EP1497324A2 - Epitopes du virus de l'hepatite c, specifiques des lymphocytes cd4+ t - Google Patents

Epitopes du virus de l'hepatite c, specifiques des lymphocytes cd4+ t

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Publication number
EP1497324A2
EP1497324A2 EP03717293A EP03717293A EP1497324A2 EP 1497324 A2 EP1497324 A2 EP 1497324A2 EP 03717293 A EP03717293 A EP 03717293A EP 03717293 A EP03717293 A EP 03717293A EP 1497324 A2 EP1497324 A2 EP 1497324A2
Authority
EP
European Patent Office
Prior art keywords
epitopes
hepatitis
virus
hcv
lymphocyte
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Withdrawn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
EP03717293A
Other languages
German (de)
English (en)
Inventor
Helmut Diepolder
Maria-Christina Jung
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.)
Immusystems GmbH
Original Assignee
Immusystems GmbH
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 Immusystems GmbH filed Critical Immusystems GmbH
Priority to EP03717293A priority Critical patent/EP1497324A2/fr
Publication of EP1497324A2 publication Critical patent/EP1497324A2/fr
Withdrawn legal-status Critical Current

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • 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 hepatitis C virus epitopes that are specific to CD4 + T lymphocytes and to vaccines that contain these epitopes.
  • HCV hepatitis C virus
  • Flaviviridae family The hepatitis C virus, hereinafter referred to as HCV, was identified in 1989 and is an RNA virus from the Flaviviridae family. It ⁇ o. , consists of an RNA single strand of approx. 9400 nucleotides which encode a precursor polyprotein approx. 3000 amino acids long. This polyprotein is translated in an open reading frame and proteolytically cleaved post-translationally.
  • the virus is highly variable, and there are various virus isolates known as genotypes
  • hepatitis C is one of the most important chronic viral infections. There are currently 5 at least 180 million infected individuals. According to calculations by the Centers of Disease Control in the USA, there will also be an increase in hepatitis C-associated diseases by 2010 due to the long latency period after infection with HCV. 0 The HCV is predominantly transmitted parenterally and was the main cause of post-transfusion hepatitis NonA-NonB until it was discovered. Routine testing of all blood products with 2nd and 3rd generation HCV antibody tests has dramatically reduced the number of post-transfusion hepatitis. The so-called sporadic hepatitis C and iv drug abuse are now considered the main means of transmission of new HCV infections. No measures are currently known to effectively prevent new infections in this way.
  • HCV causes chronic inflammation of the liver (hepatitis), which over the course of many years can lead to further complications, such as cirrhosis of the liver.
  • hepatitis As part of cirrhosis of the liver that has existed for years, about 5% of all infected people develop hepatocellular carcinoma. In the western world, hepatitis C therefore ranks first as an indication for liver transplantation. The health care costs of these transplants are significant.
  • ni is the sum of the reactions with 3 ⁇ Sl ⁇ 6
  • n 2 is the sum of the reactions with SI> 6
  • m is the number of tests against the respective peptide, where m> 15, and MW is the mean of all impact factors.
  • the Impcat factor of the CD4 + T lymphocyte-specific HCV epitopes> MW and ⁇ MW + 1 * Sta, in particular> MW +1 * Sta and ⁇ MW + 2 * Sta, particularly preferably> MW + 2 * Sta is preferred.
  • CD4 + T lymphocyte-specific HCV epitopes comprising one or more peptides selected from the group:
  • HCV epitopes specific to CD4 + T lymphocytes mentioned below containing the sequence: EP001 GPRLGVRATRKTSER
