WO1998023635A1 - Nouveaux epitopes ubiquistes de lymphocyte t auxiliaire - Google Patents

Nouveaux epitopes ubiquistes de lymphocyte t auxiliaire Download PDF

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Publication number
WO1998023635A1
WO1998023635A1 PCT/AU1997/000820 AU9700820W WO9823635A1 WO 1998023635 A1 WO1998023635 A1 WO 1998023635A1 AU 9700820 W AU9700820 W AU 9700820W WO 9823635 A1 WO9823635 A1 WO 9823635A1
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peptide
amino acid
acid sequences
sequences encoding
epitope
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PCT/AU1997/000820
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English (en)
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Ian Hector Frazer
Robert Tindle
Rania Azoury-Ziadeh
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The University Of Queensland
Csl Limited
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Priority to AU51112/98A priority Critical patent/AU5111298A/en
Publication of WO1998023635A1 publication Critical patent/WO1998023635A1/fr

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • 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
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/525—Virus
    • A61K2039/5258—Virus-like particles
    • 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
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6031—Proteins
    • A61K2039/6075—Viral proteins
    • 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
    • A61K2039/70—Multivalent vaccine
    • 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
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/20011—Papillomaviridae
    • C12N2710/20022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • 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
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/20011—Papillomaviridae
    • C12N2710/20034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • TITLE "NOVEL PROMISCUOUS T HELPER CELL EPITOPES" FIELD OF INVENTION
  • This invention relates to promiscuous T helper cell epitopes, and in particular, novel promiscuous T helper cell epitopes which have utility in the development of novel peptide-based vaccines.
  • the invention also extends to vaccine compositions which include the novel promiscuous epitopes of the invention which may be useful in eliciting an immune response against PV and particularly HPV (human papillomavirus) in a host animal.
  • HPV human papillomavirus
  • Papillomaviruses induce benign hyperproliferative lesions in humans and in many animal species, some of which undergo malignant conversion.
  • the biology of papillomavirus infection is summarised in a review by J. P. Sundberg entitled “Papillomavirus Infections in Animals” In “Papillomaviruses and Human Disease” edited by K. Syrjanen, L. Gissmann and L. G. Koss, Springer Verlag (1987).
  • Papillomaviruses are a family of small DNA viruses encoding up to eight early (E1 , E2, E3, E4, E5, E6, E7 and E8) and two late genes (L1 and L2). These viruses have been classified in several distinct groups such as HPV which are differentiated into types 1 to 70 depending upon DNA sequence homology. A clinicopathological grouping of HPV and the malignant potential of the lesions with which they are most frequently associated are summarised in "Papillomaviruses and Human Cancer" by H. Pfister, CRC Press, Inc. (1990).
  • HPV type 1 (HPV-1 ) is present in plantar warts
  • HPV-6 or HPV-11 are associated with condylomata acuminata (anogenital warts)
  • HPV-16 or HPV-18 are common in pre- malignant and malignant lesions of the cervical squamous epithelium.
  • HPV-16 E6 Stacey et al., 1992, J. Gen. Virol. 73 2337; Bleul et al., 1991 , J. Clin. Microbiol. 29 1579; Dillner, 1990, Int. J. Cancer 46 703; and M ⁇ ller e. a/., 1992, Virology 187 508
  • HPV-16 E2 Dillner et al., 1989, Proc. Natl. Acad. Sci. USA 863838; Dillner, 1990, supra; Lehtinen et al., 1992, J. Med. Virol.
  • Peptides can be synthesised in large quantities with high purity and are chemically well defined. Synthetic peptides can be designed to incorporate any antigenic B and T epitope (Tindle et al., 1991 , Proc. Natl. Acad. Sci. USA 88 5887-5891 ), and exclude potentially deleterious or dangerous functional domains of a protein (Berzofsky, J. A., 1991 , FASEB J. 5 2412-2418).
  • uncoupled, carrier free peptide or peptides must contain domains which activate T-helper (Th) cells as well as B-cells so as to facilitate their cognate interaction leading to the development of an effective immune response (Mitchinson, 1971 , Eur. J. Immunol. 1 10-17; Mitchinson, 1971 , Eur. J. Immunol. 1 18-24; Abbas et al., 1985, J. Immunol. 135 1661-1667).
  • cytotoxic T lymphocyte CTL activation which activation is important for effective immune control of tumours and viral infections.
  • CTL cytotoxic T lymphocyte
  • recent experiments have shown that induction of antigen-specific CTL can be effected by linking a Th- cell epitope directly or indirectly to a CTL epitope.
  • Th-cell determinants The identification of defined Th-cell determinants and their use to provide effective carrier help to short constructs representing a B-cell epitope or CTL epitope have made it possible to synthesize putative immunogens.
  • the use of Th-cell epitopes in the development of potentially immunogenic chimeric constructs has generally been restricted because of the propensity of Th-cells only to provide 'help' to B-cells and/or CTLs displaying the same processed MHC-restricted form of the antigen.
  • the inclusion of Th-cell epitopes in chimeric constructs comprising B-cell and/or CTL determinants is genetically restricted to only one or a few alleles of the MHC with limited activity across divergent MHC class II haplotypes.
  • Th-cell epitopes which can be recognized in the context of several MHC (as well as HLA) haplotypes have been identified in a number of proteins.
