WO2001037867A1 - Nouvel adenovirus defectif et son procede d'obtention - Google Patents
Nouvel adenovirus defectif et son procede d'obtention Download PDFInfo
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- WO2001037867A1 WO2001037867A1 PCT/CN2000/000428 CN0000428W WO0137867A1 WO 2001037867 A1 WO2001037867 A1 WO 2001037867A1 CN 0000428 W CN0000428 W CN 0000428W WO 0137867 A1 WO0137867 A1 WO 0137867A1
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- WIPO (PCT)
- Prior art keywords
- adenovirus
- deletion
- defective
- cells
- defective adenovirus
- Prior art date
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- 241000701161 unidentified adenovirus Species 0.000 title claims abstract description 53
- 238000000034 method Methods 0.000 title claims abstract description 22
- 230000002950 deficient Effects 0.000 title claims abstract description 19
- 238000012217 deletion Methods 0.000 claims abstract description 19
- 230000037430 deletion Effects 0.000 claims abstract description 19
- 239000013598 vector Substances 0.000 claims abstract description 18
- 101710114676 E1B 55 kDa protein Proteins 0.000 claims abstract description 10
- 210000004027 cell Anatomy 0.000 claims description 20
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- 239000012634 fragment Substances 0.000 claims description 9
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- 229940044683 chemotherapy drug Drugs 0.000 claims description 3
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- 230000002207 retinal effect Effects 0.000 claims description 3
- 231100000765 toxin Toxicity 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 10
- 230000035772 mutation Effects 0.000 abstract description 8
- 108010067390 Viral Proteins Proteins 0.000 abstract description 4
- 230000000259 anti-tumor effect Effects 0.000 abstract description 4
- 108090000623 proteins and genes Proteins 0.000 abstract description 3
- 108010087905 Adenovirus E1B Proteins Proteins 0.000 abstract description 2
- 102000004169 proteins and genes Human genes 0.000 abstract 2
- 108091026890 Coding region Proteins 0.000 abstract 1
- 108020005038 Terminator Codon Proteins 0.000 abstract 1
- 241001135569 Human adenovirus 5 Species 0.000 description 10
- 210000004881 tumor cell Anatomy 0.000 description 10
- 108020004414 DNA Proteins 0.000 description 9
- 238000011282 treatment Methods 0.000 description 8
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- 230000003612 virological effect Effects 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 5
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- 238000003752 polymerase chain reaction Methods 0.000 description 4
- 108091034117 Oligonucleotide Proteins 0.000 description 3
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- 201000010099 disease Diseases 0.000 description 3
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- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 2
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- 241000700584 Simplexvirus Species 0.000 description 1
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- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 238000012761 co-transfection Methods 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000002222 downregulating effect Effects 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
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- 230000010415 tropism Effects 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
Classifications
-
- 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
- C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/76—Viruses; Subviral particles; Bacteriophages
- A61K35/761—Adenovirus
-
- 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
- C12N2710/10011—Adenoviridae
- C12N2710/10021—Viruses as such, e.g. new isolates, mutants or their genomic sequences
-
- 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
- C12N2710/10011—Adenoviridae
- C12N2710/10022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
Definitions
- the invention relates to the field of life sciences, and is a defective adenovirus vector system for treating tumors and a construction scheme thereof.
- the object of the present invention is to provide a defective adenovirus with a novel mutation of the E1b 55Kda protein gene and a new method for constructing the same.
- Gene therapy is a new method for the treatment of malignant tumors that has emerged in recent years.
- the gene transfection method is divided into two methods: viral method and non-viral method.
- Viral method usually uses reverse transcription disease.
- Retroviruses have a high transfection rate in vitro, but the virus titer is low, the transfection rate is low in vivo, and they can only infect cells in the division stage. At the same time, they have the ability to integrate into the chromosome and have the potential to become cancerous. Disadvantages.
- Adeno-associated virus has the ability to transfect dividing and quiescent cells, and can be persistently expressed. In contrast, non-viral methods, including liposomes and i-invasion methods, have a shorter transfection gene expression time and a lower transfection rate.
- Adenovirus is currently the most common viral vector for tumor gene therapy.
- E1a can inhibit HER-2 / neu over-expressing tumors, including down-regulating HER-2 / neu gene expression, reducing the pathogenicity, inhibiting tumor metastasis, and inducing tumor cells Apoptosis and enhance tumor chemotherapy sensitivity and other functions.
- E1 including E1a and E1b
- E1b is missing from the commonly used adenovirus vector system, so that the adenovirus lacks the antitumor effect of E1a.
- the defective adenovirus of the present invention is a partial deletion of the E1b 55Kda protein gene and a stop codon is inserted at the deletion site, and a 2809-3329bp deletion is inserted into the deletion site.
