EP0628084A1 - Anticorps monoclonaux et anticorps anti-idiotypes diriges contre le virus de l'hepatite c - Google Patents

Anticorps monoclonaux et anticorps anti-idiotypes diriges contre le virus de l'hepatite c

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Publication number
EP0628084A1
EP0628084A1 EP94904191A EP94904191A EP0628084A1 EP 0628084 A1 EP0628084 A1 EP 0628084A1 EP 94904191 A EP94904191 A EP 94904191A EP 94904191 A EP94904191 A EP 94904191A EP 0628084 A1 EP0628084 A1 EP 0628084A1
Authority
EP
European Patent Office
Prior art keywords
antibodies
under deposit
cell line
hepatitis
idiotypic
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Withdrawn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
EP94904191A
Other languages
German (de)
English (en)
Inventor
Winand Johannes Antonius Habets
Theodorus Adrianus Maria Oosterlaken
Mario Umberto Mondelli
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.)
Akzo Nobel NV
Original Assignee
Akzo Nobel NV
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Publication date
Application filed by Akzo Nobel NV filed Critical Akzo Nobel NV
Priority to EP94904191A priority Critical patent/EP0628084A1/fr
Publication of EP0628084A1 publication Critical patent/EP0628084A1/fr
Withdrawn legal-status Critical Current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
    • C07K16/42—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
    • C07K16/4216—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig against anti-viral Ig
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P21/00—Preparation of peptides or proteins
    • C07K16/118—
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/10—Cells modified by introduction of foreign genetic material
    • 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

