EP1290018A2 - Konvergente kombinatorischen peptid-bibliotheken und deren verwendung zur impfung gegen den virus von hepatitis c - Google Patents

Konvergente kombinatorischen peptid-bibliotheken und deren verwendung zur impfung gegen den virus von hepatitis c

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Publication number
EP1290018A2
EP1290018A2 EP01938317A EP01938317A EP1290018A2 EP 1290018 A2 EP1290018 A2 EP 1290018A2 EP 01938317 A EP01938317 A EP 01938317A EP 01938317 A EP01938317 A EP 01938317A EP 1290018 A2 EP1290018 A2 EP 1290018A2
Authority
EP
European Patent Office
Prior art keywords
sequences
anchoring
virus
peptides
amino acid
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Withdrawn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
EP01938317A
Other languages
English (en)
French (fr)
Inventor
Georges Bertrand
Hélène Gras-Masse
Ahmed Bouzidi
Claude Auriault
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.)
Centre National de la Recherche Scientifique CNRS
Institut Pasteur de Lille
SEDAC-Therapeutics
Institut Pasteur
Original Assignee
Centre National de la Recherche Scientifique CNRS
Institut Pasteur de Lille
SEDAC-Therapeutics
Institut Pasteur
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 Centre National de la Recherche Scientifique CNRS, Institut Pasteur de Lille, SEDAC-Therapeutics, Institut Pasteur filed Critical Centre National de la Recherche Scientifique CNRS
Publication of EP1290018A2 publication Critical patent/EP1290018A2/de
Withdrawn legal-status Critical Current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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
    • C07K1/047—Simultaneous synthesis of different peptide species; Peptide libraries
    • 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 the design and synthesis of mixtures of immunogenic peptides corresponding to restricted regions of virus proteins and in particular of the Hepatitis C virus (HCV) and their use for the preparation of vaccine preparations against said viruses.
  • HCV Hepatitis C virus
  • the hepatitis C virus was identified in 1989 (CHOO Q.L. et al., Science, 1989, 244, 359 - 361). It is the main etiological agent of chronic hepatitis non-A, non-B, with parenteral transmission.
  • HCV infection progresses to a chronic pathology in 60 to 80 percent of cases.
  • the prevalence of these infections is high in the general population, around 1 to 2 percent in industrialized countries, especially in Western Europe (ALTER HJ et al., Blood, 1995, 85, 1681- 1695).
  • HCV is part of the viruses of the family of Flaviviridae having an AR genome encoding a single polyprotein which is cleaved into several subfragments: a capsid protein, two glycoproteins El and E2 and 6 so-called non-structural proteins NS2, NS3, NS4A, NS4B, NS5A, NS5B.
  • These viral proteins represent antigenic targets for the immune response: the envelope proteins E1 and E2 constitute targets for neutralizing antibodies and the non-structural proteins are capable of inducing an effector response cytotoxic .
  • mutations occur in. within the HCV genome with a high frequency and generate numerous quasi-species facilitating the escape of the virus in the face of the host's antiviral defenses (WEINER A. J., Proc. Natl. Acad. Sci. USA, 1992, 92 , 2755).
  • TEL type response seems to support this immunity, probably by controlling the cytotoxic response mediated by CD8 cells or by directly secreting various antiviral factors. This response must nevertheless be maintained to allow longer-term control of the virus (GERLACH J.T. et al., Gastroenterology, 1999, 117: 933).
  • Synthetic peptides derived from the capsid proteins and from the NS3 and NS4 proteins have shown their capacity to induce a T helper type response (DIEPOLDER, J. Virol., 1997, 71: 6011).
  • DIEPOLDER J. Virol., 1997, 71: 6011
  • the induction and maintenance of the CD4 response by the use of peptide epitopes derived from these proteins of interest represent a promising strategy for the induction of protective immunity against HCV.
  • peptides are generally weakly immunogenic and above all are rarely capable of inducing an immune response independently of the restriction linked to the polymorphic molecules of the Major Histocompatibility Complex (MHC).
  • MHC Major Histocompatibility Complex
  • a combinatorial library of peptides is created in which coexist, at each of the chosen positions (which will be defined below), the native amino acid and the replacement amino acid chosen to create degeneration of the selected peptide.
  • the present invention therefore relates to the process for the preparation of said mixtures of immunogenic peptides.
  • the first step of the process concerns the strategy for selecting sequences potentially capable of inducing the activation of CD4 cells. Selection involves regions of the capsid protein and the NS3 and NS4 proteins of HCV; these regions are chosen for their high density in anchoring patterns for human MHC class II molecules.
  • MHC class II molecules The role of MHC class II molecules is to present degraded antigens in the form of peptides to CD4 T cells.