  • Partidos et al. (1991 , J. Gen. Virol. 72 1293-1299) have identified a Th-cell epitope from the fusion protein (F) of measles virus which is immunogenic in a panel of mouse strains of different H-2 types and in seven of 10 humans tested.
  • F fusion protein
  • Copolymer 1 a synthetic basic random copolymer of amino acids that has been shown to be effective in suppression of experimental allergic encephalomyelitis (EAE)
  • EAE experimental allergic encephalomyelitis
  • Th-cell epitopes derived from tetanus toxin, sperm-whale myoglobin and streptococcal protein have been found capable of imparting help to B-cell determinants taken, respectively, from the human malarial parasite Plasmodium falciparum (Etlinger ef a/., 1990, Science, 249 423-425; Kumar et al., 1992, J. Immunol. 148 1499-1505), foot-and-mouth disease virus (Francis et al., 1987, Nature 300 168-170) and hepatitis B virus (LeClerc et al., 1987, Eur. J. Immunol. 17 269-273).
  • DRAHYNI the promiscuous Th-cell minimal proliferative epitope
  • HPV human papillomavirus
  • Th-cell epitopes In view of the plethora of Th-cell epitopes defined in the literature which epitopes have been derived from a myriad of different organisms, only a few have been shown to be reactive on several MHC backgrounds (Kaumaya et al., 1993, J. Mol. Recognit. 6 81-94; Domanico et al., 1993, Eur. J. Immunol. 23 1011-1016; Reece et al., 1994, J. Immunol. Methods 171 241-254).
  • the current invention arises from the unexpected discovery that peptide sequences within HPV-16 E6, which have substantially different structures to the DRAHYNI epitope of HPV-16 E7, are reactive on several
  • HPV-16 E6 peptides when combined with different B-cell epitopes in chimeric peptide constructs elicit specific antibodies which react with peptides containing the B-cell epitopes.
  • T-cell epitopes which chimeric peptides may be utilized to generate immune responses against the B-cell epitope(s) and/or the cytotoxic T-cell epitope(s).
  • a peptide encoding a promiscuous T helper cell epitope for generating an immune response against papillomavirus, said peptide selected from the group consisting of:-
  • VYRDGNPYA inclusive of a single amino acid deletion, substitution or addition made therein
  • QYNKPLCDLL inclusive of a single amino acid deletion, substitution or addition made therein
  • the invention also contemplates 'peptide homologs' of peptides according to SEQ ID NO 1 and SEQ ID NO 2.
  • the invention also includes within its scope peptides which are functionally similar to those defined in SEQ ID NO 1 and SEQ ID NO 2.
  • conservative amino acid substitutions can be made in peptides according to SEQ ID NO 1 and SEQ ID NO 2 (parent peptides) and that such substituted peptides will retain the functional characteristics of the parent peptides.
  • the peptides of the invention may be prepared using any suitable procedure. Preferably, such peptides are synthesized either manually or by using an automated peptide synthesiser.
  • Peptides according to SEQ ID NO 1 and SEQ ID NO 2 and peptide homologs thereof may be synthesised using solution synthesis or solid phase synthesis as described, for example, in Chapter 9 entitled “Peptide Synthesis” by Atherton and Shephard which is included in a publication entitled “Synthetic Vaccines” edited by Nicholson and published by Blackwell Scientific Publications.
  • a peptide in accordance with the invention may be prepared by a procedure including the steps of: (a) ligating a nucleotide sequence encoding a peptide according to SEQ ID NO 1 , SEQ ID NO 2 or peptide homolog thereof into a suitable expression vector to form an expression construct;
  • an expression construct is a nucleotide sequence comprising a first nucleotide sequence encoding a peptide according to SEQ ID NO 1 , SEQ ID NO 2 or peptide homolog thereof wherein said first sequence is operably linked to regulatory nucleotide sequences (such as a promoter and a termination sequence) that will facilitate expression of said first sequence. Both constitutive and inducible promoters may be useful adjuncts for expression of the peptides according to the invention.
  • the expression construct preferably includes a vector, such as a plasmid cloning vector.
  • a vector according the invention may be a prokaryotic or a eukaryotic expression vector, which are well known to those of skill in the art.
  • Suitable host cells for expression may be prokaryotic or eukaryotic.
  • One preferred host cell for expression of a peptide according to the invention is a bacterium.
  • the bacterium used may be Escherichia coli.
  • the recombinant peptide may be conveniently prepared by a person skilled in the art using standard protocols as for example described in Sambrook et al. (1989, second edition, Cold Spring Harbor Laboratory Press, in particular Sections 16 and 17).
  • nucleotide sequence designates mRNA, RNA, cRNA, cDNA or DNA.
  • a nucleotide sequence encoding the peptides of the invention may be conveniently prepared by taking advantage of the genetic code and synthesising, for example, by use of an oligonucleotide sequencer, a sequence of nucleotides which when translated by a host cell results in the production of a peptide according to SEQ ID NO 1 , SEQ ID NO 2 or peptide homolog thereof.
  • each of the peptides according to SEQ ID NO 1 and SEQ ID NO 2 comprises minimal T helper cell proliferative sequences which are considered to incorporate the key “anchor" amino acid residues required for binding an MHC class II molecule.
  • peptides associated with MHC class II molecules may comprise 10 to 34 amino acid residues, and the optimal length of a T helper cell epitope has been defined crystallographically and otherwise to be between 13 and 20 amino acids (Appella et al., 1995, EXS. 73 105-119 which is hereby incorporated by reference).