  • CD4 + T lymphocyte-specific HCV epitopes according to the invention are particularly preferred, selected from the group of epitopes EP001 to EP0017 with the above-mentioned sequence. These epitopes EP001 to EP017 according to the invention have an impact factor of> MW + 2 * Sta.
  • HCV epitopes are also to be used for immunotherapy of chronic hepatitis C or a vaccine, further criteria are a high degree of conservation between different virus subtypes and a high degree of promiscuity in binding to different HLA class II molecules.
  • the HCV epitopes identified and characterized in this way should be available for a vaccine for the prophylaxis and / or therapy of an HCV infection.
  • a unique group of patients was identified, namely patients with acute hepatitis C who achieve permanent or at least temporary virus elimination in over 50% of cases.
  • the entire virus was covered with overlapping synthetic peptides of 15 to 20 amino acids in length.
  • a standardized lymphocyte proliferation assay was used as the test system.
  • a formula was defined which is based on the frequency of detection of an epitope and the strength of the respective immune response.
  • the invention is based on the selection of a particular patient collective, examinations with defined peptides and an algorithm for the identification of highly immunogenic CD4 + T cell epitopes which are suitable for the development of a prophylactic or therapeutic vaccine.
  • the algorithm determines the "impact factor” (IF) of the respective epitope and is defined as follows:
  • ni corresponds to the sum of the reactions with 3 ⁇ Sl ⁇ 6, n 2 to the sum of the reactions with Sl> 6 and m to the number of tests carried out against the respective peptide, this serves to normalize the values.
  • the peptides we found were m> 15.
  • the stimulation index (Sl) is usually calculated from the raw data of a proliferation assay and represents the multiplication factor of the measured sample compared to the control. An Sl of 3 is considered significant.
  • the mean value was calculated from the impact factor of all peptides tested, each impact factor being determined according to Formula 1.
  • our solution of the task is limited to the peptides whose IF are two standard deviations above the mean of all IF.
  • HCV epitopes specific to CD4 + T lymphocytes means a defined region of a hepatitis C protein which, owing to its structure, “fits” into the complementary binding site of a CD4 + T lymphocyte receptor and thereby a highly specific reaction triggers.
  • a "peptide screening" with approximately 450 selected different peptides (15-22mers) was carried out for a virus-specific CD4 + T cell response in the patient population described above.
  • the peptides represent the entire virus protein, whereby we used 15mers with 5 amino acid overlapping areas or 20-22mers with 10 amino acids overlapping areas in order to record all relevant epitopes.
  • Table 1 shows the respective positions in the HCV genome of the epitopes according to the invention, stating the respective virus isolate reference (Table 1 / column 4).
  • the information on the amino acid position (Table 1 / Column 2) should only be understood as an approximation, because due to the high mutation rate of the virus in the different virus isolates can cause changes in position.
  • the conserved epitopes are of particular importance for prophylactic and therapeutic vaccinations, which is shown by the constant sequence of the different virus isolates of an epitope (see also Table 1 / column 5).
  • the epitopes according to the invention are listed in Table 1.
  • Genotype 1 b AUTHORS Trowbridge.R. and Gowans.E.J. TITLE Molecular cloning of an Australian isolate of hepatitis C virus JOURNAL Arch. Virol. 143 (3), 501-511 (1998)
  • Genotype 1b AUTHORS Takamizawa, A., Mori.C, Fuke.l., Manabe.S., Murakami.S., Fujita.J., Onishi.E., Andoh.T., Yoshida.l. and Okayama.H.
