EP0656116A1 - Procede de controle de l'efficacite de la therapie par interferons chez des sujets atteints d'infection a virus de l'hepatite c - Google Patents

Procede de controle de l'efficacite de la therapie par interferons chez des sujets atteints d'infection a virus de l'hepatite c

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Publication number
EP0656116A1
EP0656116A1 EP93919871A EP93919871A EP0656116A1 EP 0656116 A1 EP0656116 A1 EP 0656116A1 EP 93919871 A EP93919871 A EP 93919871A EP 93919871 A EP93919871 A EP 93919871A EP 0656116 A1 EP0656116 A1 EP 0656116A1
Authority
EP
European Patent Office
Prior art keywords
hcv
gor
igm
igg
therapy
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Withdrawn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
EP93919871A
Other languages
German (de)
English (en)
Other versions
EP0656116A4 (fr
Inventor
Lieselotte Lennartz
Gerd Michel
Smriti U. Methta
Suhas Taskar
John M. Clemens
Larry T. Mimms
Kurt H. Chau
David S. Vallari
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Abbott Laboratories
Original Assignee
Abbott Laboratories
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Filing date
Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of EP0656116A1 publication Critical patent/EP0656116A1/fr
Publication of EP0656116A4 publication Critical patent/EP0656116A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • G01N33/576—Immunoassay; Biospecific binding assay; Materials therefor for hepatitis
    • G01N33/5767—Immunoassay; Biospecific binding assay; Materials therefor for hepatitis non-A, non-B hepatitis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • This invention relates generally to interferon therapy, and more particularly, relates to the monitoring of anti-HCV IgM or anti-GOR IgG in an individual's test sample as an indication of the clinical effectiveness and/or clinical outcome of interferon therapy used to treat an individual with chronic HCV infection.
  • NANBH non-A, non-B hepatitis
  • HCV Hepatitis C virus
  • NS-4 genomic region An immunodominant region designated as c-100, encoded by the putative nonstructural (NS)-4 genomic region, has been expressed, purified, and incorporated into immunoassays which are useful in the detection of antibody to HCV in infected test samples. See, for example, Q.-L. Choo et al., Science 244:359-362 (1989); H. J. Alter et al., N. Enpl. J. Med.
  • GOR4701 a cDNA clone designated as GOR4701, from the plasma of a chimpanzee experimentally infeted with NANBH agent.
  • S. Mishiro et al. Lancet 336:1400-1403 (1990).
  • the GOR-47-1 cDNA clone was shown to lack detectable sequence homology to known HCV sequences.
  • GOR gene is coded by a single-copy gene of host cellular sequence.
  • An EIA has been developed using a 27-amino acid synthetic peptide, spGOR2, deduced from the cDNA sequence of the GOR gene. Using this EIA.
  • Biochemical relapse is predicted by increasing serum ALT levels.
  • ALT elevation recurrence of HCV viremia as measured by PCR during or after interferon treatment is discussed as a possible predictor for relapse.
  • ALT elevations may not occur for several months after viremia recurrence. It is not clear at this time if changes in anti-HCV IgG levels are associaterd with IFN treatment.
  • the present invention provides a means for determining the effectiveness and/or possible clinical outcome of interferon therapy when it is used in individuals diagnosed with chronicHCV infection, or when interferon therapy is used as a treatment for an HCV infection. Briefly, test samples from an individual are taken before the start of interferon therapy and during the course of interferon therapy, and assayed for either anti-HCV IgM and/or anti-GOR IgG antibodies. A decrease in either anti-HCV IgM level or anti-COR IgG level in indicative of a clinical response to interferon therapy.
  • HCV antigens useful in these assays include HCV CORE, HCVp33c and HCV c-100. The most preferred antigen is HCV CORE.
  • These assays can include a solid phase to which HCV antigen is attached.
  • the solid phase selected can include polymeric or glass beads, nitrocellulose, microparticles, wells of a reaction tray, test tubes and magnetic beads.
  • the signal generating compound can include an enzyme, a luminescent compound, a chromogen, a radioactive element and a chemiluminescent compound. Examples of enzymes include alkaline phosphatase, horseradish peroxidase and beta-galactosidase.
  • enhancer compounds include biotin, anti-biotin and avidin.
  • enhancer compound binding members include biotin, anti-biotin and avidin.
  • the GOR antigen most preferred in this assay is GOR2.
  • These assays can include a solid phase to which GOR antigen is attached.
  • the solid phase selected can include polymeric or glass beads, nitrocellulose, microparticles, wells of a reaction tray, test tubes and magnetic beads.
  • the signal generating compound can include an enzyme, a luminescent compound, a chromogen, a radioactive element and a chemiluminescent compound.