  • the invention contemplates a peptide of 10 to 34 amino acids corresponding to a natural sequence of amino acids encoded by HPV16 E6 or homologous sequence thereof which natural or homologous sequence comprises the amino acid sequence defined by SEQ ID NO 1 or peptide homolog thereof and/or the amino acid sequence defined by SEQ ID NO 2 or peptide homolog thereof.
  • the invention provides a peptide of 13 to 20 amino acids corresponding to a natural sequence of amino acids encoded by HPV16 E6 or homologous sequence thereof which natural or homologous sequence comprises the amino acid sequence defined by SEQ ID NO 1 or peptide homolog thereof and/or the amino acid sequence defined by SEQ ID NO 2 or peptide homolog thereof.
  • a chimeric peptide construct for generating an immune response against one or more B-cell epitopes and/or one or more CTL epitopes said peptide construct comprising a peptide in accordance with SEQ ID NO 1 or peptide homolog thereof linked directly or indirectly to one or more amino acid sequences encoding the or each B-cell epitope and/or one or more amino acid sequences encoding the or each CTL epitope.
  • a chimeric peptide construct for generating an immune response against one or more B-cell epitopes and/or one or more CTL epitopes said peptide construct comprising a peptide in accordance with SEQ ID NO 2 or peptide homolog thereof linked directly or indirectly to one or more amino acid sequences encoding the or each B-cell epitope and/or one or more amino acid sequences encoding the or each CTL epitope.
  • the chimeric peptide construct comprises between 10 and 34 amino acids. More preferably, the chimeric peptide construct comprises between 10 and 20 amino acids.
  • B-cell epitopes may be selected from any suitable source including but not necessarily limited to pathogenic organisms such as pathogenic viruses.
  • a suitable pathogenic virus which may be used as a source of B-cell epitopes includes papillomavirus.
  • the B-cell epitopes may comprise HPV16 E7 B-cell epitopes which include QAEPD, IDGP, EYMLD and YMLD.
  • suitable B-cell epitopes that may be selected from HPV 18 E7 epitopes include DEIDGVNHQL and SEENED.
  • CTL epitopes are preferably selected from a tumor or viral source.
  • the virus may be a papillomavirus.
  • the CTL epitope may be selected from human CTL epitopes in HPV16
  • the CTL epitope may comprise a measles protein CTL epitope as described in an article by Hsu et al. (1996, Vaccine 14 1159-1166 which is hereby incorporated by reference) or an Adenovirus CTL epitope as described by Toes et al. (1996,
  • X denotes a promiscuous T helper cell epitope comprising peptides selected from SEQ
  • N1 , N4 and N5 represent B-cell epitope or CTL epitope sequences that may be linked to said promiscuous epitope sequences indirectly through intervening sequences of amino acids that are not B-cell or CTL epitope sequences such as A1 and A2.
  • the B-cell or CTL epitope sequence may be linked directly to the promiscuous T helper epitope sequence and in such a case in a first situation the terminal amino acid of the B-cell or CTL epitope sequence and the first amino acid of said promiscuous epitope sequence may be merged. In other cases, in a second situation the last amino acid of the promiscuous T helper epitope sequence and the first amino acid of the B-cell or CTL epitope sequence may also be merged.
  • N2 represents a B-cell or CTL epitope sequence which refers to the first situation and N3 represents a B-cell or CTL epitope sequence that represents the second situation.
  • SEQ ID NO 1 and SEQ ID NO 2 have been identified as corresponding to two major T helper cell epitopes in the E6 open reading frame (ORF) of HPV16.
  • ORF open reading frame
  • Peptides according to SEQ ID NO 1 and SEQ ID NO 2 are each capable of eliciting strong antibody responses to HPV16 E6 challenge across a wide range of MHC class II backgrounds.
  • chimeric constructs in accordance with the present invention comprising peptides according to SEQ ID NO 1 and SEQ ID NO 2 may facilitate the production of antibody to several B-cell epitopes simultaneously as well as several CTL epitopes simultaneously.
  • the invention also includes within its scope an immunogenic composition comprising one or more of the abovementioned peptides and a suitable adjuvant or delivery vehicle.
  • Suitable adjuvants may be selected from Freunds Complete Adjuvant, Freunds Incomplete Adjuvant, QuilA and saponins generally.
  • the adjuvant is capable of eliciting CD8 + MHC class I restricted cytotoxic T lymphocytes.
  • Suitable delivery vehicles in which the peptides of the invention may be delivered into a host animal include, but are not necessarily limited to, liposomes, membranous vehicles and microspheres which are well known to those skilled in the art.
  • the delivery vehicle may be an immunostimulating complex (ISCOM).
  • ISCOM immunostimulating complex
  • Suitable methods for incorporation of peptides into ISCOMs include coupling peptides to influenza virus envelope glycoproteins which have already been incorporated into ISCOMs (Lovgren et al., 1987, supra; Lovgren and Larsson, supra), or coupling cysteine- containing peptides to preformed influenza ISCOMs using a heterobifunctional reagent (Larsson et al., 1993, J. Immunol.
  • peptides may be incorporated into ISCOMs by copolymerisation with the lipid binding peptide LAP20 (Fernando et al., 1994, In “Vaccines 94", pp 327-331 , Cold Spring Harbour Laboratory Press).
