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EP0839199A1 - Papillomavirus, agents de depistage de ceux-ci et de therapie de maladies causees par ces virus - Google Patents

Papillomavirus, agents de depistage de ceux-ci et de therapie de maladies causees par ces virus

Info

Publication number
EP0839199A1
EP0839199A1 EP96928326A EP96928326A EP0839199A1 EP 0839199 A1 EP0839199 A1 EP 0839199A1 EP 96928326 A EP96928326 A EP 96928326A EP 96928326 A EP96928326 A EP 96928326A EP 0839199 A1 EP0839199 A1 EP 0839199A1
Authority
EP
European Patent Office
Prior art keywords
dna
virus
protein
papillomavirus
genome
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.)
Ceased
Application number
EP96928326A
Other languages
German (de)
English (en)
Inventor
Vladimir Shamanin
Ethel-Michele De Villiers-Zur Hausen
Harald Zur Hausen
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.)
Deutsches Krebsforschungszentrum DKFZ
Original Assignee
Deutsches Krebsforschungszentrum DKFZ
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 Deutsches Krebsforschungszentrum DKFZ filed Critical Deutsches Krebsforschungszentrum DKFZ
Publication of EP0839199A1 publication Critical patent/EP0839199A1/fr
Ceased 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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

Definitions

  • Papillomaviruses means for their detection and for the therapy of diseases caused by them
  • the invention relates to a DNA coding for a peptide of a papillomavirus main capsid protein.
  • the invention further relates to a papilloma virus genome containing such a DNA.
  • the invention relates to proteins and virus-like particles encoded by the papillomavirus genome and to antibodies directed against them and their use in diagnosis, therapy and vaccination.
  • HP viruses Human papilloma viruses
  • benign e.g. Warts, genital condylomas, and malignancies, e.g. Carcinomas of the skin and uterus, epithelial neoplasms (see Kir Hausen, H., Cancer Research 49 (1989), pages 4677-4681).
  • HP viruses are also considered for the development of malignant tumors of the respiratory tract (cf. Ober Hausen, H., Cancer Research 36 (1976), page 530).
  • HP viruses are considered to be at least partly responsible for the development of squamous carcinomas of the lungs (cf. Syrjänen, K.J., Lung 158 (1980), pages 131-142).
  • Papilloma viruses have an icosahedral capsid without a shell, in which a circular, double-stranded DNA molecule of approximately 7900 bp is present.
  • the capsid comprises a major capsid protein (L1) and a minor capsid protein (L2). Both proteins, coexpressed or L1 expressed alone, lead to the formation of virus-like particles in vitro (cf. Kirnbauer, R. et al., Journal of Virology, (1993), pages 6929-6936).
  • Papilloma viruses cannot be propagated in monolayer cell culture. It is extremely difficult to characterize the detection of papilloma viruses creates considerable problems. This is particularly true for papilloma viruses in skin carcinomas. So far, no reliable proof of this and therefore no targeted action against it is possible.
  • the object of the present invention is therefore to provide an agent with which papilloma viruses, in particular in carcinomas of the skin, can be detected.
  • a means should also be provided to treat these papillomaviruses therapeutically.
  • the invention thus relates to a DNA coding for a peptide of a papillomavirus main capsid protein (L1), the peptide comprising the amino acid sequence of FIGS. 1, 2, 3, 4, 5, 6 , 7, 8, 9 or 10, or an amino acid sequence different from one or more amino acids.
  • L1 papillomavirus main capsid protein
  • Another object of the invention is a DNA coding for a peptide of a papillomavirus main capsid protein, the DNA being the base sequence of FIG. 1, FIG. 2, FIG. 3, FIG. 4, FIG. 5, FIG. 6, FIG 7, 8, 9 or 10 or one of these base sequences which are different by one or more base pairs.
