EP0551400A1 - Procede de traitement de l'inflammation en utilisant des anticorps anti-idiotypiques - Google Patents

Procede de traitement de l'inflammation en utilisant des anticorps anti-idiotypiques

Info

Publication number
EP0551400A1
EP0551400A1 EP91918758A EP91918758A EP0551400A1 EP 0551400 A1 EP0551400 A1 EP 0551400A1 EP 91918758 A EP91918758 A EP 91918758A EP 91918758 A EP91918758 A EP 91918758A EP 0551400 A1 EP0551400 A1 EP 0551400A1
Authority
EP
European Patent Office
Prior art keywords
icam
antibody
ab2β
binding
recited
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Withdrawn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
EP91918758A
Other languages
German (de)
English (en)
Other versions
EP0551400A4 (en
Inventor
Randall Barton
Michele 55 Wildman Street Czajkowski
Charles Kennedy
Robert Rothlein
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.)
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim Pharmaceuticals 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 Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim Pharmaceuticals Inc
Publication of EP0551400A1 publication Critical patent/EP0551400A1/fr
Publication of EP0551400A4 publication Critical patent/EP0551400A4/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2821—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against ICAM molecules, e.g. CD50, CD54, CD102
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C07K16/4208—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig
    • C07K16/4241—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig against anti-human or anti-animal Ig
    • C07K16/4258—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig against anti-human or anti-animal Ig against anti-receptor Ig
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a method for inhibiting ICAM-]-dependent inflammatory responses utilizing anti-ICAM-1 anti-idiotype antibodies or fragments thereof.
  • this invention relates to a method for treating ICAM-1-dependent inflammation in a patient by immunizing the patient with a sufficient amount of an anti-ICAM-1 anti-idotype antibody to induce an immune response against ICAM-1-bearing cells.
  • Cellular adhesion is a process through which leukocytes attach to cellular substrates, such as endothelial cells, in order to migrate from circulation to sites of ongoing in lammation, and properly defend the host against foreign invaders such as bacteria or viruses.
  • cellular substrates such as endothelial cells
  • This glycoprotein family is composed of heterodimers having one alpha chain (also referred to as "CD11") and one beta chain (also referred to as "CD18")
  • CD11 alpha chain
  • CD18 beta chain
  • Mac-1 is a heterodimer found primarily on macrophages, granulocytes and large granular lymphocytes.
  • LFA-1 is a heterodimer found on most lymphocytes (Springer, T.A. et aJL. Immunol. Rev. :1H-135 (1982)).
  • pl50,95 has a tissue distribution similar to Mac-1, and also plays a role in cellular adhesion (Keizer, G. e£. a ⁇ . , Eur. J. Immunol. 15:1142-1147 (1985)).
  • ICAM-1 interleukin-1
  • One method to inhibit or prevent ICAM-1 from binding to its CD18 receptors is to utilize a molecule which competes with the CD18 receptors for binding to ICAM-1.
  • One such competing molecule is an anti-ICAM-1 antibody.
  • Mouse monoclonal antibodies to ICAM-1 have been shown to inhibit lymphocyte proliferative response requiring cell/cell interactions as well as inhibiting granulocyte attachment and subsequent migration through endothelial cell monolayers in vitro.
  • Mouse anti-ICAM-1 antibodies are also known to inhibit leukocyte migration to inflamed lungs in rabbits, kidney allograft rejection and antigen-induced airway hyperreactivity in primates. See, e.g., Dustin et al, J. Immunol. 137:245 (1986) and egner et al Science 247:456 (1990).