  • a preferred delivery vehicle contemplated by the invention is a chimeric VLP including a modified viral capsid protein having one or more peptides of the invention fused thereto.
  • the chimeric VLP may comprise the modified viral capsid protein alone.
  • the chimeric VLP may comprise the modified viral capsid protein in association with one or more other viral capsid proteins which may be required for assembly of the chimeric VLP.
  • the modified viral capsid protein may be prepared from any parent viral capsid protein, including a natural viral capsid protein, which when fused with the one or more peptides results in a modified viral capsid protein which is capable of incorporating into a chimeric VLP.
  • the parent viral capsid protein includes, but is not limited to, a papillomavirus capsid protein or a parvovirus capsid protein. Accordingly, the parent viral capsid protein may comprise an L1 protein or an L2 protein of a papillomavirus. In the case of parvovirus, the parent viral capsid protein may comprise a VP2 capsid protein.
  • foreign peptides can be incorporated into a viral capsid protein to produce chimeric VLPs which can be used to present foreign antigens to an immune system. Suitable methodologies for production of such chimeric VLPs are also known.
  • the peptides of the invention may be fused to a papillomavirus 1 L1 capsid protein as described, for example, in Muller et al (1997, Virology 23493-111 ), or fused to a papillomavirus L2 capsid protein as described, for example, in United States Patent No 5,618,536 (Lowy et al) which is hereby incorporated by reference, or fused to a porcine parvovirus VP2 capsid protein as described, for example, in Sedlik et al (1997, Proc. Natl. Acad. Sci. USA 94 7503-7508) which is hereby incorporated by reference.
  • the above exemplary methods of producing chimeric VLPs essentially involve construction of a synthetic DNA molecule encoding the modified viral capsid protein and subsequent expression of this protein in a suitable host cell to facilitate assembly of the chimeric VLP.
  • a suitable host cell to facilitate assembly of the chimeric VLP.
  • such expression may require co-expression of one or more other viral capsid proteins for assembly of the chimeric VLP.
  • the synthetic DNA molecule may be prepared using any suitable method for altering DNA. Such methods are well known to those of skill in the art and are described for example in the relevant sections of CURRENT PROTOCOLS IN MOLECULAR BIOLOGY (Ausubel, et al., eds.) (John Wiley & Sons, Inc. 1995) and of Sambrook, et al., MOLECULAR CLONING. A LABORATORY MANUAL (Cold Spring Harbor Press, 1989) which are hereby incorporated by reference. Alternatively, suitable methods for altering DNA are set forth, for example, in U.S. Patent Nos 4,184,917, 4,321 ,365 and 4,351 ,901 which are hereby incorporated by reference.
  • the synthetic DNA molecule may be ligated into a suitable expression vector to produce a recombinant expression vector may be introduced subsequently into a host cell for expression of the modified viral capsid protein.
  • the expression vector is a baculovirus expression vector and the host cell is a Spodoptera frugiperda 9 (Sf-9) insect cell.
  • FIG. 1 refers to a set of overlapping peptides (termed GF51- GF66) spanning the putative HPV16 E6 protein molecule;
  • FIG.2 illustrates the overlapping pattern of the peptides of FIG.
  • FIG. 3A is a bar graph showing the in vitro proliferative response of LNCs from H-2 b mice immunized subcutaneously with saline: CFA, and challenged with individual HPV16 E6 peptides
  • FIG. 3B is a bar graph showing the in vitro proliferative repsonse of LNCs from H-2 b mice immunized subcutaneously with saline: CFA, and challenged with PPD + individual HPV16 E6 peptides;
  • FIG. 4A is a bar graph showing the in vitro proliferative response of LNCs from H-2 mice immunized with peptides GF51-GF54;
  • FIG. 4B is a bar graph showing the in vitro proliferative response of LNCs from H-2 b mice immunized with peptides GF55-GF58;
  • FIG. 4C is a bar graph showing the in vitro proliferative response of LNCs from H-2 b mice immunized with peptides GF59-GF62;
  • FIG. 4D is a bar graph showing the in vitro proliferative response of LNCs from H-2 b mice immunized with peptides GF63-GF66;
  • FIG. 5A illustrates the in vitro proliferative response of LNCs from H-2 mice immunized subcutaneously with an equimolar mixture of peptide GF56;
  • FIG. 5B is a bar graph showing the in vitro proliferative response of LNCs from H-2 b mice immunized subcutaneously with an equimolar mixture of peptide GF57;
  • FIG. 5C is a bar graph showing the in vitro proliferative response of LNCs from H-2 mice immunized subcutaneously with an equimolar mixture of peptide GF61 ;
  • FIG. 5D is a bar graph showing the in vitro proliferative response of LNCs from H-2 b mice immunized subcutaneously with an equimolar mixture of peptide GF66;
  • FIG. 5E is a bar graph showing the in vitro proliferative response of LNCs from H-2 b mice immunized subcutaneously with an equimolar mixture of peptide GF51 ;