  • FIG. 1 shows the base sequence and the amino acid sequence derived therefrom of a DNA coding for a peptide from L1 of a papilloma virus. This DNA was deposited as plasmid VS19-6 at DSM (German Collection of Microorganisms and Cell Cultures) under DSM 10104 on July 11, 1995.
  • Fig. 2 shows the base sequence and the amino acid sequence derived therefrom one for a peptide of L1 one DNA encoding papilloma virus. This DNA was deposited as plasmid VS200-1 with the DSM under DSM 10096 on July 11, 1995.
  • FIG. 3 shows the base sequence and the amino acid sequence derived therefrom of a DNA coding for a peptide from L1 of a papilloma virus. This DNA was deposited as plasmid VS201-1 with the DSM under DSM 10097 on July 11, 1995.
  • FIG. 4 shows the base sequence and the amino acid sequence derived therefrom of a DNA coding for a peptide from L1 of a papillomavirus. This DNA was deposited as plasmid VS202-8 with the DSM under DSM 10098 on July 11, 1995.
  • FIG. 5 shows the base sequence and the amino acid sequence derived therefrom of a DNA coding for a peptide from L1 of a papilloma virus. This DNA was deposited as plasmid VS203-2 with the DSM under DSM 10099 on July 11, 1995.
  • FIG. 6 shows the base sequence and the amino acid sequence derived therefrom of a DNA coding for a peptide from Ll of a papillomavirus. This DNA was deposited as plasmid VS204-4 with the DSM under DSM 10100 on July 11, 1995.
  • FIG. 7 shows the base sequence and the amino acid sequence derived therefrom of a DNA coding for a peptide from Ll of a papillomavirus. This DNA was deposited as plasmid VS205-1 with the DSM under DSM 10101 on July 11, 1995.
  • FIG. 8 shows the base sequence and the amino acid sequence derived therefrom of a DNA coding for a peptide from Ll of a papilloma virus. This DNA was deposited as plasmid VS206-2 with the DSM under DSM 10109 on July 13, 1995.
  • Fig. 9 shows the • base sequence and the deduced amino acid sequence of a gene coding for a peptide of a papillomavirus Ll DNA.
  • This DNA was called a plasmid VS207-22 deposited with the DSM under DSM 10102 on July 11, 1995.
  • FIG. 10 shows the base sequence and the amino acid sequence derived therefrom of a DNA coding for a peptide from Ll of a papilloma virus. This DNA was deposited as plasmid VS208-1 with the DSM under DSM 10103 on July 11, 1995.
  • the above DNA has the following sequence homology with known papilloma viruses:
  • the above DNA can be present in a vector or expression vector.
  • examples of such are known to the person skilled in the art.
  • these are e.g. pGEMEX, pUC derivatives, pGEM-T and pGEX-2T.
  • yeast e.g. to call pYlOO and Ycpadi
  • animal cells e.g. pKCR, pEF-BOS, cDM8 and pCEV4 must be specified.
  • suitable cells in order to express the above DNA present in an expression vector.
  • suitable cells include the E. coli strains HB101, DH1, xl776, JM101, JM 109 and XLl-Blue, the yeast strain Saccharomyces cerevisiae and the animal cells L, NH-3T3, FM3A, CHO, COS, Vero, and Hey.
  • the person skilled in the art knows how the above DNA has to be inserted into an expression vector. He is also aware that the above DNA can be inserted in connection with a DNA coding for another protein or peptide, so that the above DNA can be expressed in the form of a fusion protein.
  • papilloma virus genome comprising the above DNA.
  • the term "papilloma virus genome” also includes an incomplete genome, i.e. Fragments of a papilloma virus genome comprising the above DNA. This can e.g. be a DNA coding for Ll or a part thereof.
  • a method comprising the following method steps can be used to provide the above papillomavirus genome:
  • epithelial neoplasm encompasses any neoplasms of epithelial tissue in humans and animals. Examples of such Neoplasms are warts, condylomas in the genital area and carcinomas of the skin. The latter are preferably used in the present case to isolate the above papillomavirus genome.
  • vector includes any vector suitable for cloning chromosomal or extrachromosomal DNA.