  • enzymes include alkaline phosphatase, horseradish peroxidase and beta-galactosidase.
  • enhancer compounds include biotin, anti-biotin and avidin.
  • enhancer compound binding members include biotin, anti-biotin and avidin.
  • the test sample is subjected to conditions sufficient to block the effect of rheumatoid factor ⁇ like substances. These conditions comprise contacting the test sample with a quantity of anti-human IgG to form a mixture, and incubating the mixture for a time and under conditions sufficient to form a reaction mixture product substantially free of rheumatoid factor-like substance.
  • the present invention provides a means for determining the effectiveness of interferon therapy for individuals receiving such therapy for HCV infections.
  • the inventions comprises assaying for the presence of anti-GOR IgG and/or anti-HCV IgM and using these determinations to determine clinical effectiveness and/or clinical outcome of an individual.
  • the present invention employs an immunoassay which utilizes specific binding members.
  • a "specific binding member,” as used herein, is a member of a specific binding pair. That is, two different molecules where one of the molecules through chemical or physical means specifically binds to the second molecule. Therefore, in addition to antigen and antibody specific binding pairs of common immunoassays, other specific binding pairs can include biotin and avidin, carbohydrates and lectins, complementary nucleotide sequences, effector and receptor molecules, cofactors and enzymes, enzyme inhibitors and enzymes, and the like. Furthermore, specific binding pairs can include members that are analogs of the original specific binding members, for example, an analyte-analog.
  • Immunoreactive specific binding members include antigens, antigen fragments, antibodies and antibody fragments, both monoclonal and polyclonal, and complexes thereof, including those formed by recombinant DNA molecules.
  • hapten refers to a partial antigen or non-protein binding member which is capable of binding to an antibody, but which is not capable of eliciting antibody formation unless coupled to a carrier protein.
  • a “capture reagent”, as used herein, refers to an unlabeled specific binding member which is specific either for the analyte as in a sandwich assay, for the indicator reagent or analyte as in a competitive assay, or for an ancillary specific binding member, which itself is specific for the analyte, as in an indirect assay.
  • the capture reagent can be directly or indirectly bound to a solid phase material before the performance of the assay or during the performance of the assay, thereby enabling the separation of immobilized complexes from the test sample.
  • Test samples which can be tested by the methods of the present invention described herein include human and animal body fluids such as whole blood, serum, plasma, cerebrospinal fluid, urine, biological fluids such as cell culture supernatants, tissue specimens and cell specimens.
  • An enhancer can be used to detect the generated signal in the assay.
  • “enhancer” is meant a moiety which can bolster a signal generated in an immunoassay, thereby amplifying the generated signal.
  • a signal enhancer such as the use of avidin-biotin also is known.
  • U. S. Patent No. 4,228,237 to Hevey et al. describes the use of a biotin labelled specific binding substance for a ligand used in a method which also employs an enzyme labelled with avidin.
  • the use of a biotin- anti-biotin system is described in European Patent Application No. 160,900, published on November 13, 1985.
  • probe means a member of the specific binding pair attached to an “enhancer” compound.
  • An “enhancer” compound can be any compound used in the assay which can enhance the signal generated by the signal generating compound.
  • enhancer compounds include haptens such as biotin, and also include fluorescein, di-nitrophenol, and the like.
  • the indicator reagent comprises a signal generating compound (label) which is capable of generating a measurable signal detectable by external means conjugated (attached) to a specific binding member.
  • label a signal generating compound
  • Specific binding member means a member of a specific binding pair. That is, two different molecules where one of the molecules through chemical or physical means specifically binds to the second molecule.
  • the indicator reagent also can be a member of any specific binding pair, including either hapten-anti-hapten systems such as biotin or anti-biotin, avidin or biotin, a carbohydrate or a lectin, a complementary nucleotide sequence, an effector or a receptor molecule, an enzyme cofactor and an enzyme, an enzyme inhibitor or an enzyme, and the like.
  • An immunoreactive specific binding member can be an antibody, an antigen, or an antibody/antigen complex that is capable of binding either to HCV as in a sandwich assay, to the capture reagent as in a competitive assay, or to the ancillary specific binding member as in an indirect assay.