  • FIG. 6A is a bar graph showing the T-proliferative response of
  • FIG. 6B is a bar graph showing the T-proliferative response of LNCs from B10 (H-2 a ) mice immunized with an equimolar mixture of peptides GF56, GF57, and GF61 in CFA, and challenged in vitro with individual peptides;
  • FIG. 6C is a bar graph showing the T-proliferative response of LNCs from B10 (H-2 k ) mice immunized with an equimolar mixture of peptides GF56, GF57, and GF61 in CFA, and challenged in vitro with individual peptides;
  • FIG. 6D is a bar graph showing the T-proliferative response of LNCs from B10 (H-2 d ) mice immunized with an equimolar mixture of peptides GF56, GF57, and GF61 in CFA, and challenged in vitro with individual peptides;
  • FIG. 6E is a bar graph showing the T-proliferative response of
  • FIG. 6F is a bar graph showing the T-proliferative response of LNCs from B10 (H-2 h4 ) mice immunized with an equimolar mixture of peptides GF56, GF57, and GF61 in CFA, and challenged in vitro with individual peptides;
  • FIG. 7 illustrates the mapping of the minimal T-cell proliferative epitope in the GF57 peptide of HPV16E6 protein
  • FIG. 8A is a bar graph showing the in vitro proliferative response of LNCs from C57BL/6 mice immunized subcutaneously with peptide GF57, and challenged with 20 ⁇ g/mL GF57 overlapping truncated peptides;
  • FIG. 8B is a bar graph showing the in vitro proliferative response of LNCs from C57BL/6 mice immunized subcutaneously with peptide GF57, and challenged with 5 ⁇ g/mL GF57 overlapping truncated peptides;
  • FIG. 9 illustrates the mapping of the minimal T-cell proliferative epitope in the GF61 peptide of HPV16E6 protein
  • FIG. 10A is a bar graph showing the in vitro proliferative response of LNCs from C57BL/6 mice immunized subcutaneously with peptide GF61 , and challenged with 20 ⁇ g/mL GF57 overlapping truncated peptides;
  • FIG. 10B is a bar graph showing the in vitro proliferative response of LNCs from C57BL/6 mice immunized subcutaneously with peptide GF61 , and challenged with 5 ⁇ g/mL GF57 overlapping truncated peptides;
  • FIG. 11A is a bar graph showing the in vitro proliferative response of LNCs from C57BL/6 mice immunized subcutaneously with peptide GF51 , and challenged with 20 ⁇ g/mL GF57 overlapping truncated peptides;
  • FIG. 11 B is a bar graph showing the in vitro proliferative response of LNCs from C57BL/6 mice immunized subcutaneously with peptide GF51 , and challenged with 5 ⁇ g/mL GF57 overlapping truncated peptides
  • FIG. 12A is a bar graph showing the in vitro proliferative response of LNCs from C57BL/6 mice immunized subcutaneously with peptide GF51 , and challenged with 20 ⁇ g/mL GF61 overlapping truncated peptides;
  • FIG. 12B is a bar graph showing the in vitro proliferative response of LNCs from C57BL/6 mice immunized subcutaneously with peptide GF51 , and challenged with 5 ⁇ g/mL GF61 overlapping truncated peptides;
  • FIG. 13A is a bar graph showing the effect of 'VYRDGNPYA' T h -epitope on the antibody response to ⁇ YMLD' B-epitope;
  • FIG. 13B is a bar graph showing the effect of 'QYNKPLCDLL'
  • FIG. 13C is a bar graph showing the effect of 'VYRDGNPYA' T h -epitope on the antibody response to 'QAEPD' B-epitope;
  • FIG. 13D is a bar graph showing the effect of 'QYNKPLCDLL' T h -epitope on the antibody response to 'QAEPD' B-epitope.
  • FIG. 14 is a map of recombinant vector pVLBPVI L1/Thprom- QAEPD.
  • buffers Unless otherwise specified, buffers were prepared according to Sambrook et al. (1989, MOLECULAR CLONING. A LABORATORY
  • HPV16 E6 and HPV16 E7 proteins were produced as MS2- fusion proteins from a heat-inducible phage promoter in a pPLc24 expression vector (provided by L. Gissmann, DKFZ, Heidelberg, Germany) in E. coli C600/537 by sequential urea extraction, as described by Seedorf et al. 1987.
  • the expression vector pPLc24 allows the expression of inserts fused to the N-terminal part (the first 98 aas) of the MS2 polymerase under the control of the lambda P L promoter which does not contain the cl gene coding for repressor (Remaut et al., 1981 , Gene 15 81-93; Remaut et al., 1983, Gene 22 103-113; Remaut et al., 1983, Nucleic Acids Res. 11 4677- 4688). But since the E.
  • coli C600/537 strain harbors a temperature-sensitive cl repressor gene of phage lambda on a multicopy plasmid conferring kanamycin resistance
  • expression of the pPLc24 vector was induced in log phase cells by incubating at 42°C for 3 hrs. After induction, cells of a 1 L LB broth culture were first washed with Bacterial Wash Buffer, then lysed in 40 imL Bacterial Lysis Buffer in the presence of 8 mg lysozyme and incubated, with shaking, at 37°C for 30 min. Next, MS2-replicase fusion proteins were partly purified by the addition of 0.1% Triton X-100.
  • the final pellet was also stored at -70 O for further testing.
  • SDS-PAGE Western Blotting and estimating the percentage of purity of the 7M Urea supernatant, the latter was dialyzed against PBS at 4°C, using a 12,000 mwt cut off membrane.
  • the other gel was transferred by Western Blotting onto a nitrocellulose membrane using SDS Transfer Buffer at a 100 V according to standard procedures.
