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WO1993013127A1 - Peptides immunochimiquement reactifs avec des anticorps diriges contre le virus de l'hepatite non a, non b - Google Patents

Peptides immunochimiquement reactifs avec des anticorps diriges contre le virus de l'hepatite non a, non b Download PDF

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Publication number
WO1993013127A1
WO1993013127A1 PCT/EP1992/002998 EP9202998W WO9313127A1 WO 1993013127 A1 WO1993013127 A1 WO 1993013127A1 EP 9202998 W EP9202998 W EP 9202998W WO 9313127 A1 WO9313127 A1 WO 9313127A1
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WO
WIPO (PCT)
Prior art keywords
hcv
peptide
peptides
antibodies
amino acid
Prior art date
Application number
PCT/EP1992/002998
Other languages
English (en)
Inventor
Winand Johannes Antonius Habets
Jan Albert Hellings
Original Assignee
Akzo Nobel N.V.
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 Akzo Nobel N.V. filed Critical Akzo Nobel N.V.
Priority to EP93902132A priority Critical patent/EP0621868A1/fr
Priority to JP5511439A priority patent/JPH07502996A/ja
Publication of WO1993013127A1 publication Critical patent/WO1993013127A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K4/00—Peptides having up to 20 amino acids in an undefined or only partially defined sequence; Derivatives thereof
    • C07K4/02—Peptides having up to 20 amino acids in an undefined or only partially defined sequence; Derivatives thereof from viruses
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—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
    • 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
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/24011—Flaviviridae
    • C12N2770/24211—Hepacivirus, e.g. hepatitis C virus, hepatitis G virus
    • C12N2770/24222—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • the invention relates to peptides which react immunochemically with antibodies directed against hepatitis C (HCV) and nucleic acid sequences encoding these peptides.
  • HCV hepatitis C
  • the invention further relates to a method for the detection of HCV or anti-HCV antibodies in a test fluid, and to an immunochemical reagent and a test kit which may be used in said detection method.
  • Non-A Non-B hepatitis which is most probably caused by the HCV virus is a transmissable disease or family of diseases shown to be virus-induced. It can be distinguished from other forms of viral-associated liver diseases, including that caused by the known hepatitis viruses, i.e., hepatitis A virus (HAV) , hepatitis B virus (HBV) , delta hepatitis virus (HDV) , and hepatitis induced by cytomegalovirus (CMV) or Epstein-Barr virus (EBV).
  • HAV hepatitis A virus
  • HBV hepatitis B virus
  • HDV delta hepatitis virus
  • EBV Epstein-Barr virus
  • NANBH was first identified in transfused individuals. Transmission from man to chimpanzee and serial passage in chimpanzees provided evidence that NANBH is due to a transmissible infectious agent or agents. Epidemiologic evidence is suggestive that there may be three types of NANBH
  • the present invention is dealing with new peptides having surprisingly unexpected immunochemical reactivity with anti-HCV antibodies.
  • the new peptides according to the invention are immunochemically reactive with anti-HCV antibodies, and characterised by the following amino acid sequence (depicted in the ⁇ one-letter code): _ ? -
  • A represents hydrogen, an animo acid or polypeptider X l r X 2 , X 3 , X 4 , X5, Xg, X7 X ⁇ and x g can be any amino acid; and B represents hydroxy, an amino acid or polypeptide; or a fragment thereof which is immunologically reactive with anti-HCV antibodies, with the exception of the peptide having the formula A-D-R-E-V-L-Y-R-E-F-D-E-M-B, wherin A and B have the previous defined meaning.
  • sequence D-R-E-V-L-Y-R-E-F-D-E-M (II) is part of the HCV sequence and is located in the ORF-region of the SOD/HCV C100-3 clone.
  • a specific im unoreactive peptide comprising the sequence D-R-E-V-L-Y-R-E-F-D-E-M is described in a copending co-owned application with a priority date of 6 December 1991.
  • the remaining amino acids X- j ⁇ -Xg can be any amino acid with the exception mentioned.
  • Preferred peptides according to formula I are peptides that differ from the peptide having the formula A-D-R-E-V- L-Y-R-E-F-D-E-M-B in that one amino acid selected from has been replaced by another amino acid.
  • peptides have a high immune-reactivity towards anti- HCV antibodies as is shown in figure 1.
  • functional derivatives of these peptides are also considered to belong to the peptides according to the instant invention.
  • Functional derivatives of the peptides are meant to include a) acid addition salts of the peptides; b) amides of the peptides and specifically the C-terminal amides; c) esters and specifically C-terminal esters and d) N-acyl derivatives, specifically N-terminal acyl derivatives and in particular N-acetyl derivatives.
  • the peptides according to the invention are particularly suitable for use in a diagnostic method for the determination of the presence of HCV antigens or anti-HCV antibodies in a test fluid.
  • the peptides according to the invention have the advantage that these are of a safe non-infectious origin. Moreover, the present peptides have a particular high affinity to anti-HCV antibodies, which renders the present peptides extremely suitable for use in the above said diagnostic test methods.
  • fragments of the peptides according to formula I are those fragments that differ from fragments of D-R-E-V-L-Y- R-E-F-D-E-M in that one or more amino acids have been replaced by other amino acids.
  • the preparation of the peptides according to the invention can be effected by means of one of the known organic chemical methods for peptide synthesis or with the aid of recombinant DNA techniques. This latter method involves the preparation of the desired peptide by means of bringing to expression a recombinant nucleic acid sequence with a nucleic acid sequence sequence which is coding for one or more of the peptides in question in a suitable micro-organism as host.