  • mouse monoclonal anti-ICAM-1 antibodies has therapeutic potential because the mouse anti-ICAM-1 can attenuate an inflammatory response by binding to ICAM-1 and interfering with leukocyte adhesion.
  • treatment must be of short duration due to the innate immunogenicity of mouse immunoglobulin in primates.
  • Anti-idiotypic antibodies are antibodies raised against another (primary) antibody, which recognize unique epitopes on the primary antibody. Some anti-idiotypes actually mimic the epitope that the primary antibody is directed against.
  • certain anti-insulin anti-idiotypes act as agonists of the insulin receptor [Shechter et al, Anti-Idiotvpes, Receptors and Molecular Mimicry, p. 73 (D.S. Linthicum and N.R.
  • Certain anti-morphine anti-idiotypes will bind to opiate receptors (Ng et al, Eur. _, . Pharmacol. 102:187, 1984). Certain anti-viral anti-idiotypes have elicited an immune response to the virus where the host has been immunized with the anti-idiotype. (See, e.g., Gaulton et al. J. Immunol. 137:2930, 1986). U.S. Patent No. 4,918,164 describes anti-tumor anti-idiotypes and their use in immunotherapy and immunoprophylaxis. Monoclonal anti-CD18 anti-idiotypic antibodies have been described in Hildreth et al., Mol. Immunol. 26:1155 (1989).
  • This invention relates to a method for treating ICAM-1 dependent inflammation in a patient, which comprises adminstering to the patient a therapeutically effective dosage of an anti-ICAM-1 anti-idiotype (Ab2 ⁇ ) or a fragment thereof, wherein the Ab2 ⁇ or the fragment thereof, specifically recognizes an anti-ICAM-1 antibody (Abl) idiotype that inhibits the binding of ICAM-1 to the ICAM-1 receptor participating in the inflammation.
  • the Ab2 ⁇ has conformational homology with the antigenic epitope of ICAM-1. Because of this conformational homology (or internal image) , administration of the Ab2 ⁇ to the patient results in the elicitation of anti-Ab2 ⁇ antibodies (Ab3) in the patient. At least one Ab3 (Ab3') mimics the Abl.
  • the Ab3' will bind to the ICAM-1 and inhibit ICAM-1 function in adhesion, i.e., the Ab3' will inhibit ICAM-1 binding to the leukocyte receptor participating in the inflammation. As a result, the inflammation is reduced or eliminated.
  • the Abl und Ab2 ⁇ antibodies can be prepared using procedures known in the art for producing antibodies, e.g. by immunopurification of polyclonal serum, by hybridoma technology or by recombinant cell culture technology. See, e.g. Kohler et al, P.N.A.S. USA 77(4):2197 (1980) and U.S. Patent No. 4,816,567.
  • mice are initially immunized with ICAM-1. The mice are later sacrificed and their spleens removed. Spleen cells are fused with myeloma cells to produce hybridomas. The hybridomas are cultivated and their supernatants screened for anti-ICAM-1 activity, e.g. by radioimmunoassay (RIA) , enzyme-linked immunoassary (ELISA), or, preferably, by an aggregation assay as described in Rothlein et al. Hybridomas secreting monoclonal antibody (mAb) with the desired anti-ICAM-1 activity are cloned and cultivated to produce the Abl.
  • RIA radioimmunoassay
  • ELISA enzyme-linked immunoassary
  • Hybridomas secreting monoclonal antibody (mAb) with the desired anti-ICAM-1 activity are cloned and cultivated to produce the Abl.
  • the Ab2 ⁇ is a monoclonal antibody.
  • Monoclonal Ab2 ⁇ can be prepared in a manner similar to the preparation of monoclonal Abl. Mice are initially immunized with Abl. The mice are later sacrificed and their spleens removed. Spleen cells are fused with myeloma cells to produce hybridomas. The hybridomas are cultivated and their supernatants screened for anti-Abl activity, e.g., by ELISA or RIA. Hybridomas secreting Mab with the desired anti-Abl activity are cloned and cultivated to produce the Ab2 ⁇ .
  • Ab2 ⁇ can be administered to the patient.
  • administration of Ab2 ⁇ utilizes subcutaneous or intramuscular injection of the Ab2 ⁇ in the presence of various adjuvants.