  • the indicator reagent comprises a signal generating compound conjugated to an enhancer-specific compound (enhancer compound binding member), such as biotin or anti-biotin, avidin or biotin, and others known to those skilled in the art.
  • an enhancer-specific compound such as biotin or anti-biotin, avidin or biotin, and others known to those skilled in the art.
  • the enhancer compound utilized is biotin, then anti-biotin, or avidin, can be used as the enhancer-specific compound.
  • the various signal generating compounds (labels) contemplated include a chromogen such as bromo-chloro-indole-phosphate (BCIP), catalysts such as enzymes, luminescent compounds such as fluorescein and rhodamine, chemiluminescent compounds such as acridinium, phenanthridinium or 1,2-dioxetane compounds, radioactive elements, and direct visual labels.
  • chemiluminescent compounds such as acridinium, phenanthridinium or 1,2-dioxetane compounds, radioactive elements, and direct visual labels.
  • enzymes include alkaline phosphatase, horseradish peroxidase, beta- galactosidase, and the like.
  • the selection of a particular label is not critical, but it will be capable of producing a signal either by itself or in conjunction with one or more additional substances, such as the use of enzyme substrates when enzymes are employed as the signal generating compound.
  • the reagent employed for the assay can be provided in the form of a kit with one or more containers such as vials or bottles, with each container containing a separate reagent such as a monoclonal antibody, or a cocktail of monoclonal antibodies, employed in the assay.
  • the assay configuration may involve the use of a solid phase in performance of the present invention.
  • a "solid phase”, as used herein, refers to any material which is insoluble, or can be made insoluble by a subsequent reaction.
  • the solid phase can be chosen for its intrinsic ability to attract and immobilize the capture reagent.
  • the solid phase can retain an additional receptor which has the ability to attract and immobilize the capture reagent.
  • the additional receptor can include a charged substance that is oppositely charged with respect to the capture reagent itself or to a charged substance conjugated to the capture reagent.
  • the receptor molecule can be any specific binding member which is immobilized upon the solid phase and which has the ability to immobilize the capture reagent through a specific binding reaction.
  • the receptor molecule enables the indirect binding of the capture reagent to a solid phase material before the performance of the assay or during the performance of the assay.
  • an assay device can have many configurations, several of which are dependent upon the material chosen as the solid phase.
  • the solid phase can include any suitable porous material.
  • porous is meant that the material is one through which the test sample can easily pass and includes both bibulous and non-bibulous solid phase materials.
  • the solid phase can include a fiberglass, cellulose, or nylon pad for use in a pour and flow-through assay device having one or more layers containing one or more of the assay reagents; a dipstick for a dip and read assay; a test strip for wicking (e.g., paper) or thin layer chromatographic or capillary action (e.g., nitrocellulose) techniques; or other porous or open pore materials well known to those skilled in the art (e.g., polyethylene sheet material).
  • the solid phase is not limited to porous materials.
  • the solid phase can also comprise polymeric or glass beads, microparticles, tubes, sheets, plates, slides, wells, tapes, test tubes, or the like, or any other material which has an intrinsic charge or which can retain a charged substance.
  • Natural, synthetic, or naturally occurring materials that are synthetically modified can be used as a solid phase including polysaccharides, e.g., cellulose materials such as paper and cellulose derivatives such as cellulose acetate and nitrocellulose; silica; inorganic materials such as deactivated alumina, diatomaceous earth, MgS ⁇ 4, or other inorganic finely divided material uniformly dispersed in a porous polymer matrix, with polymers such as vinyl chloride, vinyl chloride-propylene copolymer, and vinyl chloride-vinyl acetate copolymer; cloth, both naturally occurring (e.g., cotton) and synthetic (e.g., nylon); porous gels such as silica gel, agarose, dextran, and gelatin; polymeric films such as polyacrilamide; and the like.
  • the solid phase should have reasonable strength or strength can be provided by means of a support, and it should not interfere with the production of a detectable signal.
  • Preferred solid phase materials for flow-through assay devices include filter paper such as a porous fiberglass material or other fiber matrix materials.
  • the thickness of such material is not critical, and will be a matter of choice, largely based upon the properties of the sample or analyte being assayed, such as the fluidity of the test sample.