Definitions

  • the present invention relates to monoclonal antibodies specifically immunoreactive with hepatitis C viral antigens, cell lines secreting said antibodies, an immunodiagnostic reagent comprising the antibodies, and a method and testkit for the detection of HCV.
  • the present invention further relates to anti-idiotypic antibodies, cell lines secreting said anti-idiotypic antibodies, immunodiagnostic reagents comprising said anti-idiotypic antibodies and a test-kit for the detection of anti-HCV antibodies in a sample, using antiidiotypic antibodies.
  • Hepatitis C virus is a 9.4-kb, single stranded polyadenylated RNA virus which has been recognized as one of the causative agents of NANB hepatitis (Non-A, Non-B). It causes acute and chronic liver disease and is implicated in hepatocellular carcinoma.
  • HCV hepatitis A virus
  • HBV hepatitis B virus
  • HDV hepatitis delta virus
  • HCV hepatitis induced by cytomegalovirus
  • EBV Epstein-Barr virus
  • Non-A, Non-B Hepatitis was first identified in transfused individuals. Transmission from man to chimpanzee and serial passage in chimpanzees provided evidence that Non-A, Non-B Hepatitis is due to a transmissible infectious agent or agents.
  • Non-A, Non-B Hepatitis exist: the water-borne epidemic type; the blood or needle associated type; and the sporadically occurring (community acguired) type.
  • the viral genome of HCV encodes a polyprotein of approximately 3010 amino acids that undergoes extensive posttranslational processing.
  • the viral structural region is located upstream from the nonstructural region and putatively includes a highly conserved 19-kDa nucleocapsid protein, and two extensively glycosylated envelope polypeptides, gp 33 (E1) and gp72 (E2/NS1).
  • HCV envelope may be under strong immune selection.
  • a variety of presumed nonstructural proteins are processed from the remainder of the HCV polyprotein, including a membrane-bound 23-kDa protein, NS2, and a soluble protein of approximately 60 kDa, NS3, which corresponds to the viral helicase and may contain a N-terminal serine protease domain, currently thought to be involved in the processing of the NS proteins.
  • the function of the NS4 protein is presently unknown, but it comprises the 5-1-1 fragment that contains immunodominant antibody binding sites (Kuo G.
  • NS5 contains the viral replicase.
  • Clinical studies have shown that, following exposure to HCV, antibodies to conserved regions of the viral nucleoprotein and NS3 may appear several weeks before seroconversion to anti-c100-3, a recombinant protein encompassing the C-terminus of NS3 and part of the NS4 protein.
  • serological assays incorporating the highly-conserved HCV nucleocapsid protein as well as NS3 are likely to become useful diagnostic markers of acute HCV infection. It is an object of the present invention to provide novel monoclonal antibodies that specifically react with the NS3 protein of the HCV virus and are particularly useful in immunodiagnostic tests for the detection of the presence or absence of HCV in clinical specimen.
  • the present invention provides monoclonal antibodies which bind to an epitope of the NS3 protein of hepatitis C virus, which epitope is specifically recognized by monoclonal antibodies secreted by the Epstein-Barr virus-transformed human lymphocyte-B cell line deposited at the European Collection of Animal Cell Cultures, Porton Down (UK) under deposit No. 92121609.
  • a preferred monoclonal antibody according to the invention is secreted by the Epstein-Barr virus-transformed human lymphocyte-B cell line deposited at the European Collection of Animal Cell Cultures, Porton Down (UK) under deposit No. 92121609.
  • Peptides comprising the NS-3 epitope recognized by the monoclonal antibodies according to this invention are described in the co-pending and co-owned Patent Application No. PCT/EP93/03478, the contents of which are incorporated herein by reference.
  • the above cell line has been deposited at the ECACC on 16 December 1992, under the terms and conditions of the Budapest treaty, 1977. Cell lines capable of excreting these monoclonal antibodies are also part of the present invention.
  • the preparation of cell lines producing monoclonal antibodies may occur by, for example, transformation with Epstein-Barr Virus, the
  • a preferred cell line according to the invention is an Epstein-Barr virus-transformed human lymphocyte-B clone cell line capable of excreting monoclonal antibodies which bind to an epitope on the NS3 protein of hepatitis C virus, which cell line is deposited at the European Collection of Animal Cell Cultures, Porton Down (UK), under deposit No. 92121609.