  • the presentation of these degraded antigens or T epitopes to T lymphocytes by MHC class II molecules is a necessary condition for the induction of an immune response.
  • the MHC molecules are polymorphic proteins, encoded by numerous alleles, each of which has specific interaction characteristics with T epitopes.
  • the crystallographic studies of several human MHC class II molecules have in particular made it possible to demonstrate the modalities of specific interaction with T epitopes Several criteria are important: on the one hand, the length of the peptides must be greater than 11 residues to allow effective interaction; on the other hand, certain residues of the antigenic peptide play a specific role in the interaction by interacting with microenvironments or pockets for anchoring the MHC molecule.
  • These anchor pockets are independent of each other and have specific physico-chemical characteristics which allow the specific anchoring of side chains of the peptide.
  • the polymorphic residues of the MHC molecules are mainly grouped at the level of the anchoring pockets and therefore influence the particular interaction characteristics of the peptide antigens.
  • the amino acid occupying the position Pi is necessarily hydr ⁇ phobic and is an aliphatic or aromatic amino acid, ie V, I, L, F, M, W or Y; the amino acids occupying positions P4, P6 and P9 are preferably I, V, L, M, F or A, respectively; A, P, G, S or T; and A, I, V, Y, L, F or M.
  • the portions of protein sequences which exhibit a high density of these anchoring motifs have been identified and selected.
  • the peptide sequences selected have a length of between 19 and 36 residues. They include at least 1 to 2 residues upstream of the first anchoring pattern and downstream of the last anchoring pattern. These ends can be extended from 1 to 6 additional natural amino acids in order to include charged amino acids in the sequence, which can facilitate the solubility of sequences too rich in hydrophobic residues.
  • TD sequences # 1 to 8 are regions of the capsid protein
  • TD sequences # 9 to 21 are regions of the NS3 protein
  • TD sequences # 22 to 26 are regions of the NS4 protein.
  • the second step of the method according to the invention consists in designing, from these sequences, convergent combinatorial peptide libraries (called convertopes).
  • the choice of amino acid substitutions intended to create the cobatory library is based on the molecular characteristics of recognition of antigens by iiraminitary receptors, in particular by molecules of the Major Histocompatibility Complex (MHC) and by T lymphocyte receptors. , and, more particularly, on the notion of degeneration of these recognition mechanisms by the immune system (see in particular Hemmer et al. Immunol. Today 1998, 19, 163-168 "Probing degeneracy in T-cell recognition using peptide coiribinatorial libraries” ).
  • MHC Major Histocompatibility Complex
  • the degeneration sought is an unnatural degeneration which is distinguished from the so-called natural degeneration which is developed on the basis of existing mutations, present in the antigen sequences of different natural variants of viruses (GRAS-MASS H ., Pept. Res., 1992, 5: 211-216).
  • This concept of unnatural degeneration for the development of convergent peptide mixtures was initially proposed by GRAS-MASSE H. (GRAS-MASSE H., Curr. Cpin. In Immunol., 1999, 11: 223-228).
  • the purpose of using said mixtures is in particular to stimulate a broader immune response, which will allow subsequent recognition of related peptides but different from the native peptide and which could be found in natural variants of the virus.
  • a first type of degeneration is created with the aim of increasing the anchoring capacity of the epitopes to the MHC molecules.
  • a second type of degeneration can be created in order to increase the recognition of epitopes by T cell receptors; it concerns only the positions which do not intervene in the anchoring to the molecules of the MHC, that is to say the residues other than 1, 4, 6 and 9.
  • the substitutions envisaged here are based on a replaceability matrix developed by Geysen (J. Mol. Recog. 1988, 1,32) which takes account of the irrational degeneration of the recognition of antigens by T receptors. All positions can give rise to a substitution, with the exclusion of common residues to 2 or more neighboring anchoring patterns and the substitution of which would be incompatible with the neighboring pattern or with a substitution already carried out in it.
  • each convertope comprises the peptide of native sequence and all the peptides whose sequence is totally or partially substituted, at the positions indicated.
  • All the peptides constituting a convertope are obtained in a single synthesis during which, for each cycle corresponding to a position which can be substituted, a mixture of the native amino acid and of the substitute amino acid is used, of which the concentrations are adjusted to produce an equimolar ratio in the synthesized peptide.