  • a charged substance can be coated directly to the material or onto microparticles which are then retained by a solid phase support material.
  • microparticles can serve as the solid phase, by being retained in a column or being suspended in the mixture of soluble reagents and test sample, or the particles themselves can be retained and immobilized by a solid phase support material.
  • retained and immobilized is meant that the particles on or in the support material are not capable of substantial movement to positions elsewhere within the support material.
  • the particles can be selected by one skilled in the art from any suitable type of particulate material and include those composed of polystyrene, polymethylacrylate, polypropylene, latex, polytetrafluoroethylene, polyacrylonitrile, polycarbonate, or similar materials.
  • the size of the particles is not critical, although it is preferred that the average diameter of the particles be smaller than the average pore size of the support material being used.
  • Solid supports are known to those in the art and include the walls of wells of a reaction tray, test tubes, polystyrene beads, magnetic beads, nitrocellulose strips, membranes, microparticles such as latex particles, chips of glass, plastic, derivatized plastic, metal and silicon, and others. Accordingly, a test sample which may contain HCV IgM is contacted with a solid support to which HCV antigen has been attached, to form a mixture. This mixture is incubated for a time and under conditions sufficient to form HCV antigen/antibody complexes. Then, a probe comprising a mammalian anti-human IgM to which an enhancer has been attached is contacted with the HCV antigen/antibody complexes, to form a second mixture.
  • This second mixture is incubated for a time and under conditions sufficient to form a second mixture reaction product.
  • an indicator reagent which comprises an enhancer compound binding member and a signal generating compound capable of generating a measurable signal is contacted with the second mixture reaction product .
  • This third mixture is incubated for a time and under conditions sufficient to form indicator reagent reaction products.
  • the presence and/or amount of HCV IgM is determined by detecting the signal generated.
  • the amount of HCV IgM present in the test sample is proportional to the signal generated.
  • Another assay comprises an assay wherein a test sample which may contain HCV IgM is contacted with a solid support to which HCV antigen has been attached, to form a mixture. This mixture is incubated for a time and under conditions sufficient to form HCV antigen/antibody complexes. Then, an indicator reagent which comprises a signal generating compound capable of generating a measurable signal attached to a specific binding member for HCV IgM is contacted with the complexes, to form a second mixture. This second mixture is incubated for a time and under conditions sufficient to form a reaction. The presence and/or amount of HCV IgM present in the test sample is determined by detecting the signal generated. The amount of HCV IgM present in the test sample is proportional to the signal generated.
  • a test sample is contacted with mammalian anti-human IgM which is coated on a solid phase, and reacted for a time and under conditions sufficient for human IgM/anti-human IgM complexes to form.
  • These complexes then are contacted with a probe which comprises at least one HCV antigen selected from HCV CORE, HCV 33c and HCV c-100 attached to an enhancer compound.
  • the preferred enhancer compound is biotin.
  • these complexes are contacted with an indicator reagent comprising a signal generating compound conjugated to an enhancer compound binding member.
  • the most preferred signal generating compound is the enzyme alkaline phosphatase.
  • the most preferred enhancer compound binding member is anti-biotin.
  • the resultant mixture is reacted for a time and under conditions sufficient for a reaction to occur. If an enzyme is utilized, the signal is detected and measured after addition of an enzyme substrate. The amount of HCV IgM present in the test sample is proportional to the signal generated.
  • anti-GOR IgG antibody also can be assayed and monitored during and after interferon therapy for HCV infection by using the assays disclosed hereinabove and substituting the appropriate GOR antigens.
  • An antibody test for GOR peptides utilizing the synthetic spGOR2 and spGOR346 peptides is known in the art and disclosed in S. U. Mehta et al., ,T f ⁇ lin. Tmmunology 12(3):178-184 (1992).
  • a test sample which may contain GOR IgG is contacted with a solid support to which GOR antigen has been attached, to form a mixture.
  • This mixture is incubated for a time and under conditions sufficient to form GOR antigen/antibody complexes.
  • a probe comprising a mammalian anti-human IgG to which an enhancer has been attached is contacted with the GOR antigen/antibody complexes, to form a second mixture .
  • This second mixture is incubated for a time and under conditions sufficient to form a second mixture reaction product.