  • TITLE Transcripts from a Single full-length cDNA clone of hepatitis C virus are infectious when directly transfected into the liver of a chimpanzee
  • Genotype 1a AUTHORS CHOO.Q.-L, RICHMAN.K.H., HAN.J.H., BERGER.K., LEE.C,
  • Genotype 1 b AUTHORS Tanaka.T., Kato.N., Nakagawa.M., Ootsuyama.Y., Cho.M.J.,
  • TITLE Molecular cloning of the human hepatitis C virus genome from Japanese patients with non-A, non-B hepatitis
  • Genotype 1 b AUTHORS Chen.P.J., Lin.M.H., Tai.K.F., Liu.P.C, Lin.C.J. and
  • Taiwanese hepatitis C virus genome sequence determination and mapping the 5 'termini of viral genomic and antigenomic RNA JOURNAL Virology 188 (1), 102-113 (1992)
  • Genotype 1a AUTHORS Inchauspe.G., Zebedee.S., Lee.D.H., Sugitani.M., Nasoff.M. and Prince.A.M.
  • Genotype 4 AUTHORS Chamberlain R, Adams N, Saeed AA, Simmonds P, Elliott RM
  • TITLE Complete nucleotide sequence of a type 4 hepatitis C virus variant, the predominant genotype in the Middle East.
  • TITLE The complete coding sequence of hepatitis C virus genotype 5a, the predominant genotype in South Africa.
  • Genotype 6a AUTHORS Adams, N.J., Chamberlain, R.W., Taylor.LA, Davidson, F.,
  • Genotype 1 b AUTHORS Honda, M., Kaneko.S., Unoura.M., Kobayashi.K. and
  • Genotype 1 b AUTHORS Okamoto.H., Kojima.M., Okada.S., Yoshizawa.H., Lizuka.H.,
  • Genotype 1a AUTHORS Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M.
  • the so-called proliferation assay according to the following protocol was used as the test system.
  • PBMC peripheral blood mononuclear cells
  • RPMI1640 fetal calf serum
  • 50 ⁇ l of this cell suspension concentration of 1x10 6 cells per ml
  • the cells were stimulated by adding the peptides.
  • the final concentration of the peptides was 10 ⁇ g / ml.
  • the cell culture plates were cultivated for 5 days at 37 ° C. and 5% CO 2 , then 3 H-thymidine was added, and the incorporation of the radioactive 3 H was measured as a measure of the cell stimulation.
  • an additional filter was defined and referred to below as an impact factor (IF).
  • the impact factor (IF) is based on a point system that not only measures the frequency of relevant reactions, i.e. Stimulation index (Sl) greater than 3, as used conventionally, but also takes into account the strength of these reactions.
  • Peptides with a high impact factor are not only characterized by a large stimulation index, i.e. strong specific reactivity but also by the repeated i.e. specific reaction found in different people.
  • Epitopes that trigger strong HCV-specific CD4 + T cell responses measured in different patients are of great relevance for future vaccination approaches.
  • the epitopes according to the invention are further distinguished by the fact that a clear specific CD4 + T cell activity on these peptides correlates with a decrease in the virus titer. These epitopes in particular are therefore likely to be ideal candidates for a vaccine.
  • a specific vaccination reaction against these peptides could prevent the disease on the one hand and / or lead to their healing on the other hand, or at least have a favorable effect on the course of an HCV infection.
  • the epitopes according to the invention are highly immunogenic, highly conserved sequences of the HCV, some of which are located in the immediate vicinity of known CD8 + T lymphocyte-specific HCV epitopes.
  • HCV epitopes specific to CD4 + T lymphocytes they can mediate so-called T cell help for cytotoxic CD8 + T lymphocytes in addition to induction of CD4 + T lymphocytes.
  • T cell help for cytotoxic CD8 + T lymphocytes are activated by the cytokines of stimulated CD4 + T lymphocytes.
  • the peptides are characterized by frequent significant reactions in different patients with different MHC class II types
  • the MHC Class II system is extremely polymorphic.