  • the process according to the invention has been developed for the Hepatitis C virus and more particularly for the capsid protein and the NS3 and NS4 proteins of this virus.
  • this method comprises:
  • convertopes libraries of convergent combinatorial peptides (called convertopes), derived from the sequences of epitopes identified in a), by directed substitution of amino acids at selected positions, to induce degeneration unnatural of each of the epitopes
  • the search for anchoring patterns is carried out by application of the following criteria which are common to the majority of MHC class II alleles: - in a pattern of 9 adjacent amino acids, the amino acid occupying the PI position is necessarily hydrophobic and is an aliphatic or aromatic amino acid, either V, I, L, F, M, W or Y; the amino acids occupying positions P4, P6 and P9 are preferably, respectively, I, V, L, M, F or A; A, P, G, S or T; and A, I, V, Y, L, F or M.
  • the design of the convertopes includes the substitution, in each anchoring motif identified, of one or more of the residues P4, P6 or P9 if they do not meet the common criteria as defined above, by a more conforming amino acid, and preferably by an alanine.
  • the design of the convertopes may, in addition, include the substitution of one or more residues other than 1, 4, 6 or 9, according to a replaceability matrix promoting the recognition of the epitope by the T cell receptor, to the exclusion of residues common to 2 or more neighboring anchoring patterns and the substitution of which would be incompatible with the neighboring motif or with a substitution already carried out in it.
  • the mixtures of immunogenic peptides obtained by the process according to the invention are mainly intended for vaccination against the viruses from which these peptides are derived. More particularly, the present invention relates to a composition intended for vaccination against the hepatitis C virus. This composition comprises pairs of native sequences and degenerate sequences obtained by the process of the invention and chosen from the convertopes presented in the table I.
  • the vaccine composition can find not only prophylactic but also therapeutic applications to stimulate the immune reactions of already infected patients.
  • the sequences of these proteins are available on the SWISS-PROT database.
  • the process of identifying potential T epitopes and of designing, from these, convergent peptide libraries or "convertopes” comprises the following steps: - First step.
  • Potential anchoring reasons are identified based on the rules common to the majority of alleles of human MHC class II molecules HLA-DR, that is to say an aliphatic or aromatic amino acid (V, I, L, F, M,, Y ) in the first position of a portion of 9 residues, capable of interacting with the PI pocket.
  • this Pi pocket is not very polymorphic (presence of a simple val / gly dimorphism in position 86 of the ⁇ chain) and represents a recognition rule shared by all the alleles.
  • the presence of a hydrophobic, aliphatic or aromatic residue in the Pi position seems to be an essential condition for interaction with the corresponding anchoring pocket, this anchoring playing a dominant role in the interaction of the antigenic peptide with the molecule.
  • CMH by allowing in particular the formation of a stable complex.
  • sequences of the capsid proteins and NS3 and NS4 which exhibit a high density of these anchoring motifs have been identified and selected. They include 1 or 2 amino acids upstream of the first anchoring pattern and downstream of the last. These ends can be extended from 1 to 6 additional natural amino acids in order to include, in the sequence, charged amino acids which can facilitate the solubility of sequences too rich in hydrophobic residues.
  • 26 sequences were thus chosen: in the capsid protein, sequences ID No. 1 to 8; in the NS3 protein, sequences ID No. 9 to 21; in the protein NS4, the sequences ID No. 22, to 26.
  • positions P2, P3 , P5, P7 and P8 For amino acids not involved in potential anchoring to MHC class II molecules and likely to be involved in the interaction with the specific T cell receptor, i.e. positions P2, P3 , P5, P7 and P8, a substitution of these positions can be made, dedicated to specific recognition by T cells. These substitutions are intended to generate variants related to native peptides capable of generating an enlargement of the number of specific T cells native antigen. This enlargement is envisaged in view of the significant degeneration of the T recognition (Hemmer, B., Immunol. Today 1998 19: 163). Indeed, a clonal T cell has the capacity to recognize a very large number of related peptide antigens but also not related to the native sequence with, in certain cases, better affinity.
  • the substitutions made are based on a replaceable matrix of the Geysen type (Geysen M. et al, J. Mol. Recog 1998. 1, 32-41). This replaceability matrix was developed on the basis of peptide / antibody recognition, which is related to the recognition mode of the T cell receptor. The amino acids in position P2, P3, P5, P7 and P8 can be substituted except if they are involved in an anchoring position at a neighboring motif. Given the various possibilities of replacement suggested by the Geysen matrix, the substitutions will favor the amino acid having one of the best replaceability indexes.