  • an indicator reagent which comprises an enhancer compound binding member and a signal generating compound capable of generating a measurable signal is contacted with the second mixture reaction product .
  • This third mixture is incubated for a time and under conditions sufficient to form indicator reagent reaction products.
  • the presence and/or amount of GOR IgG is determined by detecting the signal generated.
  • the amount of GOR IgG present in the test sample is proportional to the signal generated.
  • Another assay comprises an assay wherein a test sample which may contain GOR IgG is contacted with a solid support to which GOR antigen has been attached, to form a mixture. This mixture is incubated for a time and under conditions sufficient to form GOR antigen/antibody complexes. Then, an indicator reagent which comprises a signal generating compound capable of generating a measurable signal attached to a specific binding member for GOR IgG is contacted with the complexes, to form a second mixture. This second mixture is incubated for a time and under conditions sufficient to form a reaction. The presence and/or amount of GOR IgG present in the test sample is determined by detecting the signal generated. The amount of GOR IgG present in the test sample is proportional to the signal generated.
  • a test sample is contacted with mammalian anti-human IgG which is coated on a solid phase, and reacted for a time and under conditions sufficient for human IgG/ anti-human IgG complexes to form.
  • These complexes then are contacted with a probe which comprises at least one GOR antigen selected from spGOR346 and spGOR2 attached to an enhancer compound.
  • the preferred enhancer compound is biotin.
  • these complexes are contacted with an indicator reagent comprising a signal generating compound conjugated to an enhancer compound binding member.
  • the most preferred signal generating compound is the enzyme alkaline phosphatase.
  • the most preferred enhancer compound binding member is anti-biotin.
  • the resultant mixture is reacted for a time and under conditions sufficient for a reaction to occur. If an enzyme is utilized, the signal is detected and measured after addition of an enzyme substrate. The amount of GOR IgG present in the test sample is proportional to the signal generated. Yet other assay configurations can be adapted to detect GOR IgG by practicing the teachings of this invention, and are contemplated to be within the scope of this invention.
  • test sample be treated such as to remove rheumatoid factor-like substances which may be present in the test sample and which may interfere with the performance of the assay.
  • treatment can be performed in a variety of ways known to those skilled in the art and include preadsorbing the test sample with protein A or protein G, heat aggregated IgG, and the subjection of the test sample to an amount of anti-human IgG sufficient to bind a substantial amount of the interfering rheumatoid factor-like substances.
  • the most preferred method for treating the test sample comprises diluting the test sample in a diluent sample buffer which contains an amount of goat anti- human IgG sufficient to bind the rheumatoid factor-like substances which may be present in the test sample.
  • This dilution step preferably is performed prior to contacting the test sample with the capture reagent, HCV antigen.
  • the preferred buffer is one which can remove any interfering IgG which may be present in the test sample.
  • buffers which contain a sufficient quantity of anti-IgG can be used as the diluent sample buffer. Examples of buffers that can be used in the assay include Tris buffered saline, phosphate buffered saline, and others known to those skilled in the art.
  • the most preferred buffer comprises a Tris buffered saline (pH 7.2) to which goat anti-human IgG has been added. Further, other compounds may be added to this buffer to block non-specific binding. The selection of these compounds depends upon the constituents chosen for the assay, and are within the ordinary skill of the artisan.
  • the origin of the mammalian anti-human IgM or anti-IgG may be goat, rabbit, sheep, or other mammalian anti-human IgM known in the art.
  • the mammalian origin of the anti-human IgM and anti-human IgG is goat.
  • HCV or GOR antigen When HCV or GOR antigen is used as a capture reagent in the assays described herein, at least one HCV or GOR antigen is used, either when attached to a solid phase or in solution.
  • HCV antigens include HCV CORE, HCV 33c and HCV c-100.
  • the GOR antigens include GOR2 and GOR 346.
  • HCV CORE is the most preferred antigen to utilize in performing the assay for detection of anti-HCV IgM antibodies , but that HCV 33c and HCV c-100 also can be used alone or in any combination.
  • HCV CORE antigen can be combined with HCV 33c and/or c-100, or other HCV antigens, and used as capture antigens in methods described herein.
