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WO1995001374A1 - Peptides synthetiques du virus du papillome humain - Google Patents

Peptides synthetiques du virus du papillome humain Download PDF

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Publication number
WO1995001374A1
WO1995001374A1 PCT/GB1994/001397 GB9401397W WO9501374A1 WO 1995001374 A1 WO1995001374 A1 WO 1995001374A1 GB 9401397 W GB9401397 W GB 9401397W WO 9501374 A1 WO9501374 A1 WO 9501374A1
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WO
WIPO (PCT)
Prior art keywords
hpv
peptides
amino acids
patients
peptide
Prior art date
Application number
PCT/GB1994/001397
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English (en)
Inventor
Philip Stephen Shepherd
Original Assignee
British Technology Group Limited
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 British Technology Group Limited filed Critical British Technology Group Limited
Priority to AU70405/94A priority Critical patent/AU7040594A/en
Priority to EP94918958A priority patent/EP0706533A1/fr
Priority to JP7503350A priority patent/JPH08512045A/ja
Publication of WO1995001374A1 publication Critical patent/WO1995001374A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • 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

Definitions

  • the present invention provides synthetic peptides identified in human papillomavirus (HPV) LI proteins which are useful in the prevention and treatment of genital warts, cervical dysplasias and cervical cancer.
  • HPV human papillomavirus
  • Human papillamoviruses are a group of viruses which share a common genetic organisation with animal papi llomaviruses and which induce cutaneous and ucosal squamous epithelial lesions. Over 65 different HPV types have been identified.
  • HPV cervical intraepithelial neoplasia
  • HPV 16 alone is the most commonly found (60% of all cervical tumours) and is the type of HPV of most interest in the current application.
  • HPV infection to the development of CIN and cervical carcinoma is unclear, however it has been postulated that HPV acts as an initiator in cervical carcinogenesis and that malignant transformation depends on interaction with other factors (Zur Hausen, H. et al , Lancet. (1982) 11:1370).
  • HPV 16 contains a 7904 bp double-stranded DNA genome (Siedorf. K. et al , Virology, (1985) 145: 181-185).
  • the capsid is 50 n and contains 72 capso ers (Klug. A., J Mol . Biol., (1965), 11:403-423).
  • HPV 16 subtypes have been reported which are isolates showing greater than 50% homology (Coggin, Cancer Research, (1979), 39:545-546), but give differences in restriction fragment length polymorphism patterns with different restriction endonucleases on Southern Blotting.
  • HPV genomes have at least 8 regions which code for a number of proteins as transcripts from open reading frames (ORF). These regions are functionally divided into early regions, postulated to encode the proteins needed for replication and transformation (El to E7) and late regions, which encode the two major viral capsid proteins (LI and L2). The late regions show regions of homology in all HPV types. Little is known about the immune response to infections by HPV 16 and papillomaviruses in general. The detection of HPV in, for example, cervical samples can be carried out using sensitive DNA typing techniques such as the Polymerase Chain Reaction and Southern Blotting, but the virus cannot be isolated and grown in the laboratory to adequate amounts of antigenie material suitable for im unological testing (Tichman et al . , 0. Invest. Derm., 1984, 83: 25-65 ) .
  • Seroreactive epitopes of HPV have been identified and antibodies raised against them. These antibodies find use in the diagnosis of HPV infections, and for example are described in 091/18294 (Dillner and Dillner) wherein synthetic peptides representing the LI and L2 proteins of HPV 16 were synthesised, and tested with human sera. The synthetic peptides against which these antibodies reacted were also proposed as being useful in diagnosis of HPV infections. However, no therapeutic use of these antibodies or peptides was suggested.
  • Muller also discloses an 88 amino acid sequence from HPV 16 LI which is useful in vaccines. However in all cases, the evidence is based upon serologicei tests, which suggests that they are looking at B-cell epitopes and there is no evidence provided to show that that these peptides are sufficiently immunogenic to produce a B-cell response, and whether the resulting B-cell antibodies are HPV neutralising antibodies and are thus protective against HPV infection.
  • T-cell epitopes are also important in the immune response cf individuals to an invading antigen. T-cells, together wi ⁇ h acrophages and poly orphonuclear leucocytes, are the body's first and main line of immune defence.
  • the invention also includes a therapeutic composition er e_ or for use in therapy as defined above, comprising the three peptides as defined above.
  • the peptides can in each case be free or bound (including bound by one or more covalent chemical bonds) to any carrier or assistant molecule which may facilitate, ameliorate or at least be compatible with the above-defined therapeutic purpose.