  • the amount of Ab2 ⁇ to be administered will vary depending on the route of administration, type of inflammation, patient response, etc. but in general 0.1 mg to 100 mg of Ab2 ⁇ , preferably about 1 mg of Ab2 ⁇ , can be administered to the patient.
  • the Ab2 ⁇ can be formulated with a suitable adjuvant in order to enhance the immunological response, including e.g., mineral gels such as aluminium hydroxide; surface active substances such as lysolecithin; pluronic polyols; polyanions; peptides and oil emulsions.
  • a suitable adjuvant including e.g., mineral gels such as aluminium hydroxide; surface active substances such as lysolecithin; pluronic polyols; polyanions; peptides and oil emulsions.
  • Ab2B useful in this invention includes whole antibodies and fragments, or any chemical modifications thereof, which mimic the desired ICAM-1 binding site that binds to the idiotype of Abl.
  • Ab2 ⁇ fragments can be generated using various techniques known in the art, e.g., by proteolytic cleavage of the Ab2 ⁇ , or by recombinant construction. As an illustration of the present invention, the following examples are set forth in detail below:
  • R6.5 Monoclonal anti-ICAM-1 antibody R6.5 (hereinafter referred to as "R6.5”), produced by hybridoma cell line R6'506*E9'B2 (ATCC HB 9580), at a concentration of 1 mg/ml, was incubated with keyhole limpet hemocyanin (KLH) (Sigma Chemical, St. Louis, MO.) also at 1 mg/ml, with 0.05 % glutaraldehyde (Sigma) for two hours at room temperature and dialysed against phosphate buffered saline (PBS), to produce a KLH-R6.5 conjugate.
  • KLH keyhole limpet hemocyanin
  • PBS phosphate buffered saline
  • mice Six to eight week old femable Balb/c mice (Charles River Laboratories, Cambridge, MA.) were injected, intraperitoneally (i.p.), with 100 ⁇ g of the KLH-R6.5 conjugate in Complete Freunds Adjuvant (CFA) (Difco Labs) in a total of 0.4 ml per mouse. After three weeks mice were boosted with 100 ⁇ g of KLH-R6.5 conjugate with Incomplete Freunds Adjuvant (IFA) (Difco Labs) . The last boost (3 weeks later) was an i.p. injection of 5x10 R6.5 hybridoma cells (ATCC HB 9580) per mouse. Cells were irradiated, (1000R) before injection.
  • CFA Complete Freunds Adjuvant
  • IFA Incomplete Freunds Adjuvant
  • mice were sacrificed and spleens removed for fusion.
  • Spleen cells were fused with P3x63Ag8.653 myeloma cells at a ratio of 4:1 with PEG 4000 (VWR, Philadelphia, PA) .
  • the fusion mixture was aliquoted into 96-well microtiter plates (Costar, Cambridge, MA).
  • the resulting hybridoma supernatants were screened for anti-R6.5 activity by ELISA. Briefly, E.I.A.
  • the plates were than washed 4x with DPBS and the substrate, 2,2-Azino-di(3-ethylbenzthiozoline Sulfonic Acid) (ABTS) dissolved in 0.1 M citrate buffer, pH 4.2 and 0.03 % hydrogen peroxide (ZYMED, San Franzisco, CA) was added.
  • ABTS 2,2-Azino-di(3-ethylbenzthiozoline Sulfonic Acid)
  • ZYMED San Franzisco, CA
  • Optical density was read at 410 nM (Dynatech plate reader MR600) .
  • One hybridoma of interest was cloned and subcloned by limiting dilution.
  • the clone,, CA3/H10 secreted an IgG, class mAb (hereinafter referred to as "CA3”), as determined by Ouchterlony and ELISA.
  • CA3 2,2-Azino-di(3-ethylbenzthi
  • Pristine-primed Balb/c mice were injected i.p. with 5x 10 6 CA3/H10 cells in 0.5 ml of DPBS. Ascited tumor development was pronounced by day 14 after injection and mice were sacrificed by cervical dislocation. CA3-rich ascites fluid was collected and centrifuged to remove cells.
  • An E.I.A. microtiter plate was coated with R6.5 or normal mouse IgG F(ab') 2 , 1 ⁇ g/well, overnight at 4°C in DPBS.
  • the plates were washed 3x and blocked at 37°C for 1 hour with a 2 % bovine serum albumin (BSA) solution.
  • BSA bovine serum albumin
  • the BSA was then flicked out and replaced with 50 ⁇ l of soluble ICAM-1 (sICAM-1) (prepared as described in Marlin, S., et al. Nature 344, 70-72 (1990)) or control solution (25 ⁇ g/ml final concentration) and incubated for 30 minutes at 37°C.