  • Epstein Barr virus is capable of transforming and immortalizing human Blymphocytes. With the aid of the Epstein Barvirus immortalized human B-lymphocytes can be obtained without the need of a myeloma partner cell.
  • Epstein Barr virus can be obtained from a variety of sources. The most common used source of EBV is the B95-8 marmoset cell line. The B95-8 cell line spontaneously releases Epstein Barr virus into the medium.
  • EBV transformed cells The most commonly used are peripheral blood mononuclear cells (PBMC) and fibroblasts.
  • PBMC peripheral blood mononuclear cells
  • fibroblasts The most commonly used are peripheral blood mononuclear cells (PBMC) and fibroblasts.
  • PBMCs consist of monocytes, T lymphocytes and B-lymphocytes (5-10%). Because not all Blymphocytes will provide antibodies of the right specificity, it is advantageous to enrich PBMCs for appropriate cells.
  • T-lymphocytes can be removed, prior to EBV infection (with, for example, the supernatant from the EBV-productive B95-8 cell line), by treating the cells with washed sheep red blood cells (In: "Antibodies Vol. I, a practicle approach", Editor: Catty D, IRL Press, Oxford,
  • Immortalized B cell lines according to the invention were considered monoclonal if they satisfied the following requirements:
  • the monoclonal antibodies according to the invention are extremely suitable to be used in so-called immuno-assays in order to detect HCV or HCV-fragments in a test sample.
  • An immunodiagnostic reagent comprising the antibodies according to the invention and a test kit for the detection of HCV in a sample are also part of the present invention.
  • the immunochemical reaction that takes place can be a so-called sandwich reaction, an agglutination reaction, a competition reaction or an inhibition reaction.
  • the test kit to be used comprises a monoclonal antibody according to the invention coated on a solid support, for example the inner wall of a microtest well, and either a labelled monoclonal antibody or fragment thereof as conjugate.
  • Supports which can be used are, for example, the inner wall of a microtest well or a cuvette, a tube or capillary, a membrane, filter, test strip or the surface of a particle such as, for example, a latex particle, an erythrocyte, a dye sol, a metal sol or metal compound as sol particle, a carrier protein such as BSA or KLH.
  • Labelling substances which can be used are, inter alia, a radioactive isotope, a fluorescent compound , an enzyme , a dye sol , metal sol or metal compound or other sol as sol particle.
  • a further example of an immuno assay that can be used for the detection of HCV is a inhibition assay using human monoclonal antibodies as labelled reagent. The binding of this reagent to antigen on a solid phase can be competed by antibodies in the test sample.
  • monoclonal antibodies according to the invention are very suitable in diagnosis, while those antibodies which are neutralizing are very useful in passive immunotherapy.
  • the monoclonal antibodies according to the invention can also be used to raise antiidiotypic antibodies.
  • Anti-idiotypic antibodies are antibodies directed to the variable part of immunoglobulins. A sub-population of anti-idiotypic antibodies is known as "anti-idiotypic ⁇ " or "internal images". These anti-idiotypic ⁇ antibodies have either a structural or a three dimensional resemblance with the antigen (Uytdehaag, F.G.C.M. et al.
  • the antiidiotypic antibodies can be raised in large amounts.
  • anti-idiotypic antibodies according to the invention can be obtained by immunizing BALB/c mice with monoclonal antibodies, coupled to KLH with glutaraldehyde according to standard literature procedures, mixed with Freund's complete adjuvant.
  • the spleen cells of these mice can be immortalized and the thus obtained hybridomas can be screened for anti-idiotypic antibody production.
  • Screening of the hybridomas can be performed, for example but not limited to, by binding a HCV peptide to a solid phase (wells of microtiter plates) and incubating the solid phase with culture supernatant of growing hybridomas and the monoclonal antibodies coupled to Horse Radish Peroxidase (HRP) according to our invention.
  • HRP Horse Radish Peroxidase
  • the presence of anti-idiotypic antibodies in culture supernatant will then be indicated by inhibition of the binding of the monoclonal antibodies according to our invention and the HCV peptide coated on the solid phase.
  • Anti-idiotypic antibodies reactive with the monoclonal antibodies according to the invention, as described above, are part of the present invention.