  • a sandwich assay can be performed wherein a soluble capture reagent can include an analyte-specific binding member which has been bound to a charged substance such as an anionic substance.
  • the present invention also can be used to conduct a competitive assay.
  • the soluble capture reagent again includes a specific binding member which has been attached to a charged substance, such as an anionic polymer, with which to bind a specific binding partner.
  • the assay can be performed by scanning probe microscopy, in which an analyte, analyte analog or analyte specific substance which has been bound to a test piece, is contacted with the test sample suspected of containing the analyte, incubated for a time and under conditions sufficient for a reaction to occur, and then the presence of analyte is determined by using scanning probe microscopy.
  • Anti-HCV IgM was determined by utilizing a solid phase enzyme immunoassay ("IgM Combo", available from Abbott, GmbH Diagnostika, Weisbaden, Germany).
  • the anti-HCV IgM assay utilized recombinant antigens derived from the structural (core) and non-structural (NS3/NS4) part of the virus. These methods are detailed in Chau et al., J. Virol. Methods. 35:343-352, 1991).
  • the HCV antigens included clone cl00-3 (as described by Kuo et al., Science 244:362-364 [1989]) chimeric polypeptide expressed in yeast, plus recombinant HCV polypeptides expressed in E. coli that included those from pHCV-23 (clOO fragment, lacking the first 107 N-te ⁇ ninal amino acids), pHCV-29 (CKS-33c), pHCV-34 (CKS-CORE) and pHCV-35 ( ⁇ pL CORE), and pHCV-45 (NS4/NS5 junction).
  • the amino acids sequences of these HCV polypeptides are known in the art and are described in European Patent Application 0 388 232, published September 19, 1990 (see pages 32 and 34).
  • CKS CMP-KDO synthetase
  • Anti-HCV IgM results were expressed as specimen absorbance divided by mean absorbance (both absorbance measured at 492 nm) of three (3) negative controls (S/N). In 450 healthy blood donors, the mean S/N value was 1.0 ⁇ 0.5 (mean S/N ⁇ 1 standard deviation [SD]). Samples with S/N > 4 were characterized further for their IgM antigen specificity using single bead HCV IgM assays utilizing the HCV-Core, HCV-NS3 and HCV-NS4 antigens.
  • anti-HCV IgM (core) levels can predict response to IF therapy. It also was observed that decreasing anti-HCv IgM (core) levels can be an early indicator for relapse during and after IFN therapy. Also, it was observed that increasing anti-HCv IgM (core) levels can be an early indicator for relapse during and after IFN therapy. Finally, anti-HCv IgM can give additional diagnostic information in conjuction with ALT serum levels for patients with chronic hepatitis C infections.
  • Anti-HCV IgM was determined by utilizing a solid phase enzyme immunoassay ("IgM Combo", available from Abbott, GmbH Diagnostika, Weisbaden, Germany).
  • The. anti-HCV IgM assay utilized recombinant antigens derived from the structural (core) and non-structural (NS3/NS4) part of the virus. These methods are detailed in Chau et al., J. Virol. Methods. 35:343-352, 1991).
  • the HCV antigens included clone cl00-3 (as described by Kuo et al., Science 244:362-364 [1989]) chimeric polypeptide expressed in yeast, plus recombinant HCV polypeptides expressed in E. coli that included those from pHCV-23 (clOO fragment, lacking the first 107 N-te ⁇ ninal amino acids), pHCV-29 (CKS-33c), pHCV-34 (CKS-CORE) and pHCV-35 ( ⁇ pL CORE), and pHCV-45 (NS4/NS5 junction).
  • the amino acids sequences of these HCV polypeptides are known in the art and are described in European Patent Application 0 388 232, published September 19, 1990 (see pages 32 and 34).
  • HCV proteins were expressed as CMP-KDO synthetase (CKS) fusion proteins (as taught by T. J. Boiling and W. Mandecki, "An Escherichia coli expression vector for high-level production of heterologous proteins in fusion with CMP-KDO synthetase,” Biotechni ⁇ ues 8:488-490 [1990]), with the exception of pHCV-35, which was expressed in a lambda ( ⁇ ) pL expression system.
  • CKS CMP-KDO synthetase
  • Anti-GOR IgG and IgM levels were determined by the assay method for IgG described hereinabove and disclosed in S. U. Mehta et al., J. Clin. Immunol. 12 (3):178-183 (1992).
  • the appropriate rare reagents were those as described for the HCV IGM assay, but utilizing the synthetic peptides spGOR346 and spGOR2.
  • Non-responders numbered 22. It was observed that eight of eleven (73%) of CR showed decrease of anti-GOR IgG. Further, anti-GOR IgM was higher in NR than CR before therapy, while there were no significant changes in this value during therapy.
  • the amount of anti-HCV IgM pre-interferon therapy and/or anti-GOR IgG pre-interferon therapy is compared to the amount of of anti-HCV IgM pre-interferon therapy and or anti-GOR IgG pre-interferon therapy during therapy.
  • a decrease in the level of HCV IgM antibodies or anti- GOR IgG antibodies during therapy is an indication that the patient is responding to the interferon therapy.
  • dosages may be varied depending upon the results obtained by this monitoring.