  • the organic chemical methods for peptide synthesis are considered to include the coupling of the required amino acids by means of a condensation reaction, either in homogeneous phase or with the aid of a so-called solid phase.
  • the condensation reaction can be carried out as follows: a) condensation of a compound (amino acid, peptide) with a free carboxyl group and protected other reactive groups with a compound (amino acid, peptide) with a free amino group and protected other reactive groups where one of the protecting groups also may be a (derivatised) solid support, in the present of a condensation agent, b) condensation of a compound (amino acid, peptide) with an activated carboxyl group and free or protected other reaction groups with a compound (amino acid, peptide) with a free amino group and free or protected other reactive groups, where one of the protecting groups also may be a (derivatised) solid support.
  • Activation of the carboxyl group can take place, inter alia, by converting the carboxyl group to an acid halide, ' azide, anhydride, imidazolide or an activated ester such as the
  • the most common methods for the above condensation reactions are: the carbodiimide method, the BOP method [benzotriazolyloxytris (dimethylamino) phosphonium hexafluoro phosphate] the azide method, the mixed anhydride method and the method using activated esters, such as described in The Peptides, Analysis, Synthesis, Biology Vol. 1-3 (Ed. Gross, E. and Meienhofer, J.) 1979, 1980, 1981 (Academic Press, Inc.).
  • the reactive groups which may not participate in the condensation reaction are, as stated, effectively protected by groups which can be removed again very easily by hydrolysis with the aid of acid, base or reduction.
  • a carboxyl group can be effectively protected by, for example, esterification with methanol, ethanol, teriary butanol, benzyl alcohol or p-nitrobenzyl alcohol and a idation with amines or derivatives of alcohols and amines linked to solid supports.
  • Groups which can effectively protect an amino group are the ethoxycarbonyl, benzyloxycarbonyl, t-butoxy-carbonyl, 9-fluorenyl-methoxycarbonyl(Fmoc) or p-methoxy- benzyloxycarbonyl group, or an acid group derived from a sulphonic acid, such as the p-toluene-sulphonyl, penta- methylbenzene sulfonyl (Pms), 4-methoxy-2,3,6-trimethyl- benzene sulfonyl (Mtr) or l,2,5,7,8-pentamethylchroman-6- sulfonyl (Pmc) group, but other groups can also be used, such as substituted or unsubstituted aryl or aralkyl groups, for example benzyl and triphenylmethyl, or groups such as ortho-nitrophenyl-sulphenyl and 2-benzoy
  • a particularly suitable solid phase is, for example, the p-alkoxybenzyl alcohol resin (4-hydroxymethyl-phenoxy- methyl- ⁇ opolystrene-1% divinylbenzene resin), described by Wang (1974) J.Am.Chem.Soc, 9E5, 1328. After synthesis the peptides can be split from this solid phase under mild conditions.
  • Other suitable supports are derivatised poly ⁇ ethylene or polypropylene rods as described by Geysen, Proc. Natl. Acad. Sci., 81, 3998 (1984) and Proc. Natl. Acad. Sci., 02., 178 (1985).
  • the protective groups can be split off by various conventional methods, depending on the nature of the particular group, for example with the aid of trifluoro-acetic acid or by mild reduction, for example with hydrogen and a catalyst, such as palladium, treatment with a base as for example piperidine or hydroxide ions, or with HBr in glacial acetic acid.
  • a catalyst such as palladium
  • the peptide is synthesized on a solid support from which it can be detached this can be achieved, depending on the type of linker, for example, with trifluoro-acetic acid, trifluoromethanesulphonic acid or with methanesulphonic acid dissolved in trifluoro-acetic acid, transesterification with a lower alcohol, preferably methanol or ethanol, in which case a lower alkyl ester of the peptide is formed directly.
  • a lower alcohol preferably methanol or ethanol
  • a lower alkyl ester of the peptide is formed directly.
  • splitting with the aid of ammonia gives the amide of a peptide according to the invention.
  • the peptide according to the invention can likewise be prepared with the aid of recombinant DNA techniques. This possibility is of importance particularly when the peptide is incorporated in a repeating sequence ("in tandem") or when the peptide can be prepared as an essential constituent of a (much larger) protein or polypeptide. This type of preparation of the peptide therefore likewise falls within the scope of the invention.
  • a nucleic acid sequence is used which codes for the peptide according to the invention and which, furthermore, is substantially free from polynucleotide segments, which in the naturally occurring HCV genome flank the nucleic acid sequence indicated above.
  • a nucleic acid sequence of this type which is coding for the peptide according to the invention, and a recombinant DNA in which this nucleic acid sequence is incorporated likewise fall within the scope of the invention.
  • Nucleic acid sequence refers to a polymeric form of nucleotides of any length, both to ribonucleic acid sequences and to deoxy ribonucleic acid sequences. In principle, this term refers to the primary structure of the molecule. Thus, this term includes double and single stranded DNA, as well as double and single stranded RNA, and modifications thereof.
  • a nucleic acid sequence according to the present invention can be ligated to various replication effecting DNA sequences with which it is not associated or linked in nature resulting in a so called recombinant vector molecule which can be used for the transformation of a suitable host.
  • Useful recombinant vector molecules are preferably derived from, for example plasmids, bacteriophages, cosmids or viruses.