  • amino acids involved in the potential interaction with an anchor pocket are represented by n O.
  • the CMH anchor points Pi, P4, P6 and P9 are associated within an anchor pattern according to a diagonal representation mode.
  • the natural amino acid substitutions, according to the rational method developed in the description, are indicated in subscript.
  • TCR T cell receptor
  • the peptides are synthesized using the conventional solid phase strategy of the Boc-benzyl (or Fmoc) type, in an automated peptide synthesizer (model 430A, APPLIED BIOSYSTEM, INC.).
  • the side chain protection groups are: Asn (Trt), Gln (Trt), Asp (Ochx), Glu (Ochx), Ser (Bzl), Thr (Bzl), Cys (4-MeBzl), and His (Dnp) (SHEPPARD RC et al., Peptide Synthesis Corp. Org. Che., 1979, 5: 321).
  • the amino acids are introduced using the HBTU / HOBt activation protocol with a systematic double coupling on a Boc-X-Pam resin (X representing the amino acid in the C-terminal position).
  • X representing the amino acid in the C-terminal position.
  • the cleaved and deprotected peptide is precipitated with cold diethyl ether, then dissolved in 5% acetic acid and lyophilized.
  • the peptide is purified to more than 90% on a column of 5 xrm x 250 rrm, 100a Nucleosyl C18 RP-HPLC preparative (MACHERY NAGEL, Duren, Germany).
  • the synthesis is carried out according to the method described above unlike degenerate positions where equimolar amounts of protected amino acids are used in coupling reactions in place of a single amino acid for conventional synthesis.
  • a first coupling is carried out with 1 mol (total amount) of Boc-a ino-acid (or of a mixture).
  • a second coupling using 2 ⁇ rmol (total quantity) is then systematically carried out.
  • the crude peptide is dissolved in trifluoroacetic acid and precipitated in a solution of cold diethyl ether. After centrifugation, the precipitate is dissolved in water and then purified by gel filtration on a TSK HW40S column (MERK, Darmstadt, Germany). An aliquot is subjected to acid hydrolysis to determine the amino acid composition.
  • the sequences of the native peptides and of the convertopes which are derived therefrom are presented in the sequence listing and in Table II. These products and various combinations thereof will be used as antigens for immunizations.
  • the evaluation of the immunogenicity of the peptides and convertopes is carried out according to two complementary approaches: on the one hand, by in vivo immunization of humanized mice; on the other hand, by in vitro immunization of human cells from typed HLA donors.
  • A) Mice deficient for murine MHC class II molecules (A ⁇ o) and transgenic for different human MHC class II molecules (DR1, DR2, DR3, DQ6, DQ8) are immunized with the mixtures of peptides chosen in proportion to three mice per condition.
  • mice are immunized with 100 micrograrr ⁇ ie ⁇ of peptides in a volume of 100 microliters of a water / complete Freund's adjuvant mixture by subcutaneous route.
  • the mice are restimulated once or twice, 15 days apart, with 50 micrograms of peptides in 100 microliters of Freund's incomplete water / adjuvant mixture.
  • a sample of sera from immunized mice is recovered before each injection in order to evaluate the production of specific antibodies as well as the production of cytokines in vivo.
  • the lymph nodes as well as the spleens of the different groups of animals are collected, mixed by group, then cultured to study the capacity to induce cell proliferation in vitro and the capacity to induce the production of cytokines.
  • B) In vitro communications are carried out as follows: CD14 + blood monocytes isolated by positive selection are differentiated into dendritic cells after placing in the presence of IL4 and "" of GM-CSF for 5 days. CD4 + cells isolated from the same donor are then immunized in vitro with the various mixtures of peptides and convertopes. Subsequent restimulation is carried out under the same conditions and then B lymphocytes from the same donor are used as antigen presenting cells. The production of different cytokines is sought in culture supernatants, 24 and 48 hours after in vitro immunization.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Virology (AREA)
  • Analytical Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
EP01938317A 2000-05-26 2001-05-23 Konvergente kombinatorischen peptid-bibliotheken und deren verwendung zur impfung gegen den virus von hepatitis c Withdrawn EP1290018A2 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0006744A FR2809402A1 (fr) 2000-05-26 2000-05-26 Bibliotheques peptidiques combinatoires convergentes et leur application a la vaccination contre le virus de l'hepatite c
FR0006744 2000-05-26
PCT/FR2001/001596 WO2001092311A2 (fr) 2000-05-26 2001-05-23 Bibliotheques peptidiques combinatoires convergentes et leur applicaton a la vaccination contre le virus de l'hepatite c