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Abstract

L'invention se rapporte à un procédé de contrôle de l'efficacité de la thérapie par interférons chez les sujets infectés par le virus de l'hépatite C (VHC) et traités par cette thérapie. Contrôler le niveau d'IgM anti-VHC et/ou d'IgG anti-GOR permet de vérifier si le patient infecté réagit ou non à la thérapie par interférons; ce contrôle est particulièrement utile pour les patients chez lesquels on a diagnostiqué une infection chronique aiguë à VHC.
EP93919871A 1992-08-21 1993-08-03 Procede de controle de l'efficacite de la therapie par interferons chez des sujets atteints d'infection a virus de l'hepatite c. Withdrawn EP0656116A4 (fr)

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US93328392A 1992-08-21 1992-08-21
US933283 1992-08-21
PCT/US1993/007287 WO1994004922A1 (fr) 1992-08-21 1993-08-03 Procede de controle de l'efficacite de la therapie par interferons chez des sujets atteints d'infection a virus de l'hepatite c

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EP0656116A1 true EP0656116A1 (fr) 1995-06-07
EP0656116A4 EP0656116A4 (fr) 1997-04-02

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EP (1) EP0656116A4 (fr)
JP (1) JPH08500673A (fr)
AU (1) AU4996493A (fr)
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WO (1) WO1994004922A1 (fr)

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US5447650A (en) * 1993-10-06 1995-09-05 Allergan, Inc. Composition for preventing the accumulation of inorganic deposits on contact lenses
DE69513053D1 (de) * 1995-06-07 1999-12-02 Abbott Lab Igg/igm-verhältnis zur bestimmung der wirksamkeit von interferon therapie in einzelner mit hcv-infektionen
GB0326416D0 (en) 2003-11-12 2003-12-17 Karolinska Innovations Ab Methods and means relating to hepatitis B infection
AU2004290800B2 (en) * 2003-11-12 2009-07-16 Hbv Theranostica Ab Methods and means relating to hepatitis B infection

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US5191064A (en) * 1988-09-30 1993-03-02 The Research Foundation For Microbial Diseases (Osaka University) Non-a, non-b hepatitis virus antigen peptide

Non-Patent Citations (3)

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Title
HEPATOLOGY, vol. 14, no. 4, 1 October 1991, CHICAGO IL USA, page 74A. XP000614912 DD DOUGLAS ET AL: "Chronic hepatitis C response to interferon therapy: comparison of ALT normalization with anti-HCV IgM, anti-HCV IgG and HCV-RNA polymerase chain reaction." *
HEPATOLOGY, vol. 15, no. 6, 1 June 1992, CHICAGO IL USA, pages 998-1001, XP000614911 S. BRILLANTI ET AL.: "Significance of IgM antibody to Hepatitis C virus in patients with chronic hepatitis C." *
See also references of WO9404922A1 *

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WO1994004922A1 (fr) 1994-03-03
AU4996493A (en) 1994-03-15
CA2142872A1 (fr) 1994-03-03
EP0656116A4 (fr) 1997-04-02
JPH08500673A (ja) 1996-01-23

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