sujet souffrant de maladie auto-immune
MX2009010765A (es) * 2007-04-02 2009-10-26 Amgen Fremont Inc Anticuerpos anti-ige.
JP5504945B2 (ja) * 2010-02-12 2014-05-28 日東紡績株式会社 Ｆｔｃｄとその自己抗体との複合体の免疫測定方法、それに用いるキット及びそれを用いた癌判定方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9221031A1 *

Also Published As

Publication number Publication date
WO1992021031A1 (fr) 1992-11-26
CA2086605A1 (fr) 1992-11-11
JPH05508220A (ja) 1993-11-18

Similar Documents

Publication Publication Date Title
US5342924A (en) Extracellular segments of human ε immunoglobulin anchoring peptides and antibodies specific therefor
Lindstrom Immunobiology of myasthenia gravis, experimental autoimmune myasthenia gravis, and Lambert-Eaton syndrome
DE69931377T2 (de) Verfahren zur behandlung von ig-e assozierten krankheiten und zusammensetzungen zur verwendung in diesen verfahren
AU648022B2 (en) Monoclonal antibodies for metallic cations on small molecules
JP3421970B2 (ja) ペプチド免疫原
CA2074089C (fr) Segments extracellulaires des peptides d'ancrage de l'immunoglobuline e humaine, et anticorps specifiques
DE102005029845B4 (de) Verfahren zur Diagnose von rheumatischen Erkrankungen
US5254671A (en) Extracellular segments of human e immunoglobulin anchoring peptides and antibodies specific therefor
CA2158047C (fr) Proteine et peptides allergenes provenant d'acariens detriticoles; leur utilisation
JPH11513025A (ja) アレルゲン−ｘｃｄ３２融合タンパク質
EP0538266A1 (fr) PROCEDE DE DETECTION ET DE PREPARATION D'AUTOANTICORPS ANTI-IgE, ET UTILISATION DE CES ANTICORPS COMME AGENTS ACTIFS DANS DES COMPOSITIONS A USAGE THERAPEUTIQUE ET DIAGNOSTIQUE
Mazur et al. A common epitope on major allergens from non-biting midges (Chironomidae)
EP0517817B1 (fr) Inhibiteurs d'anticorps catalytiques
JPH10509948A (ja) Ｔ細胞受容体ペプチドに対するヒト抗体およびそれらの調製方法
Thomas et al. Heterogeneity and specificity of human anti-insulin antibodies determined by isoelectric focusing.
US20030007973A1 (en) Methods and compositions for manipulation of the immune response using anti-metallothionein antibody
Katz-Levy et al. Single amino acid analogs of a myasthenogenic peptide modulate specific T cell responses and prevent the induction of experimental autoimmune myasthenia gravis
KR101156523B1 (ko) 아토피성 피부염 유도 물질
Hemmens et al. Common antigenic and allergenic determinants on codfish proteins detected with mouse monoclonal IgG and human IgE antibodies
AU2002242273C1 (en) Compositions of multimeric profilin for diagnosis and treatment of allergies
Mourad et al. Mapping of Lol PI allergenic epitopes by using murine monoclonal antibodies
Jackson et al. Presence of plasma cells binding autologous antibody during an immune response.
Griot-Wenk et al. Characterization of two dog IgE-specific antibodies elicited by different recombinant fragments of the epsilon chain in hens
Mourad et al. Characterization of anti-idiotypic antibodies and their use as probes for determination of shared idiotopes expressed on murine and human IgE anti-rye I antibodies.
Boutin et al. Mapping of cat albumin using monoclonal antibodies: identification of determinants common to cat and dog.

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE

17P Request for examination filed

Effective date: 19930514

17Q First examination report despatched

Effective date: 19950124

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19960622