Publications (1)

Publication Number Publication Date
EP1290018A2 true EP1290018A2 (de) 2003-03-12

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EP01938317A Withdrawn EP1290018A2 (de) 2000-05-26 2001-05-23 Konvergente kombinatorischen peptid-bibliotheken und deren verwendung zur impfung gegen den virus von hepatitis c

Country Status (7)

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US (1) US20030194747A1 (de)
EP (1) EP1290018A2 (de)
JP (1) JP2004509071A (de)
AU (1) AU2001264010A1 (de)
CA (1) CA2409924A1 (de)
FR (1) FR2809402A1 (de)
WO (1) WO2001092311A2 (de)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2839722A1 (fr) * 2002-05-17 2003-11-21 Bio Merieux Nouvelles compositions peptidiques et leur utilisation notamment dans la preparation de compositions pharmaceutiques actives contre le virus de l'hepatite c
WO2010011870A2 (en) * 2008-07-24 2010-01-28 Anza Therapeutics, Inc. Compositions and methods for the treatment of hepatitis c
HK1200359A1 (zh) * 2011-09-17 2015-08-07 源道隆（苏州）医学科技有限公司 任意三个或以上氨基酸残基构成的多肽表位及其相关抗体的诱导

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BR9406652A (pt) * 1993-03-05 1996-09-10 Cytel Corp Composição
WO1995011998A1 (en) * 1993-10-26 1995-05-04 United Biomedical, Inc. Structured synthetic antigen libraries as diagnostics, vaccines and therapeutics
AU5849796A (en) * 1994-12-27 1996-08-07 United Biomedical Inc. Peptide ratchet libraries for ctl-inducing vaccines and therapeutics
GB9810756D0 (en) * 1998-05-19 1998-07-15 Angeletti P Ist Richerche Bio Mimotopes of hypervariable region 1 of the e2 glycoprotein of hcv and uses thereof

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Title
See references of WO0192311A2 *

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Publication number Publication date
US20030194747A1 (en) 2003-10-16
CA2409924A1 (fr) 2001-12-06
WO2001092311A2 (fr) 2001-12-06
WO2001092311A3 (fr) 2002-05-02
AU2001264010A1 (en) 2001-12-11
JP2004509071A (ja) 2004-03-25
FR2809402A1 (fr) 2001-11-30

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