  • examples of such vectors are cosmids such as pWE15 and Super Cosl, and phages such as ⁇ phages, e.g. ⁇ ZAP Expressvector, ⁇ ZAPII Vector and ⁇ gtlO Vector.
  • ⁇ phages are preferably used.
  • the above vectors are known and are available from Stratagene.
  • Papillomavirus genomes according to the invention can be integrated in chromosomal DNA or extrachromosomal. Methods are known to the person skilled in the art to clarify this. He also knows how to find the optimal restriction enzymes for cloning the papillomavirus genomes. It will be based on genomes of known papilloma viruses. In particular, the person skilled in the art will observe the aforementioned HP viruses accordingly.
  • a papilloma virus genome designated VS19-6 is described by way of example.
  • the total DNA is isolated from a biopsy of a squamous cell carcinoma, cleaved with BamHI and electrophoretically separated in an agarose gel.
  • the agarose gel is then subjected to a blotting process, whereby the DNA is transferred to a nitrocellulose membrane.
  • This is used in a hybridization process in which the DNA from FIG. 1, possibly in combination with a DNA from HP virus 65, is used as the labeled sample. Hybridization with the papilloma virus DNA present in the total DNA is obtained.
  • the above total DNA cleaved with BamHI is cloned in a ⁇ phage.
  • the corresponding clones ie the clones containing the papillomavirus DNA, are hybridized with the DNA from FIG. 1, if appropriate in combination with a DNA of the HP virus 65 identified.
  • the insert of these clones is then subjected to further cloning in a plasmid vector, whereby a clone is obtained which contains the papillomavirus genome VS19-6-G. The genome is confirmed by sequencing.
  • papillomavirus genomes are provided. They are named according to the DNAs used to provide them, with: VS200-1-G, VS201-1-G, VS202-8-G, VS203-2-G, VS204-4-G, VS205-1-G, VS206 -2- G, VS207-22-G or VS208-1-G.
  • Another object of the invention is a protein encoded by the above papillomavirus genome.
  • a protein is e.g. a major capsid protein (Ll) or a minor capsid protein (L2).
  • L1 or L2 of the papilloma virus genome VS19-6-G is described by way of example.
  • the HP virus 65 related to the DNA of FIG. 1 is used.
  • the complete sequence and the position of individual DNA regions coding for proteins are known from this.
  • These DNAs are identified on the papillomavirus genome VS19-6-G by parallel restriction cleavages of both genomes and subsequent hybridization with different fragments relating to the L1 or L2 coding DNA. They are confirmed by sequencing.
  • the DNA coding for L1 is designated VS19-6-G-L1-DNA and the DNA coding for L2 with VS19-6-G-L2-DNA.
  • the DNA coding for L1 or L2 is inserted into an expression vector.
  • E. coli examples of such for E. coli, yeast and animal cells are mentioned above.
  • vector pGEX-2T for expression in E. coli (cf. Kirnbauer, R. et al., Supra).
  • pGEX-2T-VS19-6-G-L1 or pGEX-2T-VS19-6-G-L2 is obtained.
  • These expression vectors express after transformation of E. coli a glutathione S-transferase-L1 or glutathione S-transferase-L2 fusion protein. These proteins are purified in the usual way.
  • the bacculovirus or vaccinia virus system is called for a further expression of the above-mentioned L1 or L2 coding DNA.
  • Expression vectors that can be used for this are, for example, pEV mod. and pSynwtVI " for the bacculovirus system (cf. Kirnbauer, R. et al., supra).
  • vectors with the vaccinia virus are" early "(p7.5k) - or” late "(Psynth, pllK) promoter (cf. Hagensee, M., E. et al., Journal of Virology (1993), pages 315-322).
  • the bacculovirus system is preferred.
  • a particle comprises an Ll protein
  • an L2 protein in addition to an Ll protein.
  • a virus-like particle of the latter case is also obtained by inserting the above VS19-6-G-L1 and VS19-6-G-L2 DNAs together into the expression vector pSynwtVI " and the resulting pSynwtVI " VS19-6-G -Ll / L2 is used to infect SF-9 insect cells.