  • sICAM-1 soluble ICAM-1
  • E.I.A. plates were coated with 1 ⁇ g/well of native or reduced sICAM-1 overnight at 4°C.
  • Reduced sICAM-1 was prepared by incubating native sICAM-1 prepared as described in Marlin, et al (supra), in 1M 2-merca ⁇ toethanol (final concentration) at room temperatur for 30 minutes.
  • a 2 % ovalbumin-coated plate (OA) was prepared as a negative control.
  • the plates were washed 3x with DPBS and blocked with 2 % OA for 1 hour at 37°C. Blocking solution was replaced with 50 ⁇ l/well of either 2 % OA, R3.1 (100 ⁇ g/ml, control IgGl) mAb (prepared as described in Smith et al, J.
  • Soluble ICAM-1 was run on an 8 % Laemmli SDS-polyacrylamide gel in a pH 6.9 sample buffer containing 6 % SDS, 4mM urea, 125 mM Tris, 4 mM EDTA, 0.25 % bromphenyl blue and 10 % glycerol.
  • sICAM-1 was loaded at a concentration of 5 ⁇ g per lane in a final volume of 150 ⁇ l and run for 16 hrs at 45 volts. Transfer to nitrocellulose membranes was performed at 4°C for 2 hrs.
  • Membranes were then washed 3x in TBST and incubated for 1 hour at room temperature with the appropriate anti-IgG alkaline phosphatase conjugated secondary antibody (Promega, Madison, WI.) .
  • Nitrocellulose membranes were again washed 3x in TBST and visualized with a solution containing 0.33 mg/ml nitroblue tetrazolium (NBT) , 0.16 mg/ml 5-bromo-4-chloro-3-indolyl phosphate (BCIP) , 100 mM Tris-HCL pH 9.5, 100 mM NaCl and 5 mM MgCl 2 .
  • NBT nitroblue tetrazolium
  • BCIP 5-bromo-4-chloro-3-indolyl phosphate
  • R6.5 was used at a concentration of 20 ⁇ l/ml as a positive control because it did not bind to reduced sICAM-1.
  • the membrane was washed with 400 ⁇ l of TBST and the appropriately diluted secondary anti-IgG alkaline phosphatase-conjugated antibody was added.
  • the membrane was then washed 3x with TBS to remove excess Tween-20 and color development was achieved by the addition of substrate containing NBT and BCIP. Color development was stopped by adding deionized water.
  • H RESULTS
  • the anti-ICAM-1 mAbs, R6.5 and RR1 have been shown to exhibit functional anti-adhesion properties.
  • the aggregation of cells from the human lymphoid cell line, JY is dependent upon the interaction of ICAM-1 and LFA-1 leukocyte adhesion molecules and antibodies to both LFA-1 and ICAM-1 inhibit aggregation (Rothlein et al.).
  • R6.5 and RR1 inhibited JY cell aggregation by 60 %;
  • CA3 blocked the ability of R6.5 but not of RR1 to inhibit JY cell aggregation.
  • CA3 as an immunogen.
  • the characterization of CA3 suggested that it shared conformation homology with the epitope bound by R6.5.
  • Rabbits were immunized with CA3 to induce a heterologous anti-antiidiotype (Ab3) response.
  • An IgG preparation of rabbit anti-CA3 sera was tested for binding to sICAM-1.
  • Figure 4 in an ELISA assay with solid phase sICAM-1, significant binding to ICAM-1 was detected at 200 ⁇ g/ml.
  • Comparison of binding to native and to reduced sICAM-1 in an immunoblot showed significant binding to reduced sICAM-1 at 10-fold lower IgG concentrations than was detected with native sICAM-1 (Fig. 5).
  • R6.5 bound to native sICAM-1 but no binding to reduced sICAM-1 was detected.
  • Western blot analysis supported the binding of anti-CA3 to reduced ICAM-1 which migrates, as expected, at an apparent higher molecular weight (Fig. 6).
  • Rabbit anti-CA3 was also tested for its ability to bind to cells expressing ICAM-1. As shown in Figure 7, rabbit anti-CA3 showed significant binding to JY cells which decreased with decreasing antibody concentration. That the binding of anti-CA3, like that of R6.5, was specific not only for ICAM-1 but also for the domains of the molecule that are functional in aggregation is indicated by the fact that the rabbit anti-CA3 inhibited JY cell aggregation.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