  • the blot was blocked with 5% skim milk powder in PBS Blocking Buffer (PBS/milk) at 4°C o/n.
  • PBS Blocking Buffer PBS/milk
  • the second day it was incubated at RT for 1-1.5 hr with a rabbit polyclonal anti HPV16 E6/MS2 antiserum (previously prepared in our laboratory) diluted 1 :200 in PBS/milk. This was followed by 3 washes (each for 10 min) with the following Wash Buffer: 5% skim milk powder in PBS + 0.1% Triton X-100.
  • Reagent A Basic reagent
  • BCA bicinchoninic acid
  • sample or bovine serum albumin, BSA, standard or blank
  • Working Reagent 50 parts Reagent A + 1 part Reagent B
  • absorbance at 540 nm was determined by spectrophotometry using a Titertek Multiskan reader.
  • the protein concentration was estimated by comparison of the mean OD540 (mean of 3 wells) obtained with the sample, with that obtained with the BSA standards.
  • inbred mouse strains were obtained from the Animal Resources Centre (Perth, Australia) and were used at 7-10 weeks of age.
  • inbred Balb/c mice these were obtained from the same source and were used at 4-12 weeks of age.
  • Overlapping synthetic peptides covering the entire HPV16 E6 ORF were used as antigens. These peptides were synthesized using 9-fluorenylmethoxycarbonyl (Fmoc) chemistry on an Applied Biosystems 431 A peptide synthesizer. After obtaining the 'peptide- resin' conjugates, the actual peptide was next cleaved from its resin by the addition of thioanisole and ethanedithiol, and then ether purified.
  • Fmoc 9-fluorenylmethoxycarbonyl
  • HPV16 E6 protein was produced as an MS2 fusion protein as described above. Fusion protein was then dialyzed against PBS for use in proliferation assays.
  • Lymph Node Cell LNC Proliferation Assays Mice were immunized subcutaneously in the base of the tail with about 50 ⁇ g of peptide emulsified in Complete Freund's Adjuvant (H37 Ra. CFA, Difco).
  • DMEM Dulbecco's Modification of Eagle's Medium
  • the LNCs suspension was prepared at a concentration of 2x10 6 cells per mL in cDMEM containing 10% FCS.
  • a four day proliferation assay (at 37°C) (Good et al. , 1987, Science 235 1059-1062) was conducted in peptide-coated microtiter plates where every peptide-coated well was allowed to interact with 4x10 5 LNCs/mL (200 ⁇ L of LNCs suspension).
  • Wells coated with Purified Protein Derivative (PPD) or cDMEM were used as positive and negative controls, respectively.
  • LNCs lymph-node cells
  • PPD purified protein derivative
  • mice were immunized with equimolar mixes of peptides GF51 - GF54, GF55 - GF58, GF59 - GF62 or GF63 - GF66 respectively in CFA. Pooled LNCs from each group were challenged in vitro with individual peptides at 2 or 20 ⁇ g/mL.
  • Peptide GF57 elicited strong proliferation and GF56 weaker proliferation in LNCs from the GF55 - GF58 immunized group (FIGS.4A, 4B, 4C and 4D). Moreover, a proliferative response was elicited with peptide GF61 in LNCs from the GF59 - GF62 immunized group (FIGS. 4A, 4B, 4C and 4D). No further peptides from GF51 - GF66 series induced proliferation in assays using LNCs from appropriately immunized H-2 b mice.
  • C57BL/6 mice were then immunized with mixtures of peptides GF56, GF57, GF61 and irrelevant peptide GF66 in CFA.
  • LNCs from these mice were challenged in vitro with individual peptides at different concentrations (20 ⁇ g/mL, 10 ⁇ g/mL, 5 ⁇ g/mL, 2.5 ⁇ g/mL, 1.25 ⁇ g/mL and 0.63 ⁇ g/mL).
  • 5A, 5B, 5C, 5D and 5E shows that the LNCs response to peptides GF56, GF57 and GF61 decreased with decreasing concentration of the challenging peptide and that the minimal dose of challenging peptide which would still elicit good proliferation is 5 ⁇ g/mL. No response to challenging control peptides GF66 or GF51 was noticed.
  • peptides GF56, GF57 and GF61 each contains a T-proliferative epitope(s) reactive in H-2 b mice; while peptide GF56 contains a "promiscuous" T-epitope, reactive on several murine MHC backgrounds.
  • LNCs from GF57 immunized mice were challenged in vitro with a series of overlapping peptides, truncated by 1 amino acid from either the N-terminal or the C-terminal, and covering the whole length of peptide GF57 (FIG. 7) at different concentrations (20 ⁇ g/mL, 5 ⁇ g/mL, 2 ⁇ g/mL and 0.5 ⁇ g/mL).
  • LNCs did not proliferate when challenged with peptides GF61 /17-18, probably because of the Leucine and Isoleucine being two hydrophobic residues at the C- terminal end of the peptide molecule competing to fit into the T-cell receptor groove on the antigen presenting cell (APC) and resulting in an unstable peptide molecule.
  • H-2 b mice were immunized three times at two weekly intervals with a subunit vaccine consisting of synthetic peptides containing either VYRDGNPYA or QYNKPLCDLL T-epitope linked to known HPV16 E7 B-cell epitopes (Tindle et al, 1990, J. Gen. Virol. 71 1347-1354):
  • the defined proliferative T-epitopes in HPV16 E6 are actually functional T-helper epitopes that can be used for eliciting cognate interaction between T- and B-lymphocytes for the production of antibody against the B-cell epitopes.