  • the invention includes the possibility of replacing two or all three of the above peptides by a single peptide of the same length as or longer than required to span the sequence represented by the combination of two or three peptides.
  • the benefits of using the shorter peptides make this course unattractive.
  • the peptide(s) should not cover HPV 16 LI sequence outside the 311-345 range, i.e. beyond the N-terminus at 311 or the C-terminus at 345.
  • the peptides for the use in the invention are those peptides which are capable of eliciting a T-cell response. The precise make up of the sequence necessary for an optimum T-cell response may vary from individual to individual.
  • peptides of the invention which are preferably 15 to 22, most preferably 15 to 20 and still more preferably 15 to 18 aa long, due allowance can be made for the diversity of T-cell epitope recognition within the human population.
  • Any additional amino acids, beyond the mandatory length of 15 set forth above, are preferably the contiguous amino acids of HPV 16.LI, especially 305-311 for peptide (1).
  • T-helper cells which in turn provide helper functions and cell to cell signal transduction to specific B-cells to produce antigen/peptide and cytokine release, HPV-specific antibody responses and/or to help cytotoxic T-cells to kill or deactivate the virus or virally infected cells.
  • T-helper cells play an important pivotal role in co-ordinating the body's two main immune defence mechanisms.
  • T-helper cell epitopes in a system used for the presentation of antigens such as B-cell epitopes or cytotoxic T-cell epitopes may, by the added stimulation of the production of T-helper cells, lead to an improved response to the B-cell epitope or cytotoxic T-cell epitope which is being presented.
  • a peptide defined hereinbefore is linked to a B-cell or cytotoxic T-cell epitope.
  • the B-cell epitope linked to the peptides for use in the invention is of preferably from HPV especially types 16,11 and 6 and more preferably HPV 16 but could be any other preferred antigen/peptide to which it is desired to generate an immune response.
  • the B-cell epitope may be from either the early regions (El to E7) or, more preferably, the late regions (LI and L2) of HPV. There may be more than one B-cell or cytotoxic T-cell epitope present together with more than one peptide of the invention.
  • peptide includes neutral (uncharged) and salt forms, and either free of modifications such as glycosylation, side chain oxidation, or phosphorylation or containing these modifications. It is well understood in the art that amino acid sequences contain acidic and basic groups, and that the particular ionization state exhibited by the peptide is dependent on the pH of the surrounding medium when the peptide is in solution, or that of the medium from which it was obtained if the peptide is in solid form.
  • peptides modified by additional substituents attached to the amino acid side chains, such as glycosyl units, lipids, or inorganic ions such as phosphates, as well as modifications relating to chemical conversions of the chains, such as oxidation of sulfhydryl groups.
  • peptide includes a molecule of the appropriate amino acid sequence defined above, subject to those of the above-described modifications which do not destroy its immunogenic properties.
  • the peptides for use in the invention may be prepared by chemical synthesis using standard techniques in the art of peptide synthesis.
  • the invention extends to conservatively modified variants of the peptides in which such substitutions have been made, without affecting the properties of the peptides. In particular it extends to replacing 1, 2 or 3 of the amino acids of SEQ ID NOS. 1-3, by other amino acids within the same category of non-polar, uncharged polar, positively charged or negatively charged.
  • the peptides listed above may have various other chemical modifications made to them and still be within the scope of the present invention.
  • the peptides may be prepared with or without an amide group at the C-terminus. Hhen prepared with an amide group at its C-terminus, the peptides have a carboxy-terminal amide group covalently linked to the carbonyl moiety of the preceding amino acid residue.
  • the peptides may also have an acetyl group covalently attached to the amino acid at the N-terminus. Other chemical modifications are possible, particularly cyclic and dimeric configurations.
  • the peptides for use in the invention may be used alone, or being of low molecular weight, may be attached to an immunogenic carrier material in order to further stimulate their antigenicity.
  • conjugate peptides as described hereinbefore which may be linked to a B-cell or cytotoxic T-cell epitope as described above, together with an immunogenic carrier material, are used in the invention.