  • the above virus-like particles are cleaned in the usual way. They also represent an object of the invention.
  • Another object of the invention is an antibody directed against an above protein or virus-like particle.
  • Such is produced in the usual way. It is described by way of example for the production of an antibody which is directed against an L1 of VS19-6-G comprising the virus-like particle.
  • the Virus-like particles BALB / c mice injected subcutaneously. This injection is repeated every 3 weeks. About 2 weeks after the last injection, the serum containing the antibody is isolated and tested in the usual way.
  • the antibody is a monoclonal antibody.
  • spleen cells are removed from the mice after the fourth injection above and these are fused with myeloma cells in the usual way. The further cloning is also carried out according to known methods.
  • the present invention makes it possible to detect papilloma viruses, in particular in carcinomas of the skin.
  • the DNA according to the invention can be used as such or encompassed by a further DNA.
  • the latter can also be a papilloma virus gome or part of it.
  • the present invention also enables the provision of previously unknown papilloma viruses. These are found particularly in carcinomas of the skin. Furthermore, the invention provides proteins and virus-like particles which are due to these papillomaviruses. Antibodies are also provided which are directed against these proteins or particles.
  • the present invention thus makes it possible to take diagnostic and therapeutic measures for papillomavirus diseases. In addition, it provides the opportunity to build a vaccine against papillomavirus infections.
  • the present invention thus represents a breakthrough in the field of papilloma virus research.
  • Example 1 Identification of the papilloma virus genome VS19-6-G
  • the total DNA is isolated from an immunosuppressed person. 10 ⁇ g of this DNA are cleaved with the restriction enzyme BamHI and electrophoresed in a 0.5% agarose gel. At the same time, 10 ⁇ g of the above DNA, which has not been cleaved, are also separated.
  • the agarose gel is subjected to a blotting process, whereby the DNA from the agarose gel is transferred to a nitrocellulose membrane. This is used in a hybridization process in which the above DNA from FIG. 1 is used in combination with HP virus 65 DNA as a p 32 -labeled sample. Hybridization with the blotted DNA is obtained.
  • the biopsy DNA obtained from Example 1 is cleaved with the restriction enzyme BamHI.
  • the fragments obtained are used in a ligase reaction in which the ⁇ ZAP Express vector, which has been cleaved and dephosphorylated with BamHI, is also present.
  • the recombinant DNA molecules obtained in this way are packaged in bacteriophages and used to infect bacteria.
  • the ZAP Express Vector Kit offered by Stratagene is used for these process steps.
  • the phage plaques obtained are then subjected to a hybridization process in which the p 32 -labeled DNA from FIG. 1 used in Example 1 is used in combination with p 32 -labeled HP virus 65 DNA. Hybridization with corresponding phage plaques is obtained.
  • the BamHI fragments of VS19-6-G are isolated from these and together with a BamHI -cleaved, phosphorylated plasmid vector, pBluescript, used in a further ligase reaction.
  • the recombinant DNA molecules obtained are used to transform bacteria, E. coli XII-Blue.
  • a bacterial clone containing the papillomavirus genome VS19-6-G is identified by restriction cleavage or hybridization with the above DNA samples.
  • the plasmid of this bacterial clone is designated pBlue-VS19-6-G.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Virology (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Peptides Or Proteins (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