  • the methods to be used for the construction of a recombinant vector molecule according to the invention are known to those of ordinarily skill in the art and are inter alia set forth in Maniatis, T. et al. (Molecular Cloning A Laboratory Manual, second edition; Cold Spring Harbor Laboratory, 1989).
  • the insertion of the nucleic acid sequence according to the invention into a cloning vector can easily be achieved when both the genes and the desired cloning vehicle have been cut with the same restriction enzyme(s) as complementary DNA termini are thereby produced.
  • control sequences may comprise promoters, enhancers, operators, inducers, ribosome binding sites etc.
  • nucleotide sequences inserted at the selected site of the cloning vector may include only a fragment of the complete nucleic acid sequence encoding for the peptides according to the invention as long as the transformed host will produce a polypeptide having at least one or more immunogenic determinants .
  • the recombinant vector molecules may additionally contain one or more marker activities that may be used to select for desired transformants, such as ampicillin and tetracycline resistance in pBR322, as for example ampicillin resistance and ⁇ -peptide of ⁇ -galactosidase in pUC8.
  • desired transformants such as ampicillin and tetracycline resistance in pBR322, as for example ampicillin resistance and ⁇ -peptide of ⁇ -galactosidase in pUC8.
  • the peptides or fragments thereof prepared and described above are used to produce antibodies, both polyclonal and monoclonal. Monoclonal antibodies directed against peptides according to the invention can be readily produced by one skilled in the art.
  • the present invention further comprises an immunochemical reagent which reagent contains one or more of the peptides of the invention.
  • the "immunochemical reagent" according to the invention usually comprises one or more peptides according to the invention and a suitable support or a labelling substance.
  • a support that may be used in this respect is, for example, a carrier protein such as BSA, the inner wall of a microtest well or a cuvette, a tube or capillary, a membrane, filter, test strip or a particle such as, for example, a latex particle, an erythrocyte, a dye sol, a metal sol or metal compound as sol particle.
  • a labelling substance that may be used can be a radioactive isotope, a fluorescent compound, a labelling protein such as (an enzyme), an enzyme, a dye sol, metal sol or metal compound as sol particle.
  • the said immunochemical reagent is the essential component in a method for the detection of antibodies directed against HCV in a test fluid.
  • the immunochemical reagent is therefore brought into contact with the said test fluid whereby an immunochemical reaction takes place resulting in the formulation of an immune complex between the peptide (according to the invention) and the anti-HCV antibodies.
  • the immunochemical reaction that takes place is a so-called sandwich reaction, an agglutination reaction, a competition reaction or an inhibition reaction.
  • the immune complex formed as a result of the above reaction is a (direct or indirect) measure for the presence of antibodies in the test fluid.
  • the immunochemical reagent according to the invention can also be used for the detection of HCV antigen in a test fluid.
  • the invention further comprises a method for the detection of antibodies directed against HCV in a test fluid, whereby one or more of the peptides according to the invention are used.
  • the invention also relates to a method for the detection of HCV in a test fluid, using one or more of the peptides according to the invention.
  • test fluid can be contacted with anti-HCV and subsequently or simultaneously with the immunochemical reagent according to the invention.
  • a particularly suitable method for the detection of HCV in a test fluid is based on a competition reaction between a peptide according to the invention provided with a labelling substance and a HCV antigen (present in the test fluid) , whereby the peptide and the antigen are competing with the antibody directed against HCV attached to a solid support.
  • the invention further comprises a test kit to be used for carrying out an immuno-assay, this test kit containing at least one immunochemical reagent according to the invention.
  • a test kit according to the invention comprises, as an essential constituent, an immunochemical reagent as described above.
  • the test kit may comprise, for example. 1) the peptide according to the invention attached to a solid support, (for example the inner wall of a microtest well) and
  • test kit may comprise
  • a labelled antibody directed against HCV preferably a monoclonal antibody directed against said peptide.
  • test kit comprises an immunochemical reagent which consists of a peptide according to the invention attached to particles or sols.
  • a test kit for the detection of HCV antigen comprises, for example, a labelled peptide according to the invention and an antibody directed against HCV, which is attached to a solid support.
  • the invention is further exemplified by the following example.
  • Peptides were synthesized which differed from the peptide having the formula D-R-E-V-L-Y-R-E-F-D-E-M, in that one amino acid was replaced by another aminoacid. Peptides were synthesized in which each amino acid of the above mentioned sequence was replaced by any aminoacid selected from the group; A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, s, T, V, W and Y. The resulting peptides were all tested for its immune reactivity with human and mouse anti-HCV sera. The results of this procedure are shown in figure 1.
  • Figure l Immune reactivity, with human and mouse anti-HCV sera, of peptides that differ from the peptide with formula D-R-E-V-L-Y-R-E-F-D-E-M in that one amino acid has been replaced by any amino acid selected from the group A, C, D, E, F, G, H, J, K, L, M, N, P, Q, R, S, T, V, W and Y.