  • immunogenic carrier material includes those materials which have the property of independently eliciting an immunogenic response in a host animal and which can be covalently coupled to peptides either directly via a formation of peptide or ester bonds between free carboxyl , amino or hydroxyl groups in the polypeptide and corresponding groups on the immunogenic carrier material or alternatively by bonding through a conventional bifunctional linking group.
  • Such carriers include albumins of animal sera, globulins of animal sera, thyroglobulins of animals, haemoglobins of animals, haemocyanins of animals, particularly Keyhole Limpet Haemocyanin (KLH), proteins extracted from ascaris (ascaris extracts, such as those described in Japanese Laid-Open Patent Application No. 16,414/81, J. Immunology, HI, 260-268 (1973), 0. Immunology, 122, 302-308 (1979), J. Immunology, 28, 893-900 (1967) and Am. 0. Physiol.
  • KLH Keyhole Limpet Haemocyanin
  • Suitable carriers are disclosed in, for example, US Patent 4,575,495, including vaccines, organic polymers etc.
  • the protein derivative of tuberculin (PPD) is particularly preferred for utilisation in the "active" immunisation scheme since (1) it does not induce a T-cell response itself (i.e. it is in effect a "T-cell hapten"), and yet it behaves as a fully processed antigen and is recognised by T-cells as such; (2) it is known to be one of the most powerful hapten "carriers" in the linked recognition mode; and (3) most importantly, it can be used in humans without further testing.
  • peptide-carrier binding agents those conventionally employed in the preparation of antigens can be widely employed.
  • the covalent coupling of the peptide to the immunogenic carrier material can be carried out in a manner well known in the art.
  • a carbodiimide most preferably dicyclohexylcarbodiimide or l-ethyl-3-(3-dimethylaminopropyl) carbodiimide, as coupling agent.
  • Glutaraldehyde may also be used as a means of the covalent coupling of the peptide to the immunogenic carrier material.
  • proportions of the peptide, peptide-carrier binding agent and immunogenic carrier material can be appropriately determined, but it is preferred that the carrier be employed in an amount of about 1 to 6 times, preferably about 1 to 5 times the weight of the peptide and the peptide-carrier binding agent be employed in an amount of about 5 to about 10 molar times the amount of the peptide.
  • the carrier is bound to the peptide via the peptide-carrier binding agent to obtain a desire antigen composed of a peptide-carrier complex.
  • the thus obtained conjugate can easily be isolated and purified by means of a dialysis method, a gel filtration method, a fractionation precipitation method, etc.
  • the peptides for use in the present invention find utilit for the prevention or treatment of genital warts, cervical cancer, especially the early signs thereof manifested by dysplasias, or other conditions caused by HPV in man.
  • the amino acid sequences of the LI region of all types of HPV are highly conserved.
  • the term "like human papillomavirus" in the definition of the invention includes those which have 50% o r greater identity, especially 65% or greater identity of aminc acid sequence - with respect to amino acids 311-345 of HPV 16 LI.
  • the peptides for use in the present invention may find utility in the prevention and treatment of many HPV associated diseases, especially those caused by HPV 6, and 11, but most especially HPV 16. The primary intended use is on patients having cervical dysplasias, as these are frequently associated with HPV 16 infection.
  • Direct administration of the peptides for use in the invention to the host can confer protective immunity to the host against HPV, or, if the subject is already infected and thus immunologically primed act as a boost to the subjects own specific HPV immune response to promote a more effective defence against the progress of their HPV or HPV-related disease.
  • the peptides of the present invention may be included in pharmaceutical compositions for the treatment or prevention of diseases involving HPV.
  • composition which comprises a therapeutically effective amount of a peptide, peptide linked to a B-cell or cytotoxic T-cell epitope or a peptide conjugate as described hereinbefore or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable diluent or carrier, other therapeutic ingredients may also be included.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic organic and inorganic bases.
  • peptides for use in this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms, depending on the form of preparation desired for administration.
  • any of the usual pharmaceutical media may be employed, such as, for example, water glycols, oils, alcohols, flavouring agents, preservatives, colouring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets.
  • tables and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coating or enteric coated by standard techniques.
  • Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tables each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion.
  • Suitable topical formulations include transdermal devices, aerosols, creams, ointments, lotions, dusting powder, and the like.