- a DNA fragment TMTGAGTMCTM is inserted into the DNA fragment, and the DNA fragment contains two stop codons, respectively TM And TGA.
- the defective adenovirus of the present invention can be combined with a chemotherapeutic drug such as cisplatin, 5-fluorouracil mitomycin C, etc., a biotoxin such as snake venom, a monoclonal antibody such as an anti-liver cancer cell antibody, etc. Antitumor drugs work better.
- a chemotherapeutic drug such as cisplatin, 5-fluorouracil mitomycin C, etc.
- a biotoxin such as snake venom
- a monoclonal antibody such as an anti-liver cancer cell antibody, etc.
- Antitumor drugs work better.
- two adenovirus vectors are transfected into cells that will produce recombination, and one E1b 55Kda protein gene in the two adenovirus vectors is used.
- the 2809-3329bp deletion inserting a stop codon 'at its deletion site, inserts the DNA fragment TMTGAGTMCTAA, which contains two stop codons, T and TGA, respectively.
- the human adenovirus has six homogeneous subgenus, divided into A, B, C, D, and E F. Their affinity for host cells, tropism, tumorigenicity, and disease history are not the same.
- Ad5 subtype 5 Ad5 as an example.
- the adenovirus system is composed of two vectors, one vector provides the left arm portion of the adenovirus, and the other vector provides the right arm. These two vectors have at least 500 nt homologous recombination regions, but the transfected cells produce recombinant adenovirus,
- the vector system plasmid pXC1 contains the left arm of wild-type Ad5.
- pBHGIO provides Ad5 right arm lacking E3 region or pBHGE3 provides Ad5 right arm (including E3 region).
- the primers for the polymerase chain reaction synthesized in the present invention inserted in the position near the two ends of the linker are
- the invention transfects the defective adenovirus into E1 transformed human embryonic kidney cell line 293 or E1 transformed human embryonic retinal cell line 911, which can be effectively made to have anti-tumor adenopathy.
- the invention has the following beneficial effects
- the present invention provides a defective adenovirus with a novel mutation in the E1b 55Kda protein gene, and animal experiments have proven that the adenovirus can be used to treat a variety of tumors.
- the invention provides a defective adenovirus with a novel mutation in the E1b 55Kda protein gene. Build method. This method can be used to construct a new type of defective adenovirus. The method is easy for the operator to master, and can be used to construct a variety of new type of defective adenovirus, which has established a good foundation for gene therapy diseases.
- Example 1 Partial deletion of the adenovirus E1b protein gene and construction of a stop codon vector inserted in the deletion region
- the pXC.1 vector was purchased from Microbix Biosystem Inc. (Toronto) of Canada.
- pXC.1 contains a type 5 adenovirus sequence bp22-5790. This vector was cut in 3329bp with endonuclease Bgl II and then partially digested with endonuclease Hind III to recover the 9372bp DNA fragment. The 3 'concave end was smoothed using E. coli DNA polymerase I Klenow fragment, which is The 2809bp-3329bp region was deleted from the pXC.1 vector (see the Molecular Cloning Experiment Guide for specific methods, published by Scientific Publishing 1992).
- the two DNA oligonucleotide fragments were each mixed with 0.1 g, and denatured at 10 CTC for 5 minutes, and then renatured with hypothermia, and then phosphorylated with T4 phage polynucleotide acid.
- the acidified adapter was ligated with the pXC.1 vector fragment lacking the 2809-3329bp region and named pXC-del E1b (for the method, see the Molecular Cloning Experiment Guide, Science (Published in 1992).
- the primers were synthesized in the positions near the two ends of the inserted connector, respectively
- the defective virus of the present invention is transfected into E1 transformed human embryonic kidney cell line 293 or E1 transformed human embryonic retinal cell line 911 cells. In the present invention, it was transfected into 293 cells.
- the 293 cell line was purchased from Microbix Biosystem Inc., Canada. (Toronto) is a type 5 adenovirus DNA transformed into human embryonic kidney cells. It contains and expresses the type 5 adenovirus E1 region, which has a high transfection rate.
- a plasmid containing adenovirus type 5 left arm was used to co-transfect 293 cells with a plasmid containing adenovirus type 5 right arm. Homologous recombination can produce infectious adenoviruses.
- PBHG10 and pBHG bow 3 purchased from Microbix Biosystems, Canada
- pBHGIO contains the right arm of type 5 adenovirus, but lacks the E3 region.
- PBHGE3 contains the right arm of type 5 adenovirus and contains the E3 region.