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  • Health & Medical Sciences (AREA)
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  • Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
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  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Virology (AREA)
  • Biomedical Technology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Genetics & Genomics (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Biophysics (AREA)
  • Physics & Mathematics (AREA)
  • Biotechnology (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
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  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention concerne des peptides réagissant immunochimiquement avec des anticorps dirigés contre le virus de l'hépatite C ainsi que les séquences d'acides nucléiques codant ces peptides. On décrit également un procédé permettant de détecter le virus de l'hépatite C ou les anticorps dirigés contre celui-ci dans un fluide d'essai, un réactif immunochimique et une trousse d'essai destinée à être utilisée lors des applications de ces procédés de détection.
PCT/EP1992/002998 1991-12-24 1992-12-24 Peptides immunochimiquement reactifs avec des anticorps diriges contre le virus de l'hepatite non a, non b WO1993013127A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP93902132A EP0621868A1 (fr) 1991-12-24 1992-12-24 Peptides immunochimiquement reactifs avec des anticorps diriges contre le virus de l'hepatite non a, non b
JP5511439A JPH07502996A (ja) 1991-12-24 1992-12-24 非ａ非ｂ型肝炎ウイルスに対する抗体に免疫化学反応性を示すペプチド

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP91203408 1991-12-24
EP91203408.9 1991-12-24