  • the task of the MHC molecules is to bind peptide fragments derived from the body's own and pathogenic (e.g. hepatitis C virus) proteins and to express them on the cell surface for the detection and activation of specific CD4 + T lymphocytes. This system enables an effective and specific
  • Class II types i.e. different people, the same peptide on their
  • MHC class II molecule can express what in vitro by measurable in different people, directed against the same peptide
  • CD4 + activity can be detected by one of these peptides
  • Epitopes according to the invention have immunological relevance in different individuals.
  • epitopes according to the invention are particularly suitable for both therapeutic and prophylactic peptide vaccination, which is directed against HCV.
  • Another solution is a vaccine which contains a combination of the epitopes EP001 to EP017 according to the invention.
  • the vaccine can particularly preferably contain a mixture of the epitopes EP001 to EP017 according to the invention.
  • other HCV epitopes may also be present.
  • the epitopes according to the invention can be used alone or with one or more auxiliary substances as medicaments, preferably as vaccines.
  • the vaccine according to the invention contains at least one epitope according to the invention, preferably a mixture of epitopes according to the invention. However, other HCV epitopes may also be present.
  • the excipients are preferably selected from the group consisting of fowl pox virus, modified vaccinia virus Ankara, virosomes, TransVax ® and other immune response enhancing substances.
  • the vaccine according to the invention can be administered orally, parenterally, intramuscularly, intravenously, subcutaneously or intracutaneously.
  • the epitopes according to the invention are epitopes that can be used as a T cell stimulating vaccine.
  • a vaccine which contains the epitopes according to the invention, has a vaccination with the entire virus protein, which contains various epitopes for virus-specific T-lymphocytes and only B-lymphocytes and CD4 + T lymphocytes induce the advantage that it selectively induces specific T lymphocytes, CD4 + and / or CD8 + T lymphocytes. It also avoids antagonistic effects or the risk of iatrogenic autoimmune reactions that can occur when vaccinating with whole proteins.
  • the epitopes according to the invention additionally have a higher immunogenicity compared to the entire virus protein, as a result of which a better vaccination result is achieved.
  • the vaccine according to the invention thus enables the induction of an immune response in healthy people and therefore serves as a prophylactic vaccination.
  • the vaccine according to the invention can also induce an immune response in chronically HCV-infected people and thus serve as a therapeutic vaccine.
  • the coding cDNA of these epitopes can be used in a DNA vaccine, a special vaccination method.
  • the DNA coding for the corresponding epitopes is cloned into a vector. This construct is in turn administered parenterally to the individual to be vaccinated (e.g. Immunology and Cell Biology, volume 75, pages 382 to 388).
  • different DNA sequences can encode one of the epitopes according to the invention (see Current protocols, Wiley).
  • the epitopes according to the invention can also be used in the diagnosis of the course of an HCV infection by monitoring the amount of CD4 + T lymphocytes which specifically recognize the epitope in question in the blood of the patient with a hepatitis C infection. This can be carried out, for example, using a diagnostic kit which comprises one or more of the epitopes according to the invention.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Virology (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Veterinary Medicine (AREA)
  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Genetics & Genomics (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