  • Anti-idiotypic antibodies can be used in mimicking antigen in a diagnostic test. Beside the use in diagnostic tests anti-idiotypic antibodies are also useful for prevention and/or treatment of Non-A, Non-B Hepatitis, as well as for the elucidation of important epitopic regions of HCV-antigens.
  • Preferred anti-idiotypic antibodies according to the present invention are the antiidiotypic antibodies secreted by the cell lines which are deposited at the European Collection of
  • Anti-idiotypic antibodies according to the invention preferably are anti-idiotypic antibodies capable of competing with an epitope for the binding to the monoclonal antibody according to the invention, where the epitope is the epitope recognized by the monoclonal antibodies secreted by the Epstein-Barr virus- transformed human lymphocyte-B cell line deposited with the European Collection of Animal Cell Cultures (ECACC), Porton Down (UK), under deposit No. 92121609.
  • ECACC European Collection of Animal Cell Cultures
  • UK Porton Down
  • Immunodiagnostic reagents comprising the anti-idiotypic antibodies according to the invention, and a test kit for the detection of anti-HCV antibodies in a sample using an immunodiagnostic reagent comprising antiidiotypic antibodies are also part of the present invention.
  • the preparation of cell lines producing anti-idiotypic antibodies may occur by, for example, transformation with Epstein-Barr Virus, the K ⁇ hler and Milstein technique (K ⁇ hler and Milstein devised the techniques that resulted in the formation monoclonal antibody-producing hybridomas (G. Köhler and C. Milstein, 1975, Nature 256:495-497; 1976, Eur. J. Immunol.
  • HCVID.OT2A under deposit No. 93122307
  • HCVID.OT2D under deposit No. 93122310
  • HCVID.OT2E under deposit No. 93122311, HCVID.OT2I under deposit No. 9312231
  • HCVID.OT2J under deposit No. 93122313
  • HCVID.OT2M under deposit No. 93122314
  • HCVID.OT2P under deposit No. 93122315
  • HCVID.OT2Q under deposit No.
  • HCVID.OT3A under deposit No. 93122317
  • HCVID.OT3D under deposit No. 93122318
  • HCVID.OT3E under deposit No. 93122319
  • HCVID.OT3H under deposit No. 93122320
  • HCVID.OT3L under deposit No. 93122321
  • HCVID.OT30 under deposit No. 93122322.
  • An immunodiagnostic reagent comprising the anti-idiotypic antibodies according to the invention and a test kit for the detection of HCV in a sample are also part of the present invention.
  • Example 1 illustrates the way in which a cell line, producing monoclonal antibodies, according to the invention may be derived.
  • Example 2 further exemplifies the specific immune reactivity of monoclonal antibodies according to the invention.
  • Example 3 exemplifies the production of anti-idiotypic antibodies and the specific ability of these anti-idiotypic antibodies to mimic a immunodominant NS-3 epitope.
  • EXAMPLE 1 Preparation of B-cell line clone.
  • Peripheral blood mononuclear cells (PBMC) were obtained from one patient with chronic HCV infection and circulating antibodies to the NS3 and nucleocapsid proteins of HCV but not to c100- 3/NS4(HCV 1st generation antibody test, Ortho Diagnostic Systems, Raritan, NJ) as shown by reactivity of the patient's serum with a commercial assay that incorporates a recombinant protein designated C22-3, the viral nucleoprotein, and the recombinant nonstructural protein c200 encoded by the NS3 and NS4 regions of the HCV genome (Ortho HCV ELISA Test System, 2nd generation).
  • PBMC peripheral blood mononuclear cells
  • RPMI-1640 medium containing 10% heat-inactivated pooled human serum, supplemented with 10% human endothelial culture supernatant (HECS) + 20 U/ml rIL6 and cultured in 25 cm2 flasks at the concentration of 4 x 10E6/ml in the presence of recombinant NS3 protein (Organon Teknika) at the concentration of 25, 125, and 625 ng/ml for 6 days at 37 °C in 5% CO2.
  • HECS human endothelial culture supernatant
  • lymphocytes-B After washing, cells were enriched in lymphocytes-B by removing lymphocytes-T with S- (2-amino-ethyl)-isothiouronium-bromide- hydrobromide treated sheep red blood cells and infected with supernatant from the EBV-productive B95-8 cell line as described in Cerino A et al. J. Immunol., 147, p2692, 1991.
  • IgG heavy and light (L) chains were determined as described in Cerino A et al. J.Tmiminol., 147, p2692, 1991. Briefly, B cell line supernatants were incubated on NS3 coated wells for 1 hour at 37 °C and, after washing, human IgG subclass-specific murine mAb were added for 1 hour followed by a peroxidase-conjugated rabbit anti-mouse Ig for another hour. To determine IgG L chains, peroxidase-conjugated rabbit anti-human Ig kappa- or lambda-chain were used in a direct assay. In both cases the reaction was developed with orthophenylen- diamine/2 HCl as substrate.