- Viral plaques appeared 9-14 days after co-transfection. After three viral plaque purifications, the adenoviruses were named CNHK201 and CNHK202. For specific methods, refer to Gene Transfer and Expression Protocols, edited by Murray EJ, published by Humana Press 1991.
- Ad5 left arm plasmid Ad5 right arm plasmid
- Ad5-del E1b CNHK202 pXC-de! E1b PBHGE3 Adenoviruses multiply in 293 cells. Adenoviruses are purified by mass centrifugation using a gaseous cesium gradient centrifugation method. ). Its insertion sequence was confirmed by sequencing.
- Ad5-del E1b E3 (CNHK201) is a type 5 adenovirus with deletion mutations in the 2809-3329bp region (partial sequence of the E1b 55Kda protein gene), and inserted a sequence containing two stop codons in the deletion mutation region TAATGAGTAACTAA, accompanied by 28133-30818bp (partial sequence of E3 region), other DNA sequences of the virus are the same as type 5 adenovirus.
- Ad5-del E1b (CNHK202) is a type 5 adenovirus with deletion mutations in the 2809-3329bp region (partial sequence of the E1b 55Kda protein gene), and a sequence containing two stop codons, TAATGAGTAACTAA, is inserted in the deletion mutation region, and other viral DNA sequences Same as adenovirus type 5.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Virology (AREA)
- Genetics & Genomics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- General Health & Medical Sciences (AREA)
- Microbiology (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Mycology (AREA)
- Biomedical Technology (AREA)
- Biotechnology (AREA)
- Public Health (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Biochemistry (AREA)
- General Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
L'invention porte sur un nouvel adénovirus défectif présentant un manque partiel de la séquence codant pour la protéine d'adénovirus naturel E1b de 55kDa, sur son procédé d'obtention, et sur des adénovirus défectifs produits d'assemblage de recombinaison présentant un déficit fonctionnel en protéine E1b de 55kDa du à une mutation suppressive combinée à l'insertion d'un codon terminal, et restreignant la fonction des protéines E1a et E1b de 19kDa et d'autres protéines virales. L'E1a et d'autres protéines virales d'adénovirus sont bénéfiques contre les tumeurs; le système de vecteurs d'adénovirus défectifs peut donc servir à la thérapie des tumeurs.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU13794/01A AU1379401A (en) | 1999-11-19 | 2000-11-17 | A new defective adenovirus and process for producing said adenovirus |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN99124030.8 | 1999-11-19 | ||
| CN99124030A CN1254719A (zh) | 1999-11-19 | 1999-11-19 | 一种缺陷型腺病毒及其构建方法 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2001037867A1 true WO2001037867A1 (fr) | 2001-05-31 |
Family
ID=5283127
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2000/000428 WO2001037867A1 (fr) | 1999-11-19 | 2000-11-17 | Nouvel adenovirus defectif et son procede d'obtention |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN1254719A (fr) |
| AU (1) | AU1379401A (fr) |
| WO (1) | WO2001037867A1 (fr) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1388248A (zh) * | 2001-05-25 | 2003-01-01 | 钱其军 | 高效表达干扰素的肿瘤细胞内特异性增殖的腺病毒及其构建方法 |
| ES2344253T3 (es) * | 2001-10-11 | 2010-08-23 | MERCK SHARP & DOHME CORP. | Vacuna contra el virus de la hepatitis c. |
| CN101781636A (zh) * | 2009-01-19 | 2010-07-21 | 中国人民解放军第二军医大学东方肝胆外科医院 | 一种含11型腺病毒纤毛蛋白基因的增殖型重组溶瘤腺病毒、其构建方法及其用途 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994028152A1 (fr) * | 1993-05-28 | 1994-12-08 | Transgene S.A. | Adenovirus defectifs et lignees de complementation correspondantes |
| WO1996012030A1 (fr) * | 1994-10-17 | 1996-04-25 | Rhone-Poulenc Rorer S.A. | Adenovirus defectifs comprenant un gene therapeutique et un gene immunoprotecteur |
-
1999
- 1999-11-19 CN CN99124030A patent/CN1254719A/zh active Pending
-
2000
- 2000-11-17 AU AU13794/01A patent/AU1379401A/en not_active Abandoned
- 2000-11-17 WO PCT/CN2000/000428 patent/WO2001037867A1/fr active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994028152A1 (fr) * | 1993-05-28 | 1994-12-08 | Transgene S.A. | Adenovirus defectifs et lignees de complementation correspondantes |
| WO1996012030A1 (fr) * | 1994-10-17 | 1996-04-25 | Rhone-Poulenc Rorer S.A. | Adenovirus defectifs comprenant un gene therapeutique et un gene immunoprotecteur |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1254719A (zh) | 2000-05-31 |
| AU1379401A (en) | 2001-06-04 |
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