L'invention concerne des épitopes du virus de l'hépatite C, spécifiques relativement aux lymphocytes CD4+ T, ainsi que des agents d'inoculation contenant ces épitopes.
EP03717293A 2002-04-10 2003-04-10 Epitopes du virus de l'hepatite c, specifiques des lymphocytes cd4+ t Withdrawn EP1497324A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP03717293A EP1497324A2 (fr) 2002-04-10 2003-04-10 Epitopes du virus de l'hepatite c, specifiques des lymphocytes cd4+ t

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP02008033A EP1357127A1 (fr) 2002-04-10 2002-04-10 Epitopes du virus de l'hépatite C spécifiques à des lymphocytes T de type CD4+
EP02008033 2002-04-10
PCT/EP2003/003732 WO2003084988A2 (fr) 2002-04-10 2003-04-10 Épitopes du virus de l'hépatite c, spécifiques des lymphocytes cd4+ t
EP03717293A EP1497324A2 (fr) 2002-04-10 2003-04-10 Epitopes du virus de l'hepatite c, specifiques des lymphocytes cd4+ t

Publications (1)

Publication Number Publication Date
EP1497324A2 true EP1497324A2 (fr) 2005-01-19

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EP02008033A Withdrawn EP1357127A1 (fr) 2002-04-10 2002-04-10 Epitopes du virus de l'hépatite C spécifiques à des lymphocytes T de type CD4+
EP03717293A Withdrawn EP1497324A2 (fr) 2002-04-10 2003-04-10 Epitopes du virus de l'hepatite c, specifiques des lymphocytes cd4+ t

Family Applications Before (1)

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Country Status (4)

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US (2) US7270820B2 (fr)
EP (2) EP1357127A1 (fr)
AU (1) AU2003221569A1 (fr)
WO (1) WO2003084988A2 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1676856A4 (fr) * 2003-09-22 2008-03-05 Greenpeptide Co Ltd Peptide provenant du virus de l'hepatite c
WO2013150450A1 (fr) * 2012-04-02 2013-10-10 Universidade Do Porto Fragments homologues du vhc, lignées cellulaires et applications associées
US10351604B2 (en) * 2015-06-25 2019-07-16 Nanyang Technological University Broad-spectrum anti-infective peptides
CN109963587A (zh) 2016-09-21 2019-07-02 艾伯塔大学理事会 丙型肝炎病毒免疫原性组合物及其使用方法

Family Cites Families (13)

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Publication number Priority date Publication date Assignee Title
US6027729A (en) * 1989-04-20 2000-02-22 Chiron Corporation NANBV Diagnostics and vaccines
US6007982A (en) * 1990-12-14 1999-12-28 Innogenetics N.V. Synthetic antigens for the detection of antibodies to hepatitis C virus
DE69200512T2 (de) * 1991-03-01 1995-03-09 Akzo Nv Mit Antikörper gegen Hepatitis non-A, non-B-Virus immunochemische reaktive Peptide.
CA2070952A1 (fr) * 1991-06-11 1992-12-12 Makoto Seki Gene du virus de l'hepatite c ou fragment dudit gene, polypeptide code par le gene
DE4209215A1 (de) * 1991-07-04 1993-01-07 Boehringer Mannheim Gmbh Hcv peptidantigene und verfahren zur bestimmung von hcv
US6689363B1 (en) * 1992-01-29 2004-02-10 Epimmune Inc. Inducing cellular immune responses to hepatitis B virus using peptide and nucleic acid compositions
US5980899A (en) * 1992-06-10 1999-11-09 The United States Of America As Represented By The Department Of Health And Human Services Identification of peptides that stimulate hepatitis C virus specific cytotoxic T cells
CA2314267A1 (fr) * 1997-12-10 1999-06-17 Washington University Systeme anti-pathogene et procedes d'utilisation
CA2377525A1 (fr) * 1999-07-19 2001-03-29 Epimmune Inc. Induction de reponses immunitaires cellulaires au virus de l'hepatite c mettant en oeuvre des compositions de peptides et d'acide nucleique
MXPA02008873A (es) * 2000-03-14 2003-02-10 Anton Mayr Cepa alterada del virus de vaccinia ankara modificado (mva).
AUPQ776100A0 (en) * 2000-05-26 2000-06-15 Australian National University, The Synthetic molecules and uses therefor
ATE303597T1 (de) * 2000-07-07 2005-09-15 Medmira Inc Hcv mosaik antigen zusammensetzung
EP1195381A1 (fr) * 2000-09-28 2002-04-10 Immusystems GmbH Epitopes du virus de l'hépatite C spécifiques à des lymphocytes T de type CD4+

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See references of WO03084988A2 *

Also Published As

Publication number Publication date
US20080089903A1 (en) 2008-04-17
WO2003084988A2 (fr) 2003-10-16
EP1357127A1 (fr) 2003-10-29
AU2003221569A1 (en) 2003-10-20
US20050249754A1 (en) 2005-11-10
AU2003221569A8 (en) 2003-10-20
US7270820B2 (en) 2007-09-18
WO2003084988A3 (fr) 2004-11-11

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