  • the peptides are to be administered parenterally, more preferably as vaccines.
  • the vaccines include some form of adjuvant for stimulating the response to the antigenic material. Examples of adjuvant materials include aluminium hydroxide and saponin.
  • adjuvant materials include aluminium hydroxide and saponin.
  • Preparation of vaccines which contain peptide sequences as active ingredients are well understood in the art.
  • the vaccines are prepared as injectable forms and are administered preferably by injection, for example intravenously, subcutaneously, intramucosally, intraepidermally or intradermally, preferably intramucosally.
  • compositions may be formulated in unit dosage form, or a multiple or a submultiple of a unit dose.
  • the vaccine may be in a form which provides delayed release of the peptides of peptide conjugated with time.
  • the vaccines are administered in a manner compatible with the dosage formulation and in such amount as will be therapeutical ly effective and immunogenic.
  • the quantity to be treated, the capacity of the subject's immune system to synthesise antibodies and the degree of protection desired. Precise amounts depend upon various factors. Whilst the dosage of active compound given will depend upon various factors, by way of guidance the dosage will usually be 0.1 mg to 20 mg/kg body weight.
  • the present invention also includes a method of preventing or treating HPV infections in the human body, which comprises administering the peptides for use in the invention to a human patient in a therapeutical ly effective dose, e.g. in the range 0.1-20 mmole/kg body weight, preferably 1-2 mmole/kg, administered daily or twice daily during the course of treatment.
  • a therapeutical ly effective dose e.g. in the range 0.1-20 mmole/kg body weight, preferably 1-2 mmole/kg, administered daily or twice daily during the course of treatment.
  • the invention includes the compounds of the invention for use in said therapy and their use in the manufacture of medicaments for that purpose.
  • the peptides may also be administered by controlled release means and/or delivery devices.
  • the following Examples illustrate the invention.
  • Synthetic Peptides of HPV16 LI Synthetic peptides were synthesised by the standard F-moc method of peptide synthesis. They had the following aa sequences from HPV 16 LI:
  • HPV16 LI Fusion Protein was prepared by the method described by Patel et al. , 3. Gen. Virol., 1989, 70, 69-77. Derivation of short term lines from patients with cervical dysplasias
  • Lymphoprep (Nycorned, Oslo, Norway) Dimethylsulphoxide (10323; BDH, Poole, UK) Tissue culture medium: RPMI 1640 with L-glutamine (041-01875M: Life Technologies Ltd, Paisley, Scotland), supplemented with:- ImM sodium pyruvate (16-820-49); Flow Laboratories, Irvine, Scotland) 2mm L-glutamine (043-05030H: Life Technologies, Paisley, Scotland).
  • lOmM HEPES (44285; BDH, Poole, UK) lOO ⁇ /ml of penicillin, 25 ⁇ g/ml of gentamycin (16-762-45; Flow Laboratories, Irvine, Scotland), 50 ⁇ M 2-mercaptoethanol (M-6250; Sigma, Poole, UK), and 0.25 ⁇ g/m1 "Fungizone” Registered Trademark) (16-723-46; Flow Laboratories).
  • Antigen specificity assays on short term lines Antigen specificity assays were performed on day 14. Twenty-five short term lines were prepared and 20 were tested per patient. Each of the 20 short term lines was tested against HPV16 LI fusion protein (l ⁇ g/ml); ⁇ -galactosidase (G-6008, Sigma, UK) lO ⁇ g/ml; each of the nine HPV16 LI synthetic peptides (4) to (12) referred to above and culture medium. Peptides were used at 10 ⁇ M in all assays. Cell counts were performed on 5 pooled cell lines and the mean counts used to estimate the numbers of cells per line (+2x10 ⁇ cells).
  • APC autologous antigen-presenting cells
  • the plates were incubated for three days at 37°C in 5% C0 2 before adding 20 ⁇ l of [Methyl- 3 H3 thymidine (TRA 120, Amersham; 9.25KBq/we11) and incubating for a further 18h. Incorporation of labelled thymidine was measured by counting the harvested wells in a liquid scintillation (3-spectrometer (LKB). The data were plotted as disintegrations per minute (dpm) for all the antigens and medium controls for each cell line and a positive response was taken as a stimulation index (SI) of > 2.5 that of the medium control for each line and having a ⁇ dpm (the difference in dpm over the background) of >500. The positive response was considered significant when ten percent or more of the short term lines, i.e. 2 or more of the 20 lines, responded positively to the antigen.
  • SI stimulation index
  • Table 3 Also illustrated in Table 3 are the patients proliferative T-cell responses to HPV 16.LI peptides, their cervical biopsy histology and HPV DNA typing results.
  • No proliferative T-cell responses were detected in the HPV 18 positive group. The most striking finding was that all the patients who were HPV 16 positive responded to one or more peptides and 92% of them had CIN III lesions.
  • Gin lie Phe Asn Lys Pro Tyr Trp Leu Gin Arg Ala Gin Gly His