  • Recombinant immunoblot assay (RIBA II generation, Ortho Diagnostics). This is a nitrocellulose-based assay that includes 4 recombinant HCV antigens:
  • Sueernatant from clone HCVHU.OT3 was analyzed for specificity in the above described way.
  • Figure 1 illustrates the specific binding capacity of antibodies according to the invention.
  • the binding of the antibodies according to the invention (HCVHU.OT3) to different HCV derived proteins is compared with the binding of antibodies specific for HCV core and NS4 proteins respectively.
  • the monoclonal antibodies according to the invention (HCVHU.OT3) recognized a recombinant NS3 prctein preparation and gave a clear positive reaction in Ortho II generation assay, whereas no binding to recombinant HCV core and NS-5 proteins could be documented.
  • HCVHU.OT3 supernatant by recombinant immunoblot revealed clear binding to the c33c polypeptide only, further attesting to the specificity of the mAb as can be seen from figure 2, where lane 2 represents an antibody according to the invention (HCVHU.OT3).
  • Monoclonal human IgG (HCVHU.OT3) was purified from the culture supernatant of the cell-line deposited at the European Collection of Animal Cell Cultures, Porton Down (UK) under deposit No. 92121609. This IgG was conjugated to KLH (Oosterlaken T.A.M. et al., (1990) Scandinavian Journal of Immunology, 31, 159) mixed with Complete Freunds adjuvant or Quil A and injected into 4 mice and 4 rats. Immunizations were performed according to the scheme in table 1. After 2 immunizations the animal with the highest serum titer, one mouse and one rat, was used for making monoclonal antibodies, essentially as described in
  • Clones secreting putative anti-idiotypic antibodies were also detected with the assay described in figure 3. In this way 16 clones were obtained that reacted well in this assay.
  • the clones secreting putative anti-idiotypic antibodies were cultured and subcloned to 100% clonality according to standard procedures (Köhler, G. and Milstein, C.
  • the cell lines were grown in higher cell densities and cultured for 5 days in serumfree medium. Antibodies were purified from the culture supernatant using a Protein A-Sepharose R column. Purification was performed according to the manufacturers instructions (Pharmacia-LKB).
  • the anti-idiotypic antibodies were further analysed for their ability to mimic the NS-3 epitope recognized by the human monoclonal antibody HCVHU.OT3.
  • the purified monoclonal antibodies were conjugated to HRP with the Actizyme-peroxidase kit (Zymed laboratories). The procedure was performed according to the manufacturers instructions.
  • Serum dilutions or dilutions of HCVHU.OT3 were added to the wells followed by 1 hour incubation at 37 °C.
  • reaction with HCVHU.OT3 is shown as black bars
  • reaction with an irrelevant human monoclonal antibody with the same subclass as HCVHU.OT3 is shown as shaded bars.
  • Other monoclonal anti-idiotypic antibodies gave comparable results.
  • Table 3 shows the reactivity of human sera from HCV infected patients and normal controls with anti-idiotypic antibodies HCVID.OT2A and HCVID.OT2I.
  • N.R. normalised response, calculated as OD450 of serum sample divided by cut off value.
  • Figure 1 is a graph illustrating the binding specificity of monoclonal antibody HCVHU.OT3 for the NS3 protein.
  • Figure 2 is a photograph of a recombinant immunoblot assay.
  • the characters A-G represent the following proteins;
  • Lane 1 represents negative control serum
  • lane 2 represents an anti NS-3 monoclonal antibody (HCVHU.OT3)
  • lane 3 represents an anti-core monoclonal (HCVHU.OT2)
  • lane 4 represents polyclonal serum from a HCV- infected patient.
  • Figure 3 represents a screening procedure used for detection of anti-idiotypic antibodies against human monoclonal antibody HCVHU.OT3 in serum and in culture supernatant of monoclonal antibody producing cells.
  • Figure 4 represents an assay procedure used to validate putative anti-idiotypic antibodies which emerged from the screening procedure described in figure 3.
  • Figure 5 represents a sandwich assay (as shown in figure 4) to determine the specificity of 6 different anti-idiotypic antibodies (2A, 2B, 2I, 2P, 2Q and 3A) for HCVHU.OT3.
  • Reaction with HCVHU.OT3 is shown as black bars, reaction with an irrelevant human monoclonal antibody with the same subclass as HCVHU.OT3 is shown as shaded bars. Other monoclonal anti-idiotypic antibodies gave comparable results.