Procédé d'inhibition de réponse aux inflammatoires dépendant de ICAM-1 par immunisation d'un patient avec des anticorps anti-idiotypiques anti-ICAM-1 ou des fragments de ceux-ci. Les anticorps anti-idiotypiques anti-ICAM-1 sont également décrits et leur site de combinaison d'antigènes se lie à un idiotype d'un anticorps anti-ICAM-1 qui inhibe la liaison de ICAM-1 sur un récepteur de leukocytes de ICAM-1.
EP19910918758 1990-10-03 1991-10-02 Method for treating inflammation using anti-idiotypic antibodies Withdrawn EP0551400A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US59214790A 1990-10-03 1990-10-03
US592147 1990-10-03

Publications (2)

Publication Number Publication Date
EP0551400A1 true EP0551400A1 (fr) 1993-07-21
EP0551400A4 EP0551400A4 (en) 1993-10-13

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ID=24369494

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19910918758 Withdrawn EP0551400A4 (en) 1990-10-03 1991-10-02 Method for treating inflammation using anti-idiotypic antibodies

Country Status (5)

Country Link
EP (1) EP0551400A4 (fr)
JP (1) JPH06504426A (fr)
AU (1) AU8765391A (fr)
CA (1) CA2092801A1 (fr)
WO (1) WO1992006119A1 (fr)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6130202A (en) * 1990-07-20 2000-10-10 Bayer Corporation Antiviral methods
US6107461A (en) * 1990-07-20 2000-08-22 Bayer Corporation Multimeric forms of human rhinovirus receptor and fragments thereof, and method of use
US5629162A (en) * 1991-06-11 1997-05-13 The Center For Blood Research Method of identifying agents which modulate ICAM-3 binding to LFA-1
US5989843A (en) * 1992-01-27 1999-11-23 Icos Corporation Methods for identifying modulators of protein kinase C phosphorylation of ICAM-related protein
US6818743B1 (en) 1992-01-27 2004-11-16 Icos Corporation I-CAM related protein
JP3616090B2 (ja) * 1992-01-27 2005-02-02 イコス コーポレイション 細胞間接着分子関連タンパク質
US5837822A (en) * 1992-01-27 1998-11-17 Icos Corporation Humanized antibodies specific for ICAM related protein
US5525487A (en) * 1992-01-27 1996-06-11 Icos Corporation DNA encoding I-CAM related protein
US5532127A (en) * 1992-01-27 1996-07-02 Icos Corporation Assay for 1-CAM related protein expression
US6100383A (en) * 1992-01-27 2000-08-08 Icos Corporation Fusion proteins comprising ICAM-R polypeptides and immunoglobulin constant regions
US6153395A (en) * 1992-01-27 2000-11-28 Icos Corporation ICAM-related protein
US5869262A (en) * 1992-01-27 1999-02-09 Icos Corporation Method for monitoring an inflammatory disease state by detecting circulating ICAM-R
FR2858326A1 (fr) * 2003-08-01 2005-02-04 Abtech Procede de preparation d'anticorps mimetiques d'une substance et les anticorps ainsi obtenus

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4918164A (en) * 1987-09-10 1990-04-17 Oncogen Tumor immunotherapy using anti-idiotypic antibodies
ATE79270T1 (de) * 1989-03-09 1992-08-15 Boehringer Ingelheim Pharma Verwendung von interzellularen adhaesionsmolek¨len und deren bindungsliganden bei der behandlung von asthma.

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
IMMUNOLOGY vol. 67, no. 4, August 1989, OXFORD, GB pages 525 - 530 E. AUSTIN ET AL. 'Human monoclonal anti-idiotypic antibody to the tumour-associated antibody 791T/36.' *
MOLECULAR IMMUNOLOGY vol. 26, no. 12, 1989, OXFORD, GB pages 1155 - 1167 J. HILDRETH ET AL. 'Production and characterization of monoclonal anti-CD18 anti-idiotype antibodies.' *
See also references of WO9206119A1 *

Also Published As

Publication number Publication date
WO1992006119A1 (fr) 1992-04-16
EP0551400A4 (en) 1993-10-13
CA2092801A1 (fr) 1992-04-04
AU8765391A (en) 1992-04-28
JPH06504426A (ja) 1994-05-26

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