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Abstract

L'invention concerne des peptides s'utilisant conjointement dans des méthodes thérapeutiques s'appliquant à des patients ayant une infection due au VPH 16 ou à un virus du papillome humain analogue, ou chez lesquels ce type de virus, VPH, a été incriminé, notamment les dysplasies cervicales, ces peptides ayant une longueur de 15 à 24 acides aminés et se composant de ou comprenant les séquences suivantes d'acides aminés de la protéine L1 du virus du papillome humain (VPH) 16: (1) NO. d'identification de séquence: 1 = restes aa 311-325, ou une variante modérément modifiée de celle-ci; (2) NO. d'identification de séquence: 2 = restes aa 321-335, ou une variante modérément modifiée de celle-ci; et (3) NO. d'identification de séquence: 3 = restes aa 331-345, ou une variante modérément modifée de celle-ci. Les compositions de ces trois peptides en soi ou s'utilisant dans cette thérapie sont également décrites dans l'invention.
PCT/GB1994/001397 1993-07-01 1994-06-28 Peptides synthetiques du virus du papillome humain WO1995001374A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU70405/94A AU7040594A (en) 1993-07-01 1994-06-28 Synthetic peptides of human papillomavirus
EP94918958A EP0706533A1 (fr) 1993-07-01 1994-06-28 Peptides synthetiques du virus du papillome humain
JP7503350A JPH08512045A (ja) 1993-07-01 1994-06-28 ヒトパピローマウイルスの合成ペプチド

Applications Claiming Priority (2)

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GB9313556.4 1993-07-01
GB939313556A GB9313556D0 (en) 1993-07-01 1993-07-01 Synthetic peptides of human papillomavirus

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WO1995001374A1 true WO1995001374A1 (fr) 1995-01-12

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JP (1) JPH08512045A (fr)
AU (1) AU7040594A (fr)
CA (1) CA2166333A1 (fr)
GB (1) GB9313556D0 (fr)
NZ (1) NZ267682A (fr)
WO (1) WO1995001374A1 (fr)

Cited By (6)

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WO1996033737A1 (fr) * 1995-04-24 1996-10-31 Euro-Diagnostica Ab Vaccin a base de peptides contre l'infection a virus du papillome
WO2000073335A1 (fr) * 1999-06-01 2000-12-07 Medigene Aktiengesellschaft Epitopes cytotoxiques de cellule t de la proteine l1 du papillomavirus et leur application en diagnostic et therapie
US6251406B1 (en) 1996-10-09 2001-06-26 Btg International Limited Attenuated microorganism strains and their uses
WO2003054002A1 (fr) * 2001-12-20 2003-07-03 Centro De Ingenieria Genetica Y Biotecnologia Peptides pour le traitement du cancer associe au virus du papillome humain (vph) et d'autres tumeurs epitheliales
US6911207B1 (en) 1999-06-01 2005-06-28 Medigene Aktiengesellschaft Cytotoxic T-cell epitopes of the papillomavirus L1-protein and use thereof in diagnostics and therapy
CN103483447A (zh) * 2012-06-08 2014-01-01 厦门大学 抗hpv l1 蛋白的广谱单克隆抗体或其抗原结合片段及它们的用途

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WO2013111448A1 (fr) * 2012-01-25 2013-08-01 学校法人 久留米大学 Peptide épitopique de lymphocyte b dérivé du papillomavirus humain de type 16l1