Publications (1)

Publication Number Publication Date
WO1993013127A1 true WO1993013127A1 (fr) 1993-07-08

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PCT/EP1992/002998 WO1993013127A1 (fr) 1991-12-24 1992-12-24 Peptides immunochimiquement reactifs avec des anticorps diriges contre le virus de l'hepatite non a, non b

Country Status (7)

Country Link
EP (1) EP0621868A1 (fr)
JP (2) JPH07502996A (fr)
AU (1) AU3347393A (fr)
CA (1) CA2126693A1 (fr)
FI (1) FI925437A0 (fr)
WO (1) WO1993013127A1 (fr)
ZA (1) ZA928954B (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999020295A1 (fr) * 1997-10-17 1999-04-29 Trustees Of The University Of Pennsylvania Compositions et procedes permettant de favoriser l'internalisation et la degradation de l'activateur du plasminogene de type urokinase
US7211424B1 (en) * 1998-11-04 2007-05-01 Institut De Recherches Cliniques De Montreal Mammalian Subtilisin/kexin isozyme SKI-1: a proprotein convertase with a unique cleavage specificity

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6709828B1 (en) 1992-03-06 2004-03-23 N.V. Innogenetics S.A. Process for the determination of peptides corresponding to immunologically important epitopes and their use in a process for determination of antibodies or biotinylated peptides corresponding to immunologically important epitopes, a process for preparing them and compositions containing them
US6667387B1 (en) 1996-09-30 2003-12-23 N.V. Innogenetics S.A. HCV core peptides

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3707710A1 (de) * 1987-03-11 1988-09-22 Hoechst Ag Neue biologisch wirksame eicosa-peptide, verfahren zu deren herstellung und deren verwendung
EP0442394A2 (fr) * 1990-02-16 1991-08-21 United Biomedical, Inc. Peptides synthétiques spécifiques pour la détection d'anticorps contre HVC, diagnostic des infections par HVC et prévention de celles-ci comme vaccins
EP0463848A2 (fr) * 1990-06-25 1992-01-02 The Research Foundation for Microbial Diseases of Osaka University Particules du virus de l'hépatite non-A non-B
WO1992010514A2 (fr) * 1990-12-14 1992-06-25 Innogenetics N.V. Antigenes synthetiques pour la detection d'anticorps diriges contre le virus de l'hepatite c

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3707710A1 (de) * 1987-03-11 1988-09-22 Hoechst Ag Neue biologisch wirksame eicosa-peptide, verfahren zu deren herstellung und deren verwendung
EP0442394A2 (fr) * 1990-02-16 1991-08-21 United Biomedical, Inc. Peptides synthétiques spécifiques pour la détection d'anticorps contre HVC, diagnostic des infections par HVC et prévention de celles-ci comme vaccins
EP0463848A2 (fr) * 1990-06-25 1992-01-02 The Research Foundation for Microbial Diseases of Osaka University Particules du virus de l'hépatite non-A non-B
WO1992010514A2 (fr) * 1990-12-14 1992-06-25 Innogenetics N.V. Antigenes synthetiques pour la detection d'anticorps diriges contre le virus de l'hepatite c

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999020295A1 (fr) * 1997-10-17 1999-04-29 Trustees Of The University Of Pennsylvania Compositions et procedes permettant de favoriser l'internalisation et la degradation de l'activateur du plasminogene de type urokinase
AU739373B2 (en) * 1997-10-17 2001-10-11 Trustees Of The University Of Pennsylvania, The Compositions and methods for promoting internalization and degradation of urokinase-type plasminogen activator
US7211424B1 (en) * 1998-11-04 2007-05-01 Institut De Recherches Cliniques De Montreal Mammalian Subtilisin/kexin isozyme SKI-1: a proprotein convertase with a unique cleavage specificity

Also Published As

Publication number Publication date
JPH07502996A (ja) 1995-03-30
CA2126693A1 (fr) 1993-07-08
EP0621868A1 (fr) 1994-11-02
FI925437A0 (fi) 1992-11-30
ZA928954B (en) 1993-05-19
AU3347393A (en) 1993-07-28
JPH05271277A (ja) 1993-10-19

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