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Abstract

La présente invention concerne des anticorps monoclonaux réagissant, de façon immunitaire, spécifiquement avec les antigènes viraux de l'hépatite C, des lignées de cellules sécrétant lesdits anticorps, un réactif immunodiagnostique comprenant ces anticorps, ainsi qu'un procédé et un kit de test permettant de détecter le virus de l'hépatite C. L'invention concerne également des anticorps anti-idiotypes, des lignées de cellules sécrétant ces anticorps anti-idiotypes, des réactifs immunodiagnostiques comprenant lesdits anticorps anti-idiotypes, et un kit de test permettant la détection d'anticorps dirigés contre le virus de l'hépatite C, dans un échantillon, faisant appel auxdits anticorps anti-idiotypes.
EP94904191A 1992-12-29 1993-12-27 Anticorps monoclonaux et anticorps anti-idiotypes diriges contre le virus de l'hepatite c Withdrawn EP0628084A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP94904191A EP0628084A1 (fr) 1992-12-29 1993-12-27 Anticorps monoclonaux et anticorps anti-idiotypes diriges contre le virus de l'hepatite c

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP92204107 1992-12-29
EP92204107 1992-12-29
EP94904191A EP0628084A1 (fr) 1992-12-29 1993-12-27 Anticorps monoclonaux et anticorps anti-idiotypes diriges contre le virus de l'hepatite c
PCT/EP1993/003707 WO1994014974A1 (fr) 1992-12-29 1993-12-27 Anticorps monoclonaux et anticorps anti-idiotypes diriges contre le virus de l'hepatite c

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EP0628084A1 true EP0628084A1 (fr) 1994-12-14

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EP (1) EP0628084A1 (fr)
JP (1) JPH07504333A (fr)
KR (1) KR950700423A (fr)
AU (1) AU682335B2 (fr)
CA (1) CA2127797A1 (fr)
FI (1) FI943524A0 (fr)
WO (1) WO1994014974A1 (fr)
ZA (1) ZA939756B (fr)

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US6822563B2 (en) 1997-09-22 2004-11-23 Donnelly Corporation Vehicle imaging system with accessory control
JP3217600B2 (ja) * 1994-07-12 2001-10-09 株式会社先端生命科学研究所 非ａ非ｂ型肝炎ウイルス関連抗原のイムノアッセイ、それに使用するモノクローナル抗体、およびこの抗体を産生するハイブリドーマ
JP2002171972A (ja) * 1996-10-14 2002-06-18 Chemo Sero Therapeut Res Inst 肝炎ウイルスエピトープ
DE10112748A1 (de) * 2001-03-14 2002-09-19 Transmit Technologietransfer Erfindung betreffend HCV-Erkrankungen
WO2002082089A2 (fr) * 2001-04-03 2002-10-17 Immune Network Ltd. Anticorps anti-idiotypique et son utilisation dans le diagnostic et la therapie de maladies liees au virus de l'hepatite c
EP1504276B1 (fr) 2002-05-03 2012-08-08 Donnelly Corporation Systeme de detection d'objets pour vehicule
US7526103B2 (en) 2004-04-15 2009-04-28 Donnelly Corporation Imaging system for vehicle

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AU4046489A (en) * 1988-07-06 1990-02-05 Genelabs Incorporated Post-transfusion, non-a, non-b hepatitis virus and antigens

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See references of WO9414974A1 *

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ZA939756B (en) 1994-08-18
JPH07504333A (ja) 1995-05-18
FI943524L (fi) 1994-07-27
CA2127797A1 (fr) 1994-07-07
WO1994014974A1 (fr) 1994-07-07
KR950700423A (ko) 1995-01-16
FI943524A7 (fi) 1994-07-27
AU5834694A (en) 1994-07-19
FI943524A0 (fi) 1994-07-27
AU682335B2 (en) 1997-10-02

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