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WO1990004790A1 (fr) * 1988-10-28 1990-05-03 Medscand Ab Procede de detection du virus du papillome humain a des fins de diagnostic
WO1993002184A1 (fr) * 1991-07-19 1993-02-04 The University Of Queensland Vaccin contre le virus du papillome

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Publication number Priority date Publication date Assignee Title
WO1990004790A1 (fr) * 1988-10-28 1990-05-03 Medscand Ab Procede de detection du virus du papillome humain a des fins de diagnostic
WO1993002184A1 (fr) * 1991-07-19 1993-02-04 The University Of Queensland Vaccin contre le virus du papillome

Non-Patent Citations (1)

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Title
G. STRANG ET AL: "Human T cell responses to human papillomavirus type 16 L1 and E6 synthetic peptides: identification of T cell determinants, HLA-DR restriction and virus type specificity", JOURNAL OF GENERAL VIROLOGY, vol. 71, no. 2, February 1990 (1990-02-01), pages 423 - 431 *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5989548A (en) * 1995-04-24 1999-11-23 Euro-Diagnostica Ab Peptide-based composition against papillomavirus infection
WO1996033737A1 (fr) * 1995-04-24 1996-10-31 Euro-Diagnostica Ab Vaccin a base de peptides contre l'infection a virus du papillome
US6251406B1 (en) 1996-10-09 2001-06-26 Btg International Limited Attenuated microorganism strains and their uses
US6458368B1 (en) 1996-10-09 2002-10-01 Btg International Limited Attenuated microorganism strains expressing HPV proteins
US6911207B1 (en) 1999-06-01 2005-06-28 Medigene Aktiengesellschaft Cytotoxic T-cell epitopes of the papillomavirus L1-protein and use thereof in diagnostics and therapy
WO2000073335A1 (fr) * 1999-06-01 2000-12-07 Medigene Aktiengesellschaft Epitopes cytotoxiques de cellule t de la proteine l1 du papillomavirus et leur application en diagnostic et therapie
US6838084B1 (en) 1999-06-01 2005-01-04 Medigene Aktiengesellschaft Cytotoxic T-cell epitopes of the papilloma virus l1-protein and use thereof in diagnosis and therapy
CN100368431C (zh) * 2001-12-20 2008-02-13 遗传和生物技术工程中心 用于治疗人乳头状瘤病毒相关性癌症和其他上皮性肿瘤的肽
WO2003054002A1 (fr) * 2001-12-20 2003-07-03 Centro De Ingenieria Genetica Y Biotecnologia Peptides pour le traitement du cancer associe au virus du papillome humain (vph) et d'autres tumeurs epitheliales
US7374767B2 (en) 2001-12-20 2008-05-20 Centro De Ingenieria Genetica Y Biotechologia Peptides for the treatment of cancer associated with the human papilloma virus (HPV) and other epithelial tumors
EP2383282A1 (fr) * 2001-12-20 2011-11-02 Centro De Ingenieria Genetica Y Biotecnologia Peptides pour le traitement du cancer lié au papillomavirus humain (HPV) et d'autres tumeurs épithéliales
HRP20040663B1 (hr) * 2001-12-20 2013-05-31 Centro De Ingenieria Genetica Y Biotecnologia Peptidi za lijeäśenje raka povezanog s humanim papiloma virusom (hpv) i drugih vrsta epitelnih tumora
CN103483447A (zh) * 2012-06-08 2014-01-01 厦门大学 抗hpv l1 蛋白的广谱单克隆抗体或其抗原结合片段及它们的用途
CN103483447B (zh) * 2012-06-08 2015-11-25 厦门大学 抗hpv l1蛋白的广谱单克隆抗体或其抗原结合片段及它们的用途
CN105175537A (zh) * 2012-06-08 2015-12-23 厦门大学 抗hpv l1蛋白的广谱单克隆抗体或其抗原结合片段及它们的用途
CN105175537B (zh) * 2012-06-08 2019-03-05 厦门大学 抗hpv l1蛋白的广谱单克隆抗体或其抗原结合片段及它们的用途

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NZ267682A (en) 1996-10-28
EP0706533A1 (fr) 1996-04-17
GB9313556D0 (en) 1993-08-18
CA2166333A1 (fr) 1995-01-12
JPH08512045A (ja) 1996-12-17
AU7040594A (en) 1995-01-24

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