  • the , 51 DFAFRDLCIVYRDGNPYA 68 ' peptide GF56 was shown to contain a promiscuous T-proliferative epitope, reactive on several MHC backgrounds.
  • T-epitope immunodominance depends on several mechanisms such as antigen processing, competition for binding to MHC, hindering structures outside the minimal epitopes and structures of the T-cell site (Partidos and Steward, 1992, J. Gen. Virol. 73 1987-1994; Boehncke et al., 1993, ; Grewal et al., 1995; Moudgil et al., 1996).
  • GF56 contains a T-epitope other than 'VYRDGNPYA', which is proliferative on several MHC haplotypes.
  • 'QYNKPLCDLL' are located adjacently to 'Cys-X-X-Cys' motifs, 'VYRDGNPYA' being localised to the first loop formed by the four 'Cys-X-X- Cys' motifs present in HPV16 E6 and 'QYNKPLCDLL' present in the region between the loops. It is believed that these motifs play an important role in the function of the E6 protein. They are involved in metal binding and have been shown to be involved in transcriptional regulation (Lamberti et al., 1990, EMBO J. 9 1907-1913) and contribute to E6-mediated transformation by binding to p53 and enhancing its degradation.
  • 'VYRDGNPYA' and 'QYNKPLCDLL' are capable of eliciting cognate interaction between T- and B-lymphocytes and therefore may be used generically to produce a subunit synthetic peptide vaccine consisting of a promiscuous T helper cell epitope according to the invention, in combination with one or more B-cell epitopes and/or one or more CTL epitopes, to generate immune responses against the B-cell and/or CTL epitopes.
  • the defined promiscuous T-helper epitopes in HPV16 E6 protein are reactive with a plurality of different MHC class II haplotypes and thus may be used in a vaccine construct to treat HPV infections by providing immunity to HPV infection across a broad spectrum of MHC backgrounds.
  • baculovirus transfer vector Primers 5'-CCGCAATCCATGGCGTTGTGGCAACAAGGCC- AGAAGC-3' and 5'-CCGGAATTCTTATTTTTTATCAGGTTCAGCTT- GAGCATAAGGATTGCCATCCCGATAAACTCCTGCCCCTTGCTGTGCT AAAAATCTTCTTCC-3' may be utilized to allow amplification by PCR of a hybrid nucleotide sequence encoding a modified BPV1 L1 gene in which a chimeric peptide comprising the minimal promiscuous epitope VYRDGNPYA and the HPV16 E7 B-cell epitope QAEPD, is fused to the C-terminus of the BPV1 L1 sequence.
  • This fusion would result in deletion of nucleotides from 7625 downstream of the BPV1 nucleotide sequence.
  • the above primers would also facilitate insertion of a stop codon, and one flanking BamYW site at the 5' end and a flanking ⁇ coRI site at the 3' end of the hybrid nucleotide sequence.
  • the PCR products could be digested with SamHI and EcoRI and inserted subsequently into the baculovirus transfer vector pVL1393 (Pharmingen) at the BamYW and EcoRI sites thereof before transformation of DH-5 ⁇ cells. Recombinant clones having the correct sequence could be confirmed by restriction endonuclease and nucleotide sequence analyses.
  • a map of a recombinant baculovirus transfer vector pVLBPV1 L1/Thprom-QAEPD so produced is shown in FIG. 14.
  • Recombinant baculoviruses could be produced according to Pharmingen's BaculoGoldTM transfection kit. Briefly, Spodoptera frugiperda 9 (Sf-9) insect cells are co-transfected with BaculoGoldTM linearized DNA and the recombinant transfer vectors. Preferably, plaque purification is used to ensure no non-recombinant (wild-type) plaques are detected. High-titer (> 10 8 /mL virus particles) stocks of recombinant baculoviruses are obtained subsequently by two rounds of amplification.
  • Spodoptera frugiperda 9 (Sf-9) insect cells are co-transfected with BaculoGoldTM linearized DNA and the recombinant transfer vectors.
  • plaque purification is used to ensure no non-recombinant (wild-type) plaques are detected.
  • High-titer (> 10 8 /mL virus particles) stocks of recombinant baculoviruses are obtained subsequently
  • the cell suspension is then homogenized with a dounce homogenizer (tight pestle) by 50 strokes on ice and then centrifuged at 3000 rpm for 10 min at 4°C to separate the nuclear fraction.
  • the nuclear pellet is then resuspended in an appropriate resuspension buffer and sonicated for 45 sec on ice.
  • the nuclear suspension is then loaded onto a 20% sucrose cushion and centrifuged at 26,000 rpm in a Beckman SW-26 rotor at 4°C for 2 h. The pellets are then resuspended in resuspension buffer and sonicated again for another 45 sec.
  • the resulting sonicate is then mixed with CsCI and centrifuged at 21 °C in a Beckman SW 41 rotor for 20 H.
  • a band at the CsCI density of about 1.30 g/mL is then collected and dialysed against PBS.
  • the sample may then be used for Western immunoblotting and for transmission electron microscopic analysis for confirming respectively the integrity of the modified BPV1 L1 capsid protein and chimeric VLP structure.