L'invention concerne un ADN qui code un peptide de la principale protéine constitutive de la capside d'un papillomavirus, ainsi qu'un génome de papillomavirus qui contient cet ADN, les protéines et des particules analogues à des virus codées par le génome de papillomavirus, ainsi que les anticorps qui les attaquent et leur utilisation en diagnostic, en thérapie et en immunisation.
EP96928326A 1995-07-19 1996-07-19 Papillomavirus, agents de depistage de ceux-ci et de therapie de maladies causees par ces virus Ceased EP0839199A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19526386 1995-07-19
DE19526386A DE19526386C1 (de) 1995-07-19 1995-07-19 Papillomviren, Mittel zu deren Nachweis sowie zur Therapie von durch sie verursachten Erkrankungen
PCT/DE1996/001369 WO1997004099A2 (fr) 1995-07-19 1996-07-19 Papillomavirus, agents de depistage de ceux-ci et de therapie de maladies causees par ces virus

Publications (1)

Publication Number Publication Date
EP0839199A1 true EP0839199A1 (fr) 1998-05-06

Family

ID=7767261

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96928326A Ceased EP0839199A1 (fr) 1995-07-19 1996-07-19 Papillomavirus, agents de depistage de ceux-ci et de therapie de maladies causees par ces virus

Country Status (5)

Country Link
US (4) US6322795B1 (fr)
EP (1) EP0839199A1 (fr)
JP (1) JPH11512925A (fr)
DE (1) DE19526386C1 (fr)
WO (1) WO1997004099A2 (fr)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19648962C1 (de) * 1996-11-26 1998-02-26 Deutsches Krebsforsch Papillomviren, Mittel zu deren Nachweis sowie zur Therapie von durch sie verursachten Erkrankungen
DE19712541C1 (de) * 1997-03-25 1998-11-05 Deutsches Krebsforsch Papillomviren, Mittel zu deren Nachweis sowie zur Therapie von durch sie verursachten Erkrankungen
DE19735118C1 (de) * 1997-08-13 1998-08-13 Deutsches Krebsforsch Papillomviren, Mittel zu deren Nachweis sowie zur Therapie von durch sie verursachten Erkrankungen
JP5100956B2 (ja) * 2001-08-31 2012-12-19 ジェン−プローブ・インコーポレーテッド ヒトパルボウイルスｂ１９核酸の検出のためのアッセイ
CA2611861C (fr) 2005-06-08 2017-11-28 The Brigham And Women's Hospital, Inc. Methodes et compositions pour le traitement d'infections persistantes
US20100040614A1 (en) 2006-12-27 2010-02-18 Rafi Ahmed Compositions and methods for the treatment of infections and tumors
JP5520961B2 (ja) 2008-11-28 2014-06-11 エモリー ユニバーシティ 感染症および腫瘍を処置するための方法
JP6153866B2 (ja) 2010-05-25 2017-06-28 キアゲン ガイサーズバーグ アイエヌシー． 迅速なハイブリッド捕捉アッセイ、及び関連する戦略的に切断されたプローブ
KR20190080825A (ko) 2016-03-21 2019-07-08 다나-파버 캔서 인스티튜트 인크. T-세포 기능소실 상태-특이적 유전자 발현 조절인자 및 그 용도

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3722968A1 (de) 1987-07-11 1989-01-19 Behringwerke Ag Humaner papillomvirus typ 41, seine dna und die dafuer kodierenden proteine
CA1339729C (fr) 1988-10-26 1998-03-17 Wayne D. Lancaster Sequences d'and pour virus des papillomes humains de type 52 methode d'utilisation
US5437951A (en) 1992-09-03 1995-08-01 The United States Of America As Represented By The Department Of Health And Human Services Self-assembling recombinant papillomavirus capsid proteins
DE4415743C2 (de) 1994-05-04 1996-10-10 Deutsches Krebsforsch Papillomviren, Mittel zu deren Nachweis sowie zur Therapie von durch sie verursachten Erkrankungen

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9704099A3 *

Also Published As

Publication number Publication date
US20020110865A1 (en) 2002-08-15
WO1997004099A2 (fr) 1997-02-06
DE19526386C1 (de) 1997-01-02
JPH11512925A (ja) 1999-11-09
US20020110866A1 (en) 2002-08-15
US6555345B2 (en) 2003-04-29
US6368832B1 (en) 2002-04-09
WO1997004099A3 (fr) 2001-04-12
US6322795B1 (en) 2001-11-27
US6562597B2 (en) 2003-05-13

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