  • FIG. 1 A set of overlapping peptides (termed GF51-GF66) spanning the putative HPV16 E6 protein molecule. These peptides were synthesized by Fmoc chemistry. Peptides are shown using the single letter code. The numbers of the first and last amino acids of each peptide correspond to amino acid numbers of the HPV16 E6 polypeptide sequence.
  • FIG. 2 Overlapping pattern of the peptides of FIG. 1 relative to the amino acid sequence of HPV16 E6 protein.
  • the first and last amino acid (single letter code) indicated for each peptide correspond to the amino acid numbering of HPV16 E6 protein.
  • FIGS. 3A and 3B Mitogenicity and toxicity assays of the HPV16 E6 overlapping peptides. Each recall peptide was used at two different concentrations: 20 ⁇ g/mL (hatched bars), and 2 ⁇ g/mL (dotted bars). "NIL" represents background (no added antigen).
  • FIGS. 4A - 4D LNC proliferation assays. Each recall peptide was used at two different concentrations: 20 ⁇ g/mL (hatched bars), and 2 ⁇ g/mL (dotted bars). "NIL” represents background (no added antigen). Irrelevant peptides GF55 (FIG. 4A), GF59 (FIG. 4B), GF63 (FIG. 4C) and GF51 (FIG. 4D) were used as negative controls in their respective groups.
  • FIGS. 5A - 5E In vitro proliferative response of LNCs from H-2 b mice immunized subcutaneously with an equimolar mixture of peptide GF56 FIG. 5A), GF57 (FIG. 5B), GF61 (FIG. 5C), GF66 (FIG. 5D) and GF51 (FIG. 5E). Recall peptide GF51 was used as a negative control. Mean proliferation with PPD positive control was 122.0541 x 10 3 cpm. "NIL" represents background (no added antigen).
  • FIGS. 6A - 6F In vitro proliferative response of LNCs from H-2 b mice immunized subcutaneously with an equimolar mixture of peptide GF56 FIG. 5A), GF57 (FIG. 5B), GF61 (FIG. 5C), GF66 (FIG. 5D) and GF51 (FIG. 5E). Recall peptide GF51 was used as
  • FIG. 7 Mapping of the minimal T-cell proliferative epitope in the GF57 peptide of HPV16E6 protein. Underlined amino acids indicate the minimal T-cell proliferative epitope.
  • FIGS. 8A and 8B In vitro proliferative response of LNCs from C57BL/6 mice immunized subcutaneously with peptide GF57, and challenged with GF57 overlapping truncated peptides. Recall peptides GF57 and GF51 were used as positive and negative controls respectively. "NIL" represents background (no added antigen).
  • FIG. 9 Mapping of the minimal T-cell proliferative epitope in the GF61 peptide of HPV16E6 protein. Underlined amino acids indicate the minimal T-cell proliferative epitope.
  • FIGS. 10A and 10B In vitro proliferative response of LNCs from C57BL/6 mice immunized subcutaneously with peptide GF61 , and challenged with GF57 overlapping truncated peptides. Recall peptides GF61 and GF51 were used as positive and negative controls respectively. "NIL" represents background (no added antigen).
  • FIGS. 11A and 11B In vitro proliferative response of LNCs from C57BL/6 mice immunized subcutaneously with peptide GF51 , and challenged with GF57 overlapping truncated peptides. "NIL” represents background (no added antigen).
  • FIGS. 12A and 12B In vitro proliferative response of LNCs from C57BL/6 mice immunized subcutaneously with peptide GF51 , and challenged with GF61 overlapping truncated peptides. "NIL” represents background (no added antigen).
  • FIGS. 13A - 13D Effect of 'VYRDGNPYA' and 'QYNKPLCDLL' T h -epitopes on the antibody response to 'EYMLD' and 'QAEPD' B-epitopes.
  • Peptide GF101 MHGDTPTLHEYMLDLQPE
  • 8Q QAEPDRAHYNIVTFCCKCD
  • 8F and 6D are MAbs to EYMLD and QAEPD respectively.
  • Sera were collected from H-2 b mice before and after immunization with either VYRDGNPYA (VYR) alone, QYNKPLCDLL (QYN) alone, VYRDGNPYA linked to EYMLD and QAEPD (E-VYR-Q), QYNKPLCDLL linked to EYMLD and QAEPD (E-QYN-Q) or with a peptide consisting of EYMLD and QAEPD epitopes only (E-Q).
  • FIG. 14 Construction of recombinant baculovirus transfer vector pVLBPV1 L1/Thprom-QAEPD.

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Abstract

L'invention a trait à un peptide codant un épitope ubiquiste de lymphocyte T auxiliaire aux fins du déclenchement d'une réaction immunitaire à l'encontre d'un papillomavirus. Ce peptide est choisi dans le groupe constitué par, (i) VYRDGNPYA, comprenant une délétion, une substitution ou une adjonction d'un seul acide aminé pratiquée dans VYRDGNPYA (SEQ ID NO. 1) et (ii), QYNKPLCDLL comprenant une délétion, une substitution ou une adjonction d'un seul acide aminé pratiquée dans QYNKPLCDLL (SEQ ID NO. 2). Cette invention concerne également des produits d'assemblage de peptide chimère ainsi que des compositions immunogènes renfermant les peptides de l'invention.
PCT/AU1997/000820 1996-11-29 1997-12-01 Nouveaux epitopes ubiquistes de lymphocyte t auxiliaire WO1998023635A1 (fr)

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