WO2007026973A1 - Virus adeno-associe de recombinaison contenant un adnc tronque de vegfr et agent therapeutique genique permettant de traiter le cancer renfermant ledit virus - Google Patents

Virus adeno-associe de recombinaison contenant un adnc tronque de vegfr et agent therapeutique genique permettant de traiter le cancer renfermant ledit virus Download PDF

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Publication number
WO2007026973A1
WO2007026973A1 PCT/KR2005/002881 KR2005002881W WO2007026973A1 WO 2007026973 A1 WO2007026973 A1 WO 2007026973A1 KR 2005002881 W KR2005002881 W KR 2005002881W WO 2007026973 A1 WO2007026973 A1 WO 2007026973A1
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vegfr
cancer
raav
gene
therapeutic agent
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PCT/KR2005/002881
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Keerang Park
Wun-Jae Kim
Young-Hwa Cho
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Juseong College Industry Academy Cooperation Group
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Priority to PCT/KR2005/002881 priority Critical patent/WO2007026973A1/fr
Publication of WO2007026973A1 publication Critical patent/WO2007026973A1/fr

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    • 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
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/86—Viral vectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/71—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators
    • 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
    • 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
    • C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
    • C12N2750/00011—Details
    • C12N2750/14011—Parvoviridae
    • C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
    • C12N2750/14141—Use of virus, viral particle or viral elements as a vector
    • C12N2750/14143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector

Definitions

  • the present invention relates to a gene therapeutic agent using truncated cDNA of VEGF receptor protein (VEGFR) and adeno-associated virus (AVV) system, and more particularly, relates to a gene therapeutic agent specific to cancer, comprising a rAAV vector containing truncated cDNA of VEGFR- 1 , a rAAV vector containing truncated cDNA of VEGFR-2 and said vector.
  • VEGFR VEGF receptor protein
  • AMV adeno-associated virus
  • the radiotherapy is a method of treating cancer by external radiation or by irradiating cancer cells with X-rays or ⁇ -rays from radioactive substances administered in vivo.
  • the drug therapy is a method of administering an anticancer agent orally or by injection to destroy or suppress the DNA or related enzymes, required for the proliferation of cancer cells.
  • the advantages of the drug therapy are that it allows a drug to be delivered to cancer occurred in any site of the body and can treat metastasized cancer.
  • the drug therapy is used as a standard therapy for the treatment of metastatic cancer.
  • the drug therapy plays an important role in increasing life span by alleviating symptoms.
  • chemical therapeutic agents used in this chemical therapy have problems, such as side effects and anticancer drug resistance.
  • biotherapeutic agents are rapidly being developed.
  • the biotherapeutic agents are used for the basic purpose of restoring or increasing the natural immune function of the body to weaken the activity of cancer cells, thus preventing the progression of cancer. If the immune system of the body exhibits its own function, the death of cancer cells can be effectively induced, but if not, cancer cells will be easily proliferated or our body gets easily attacked by other germs.
  • the biotherapeutic agents are sometimes used in combination with other therapies, such as surgical therapy, radiotherapy and chemotherapy.
  • biotherapeutic agents receiving attention in the bioscience field may include anti-sense anticancer agents and angiogenesis inhibitors.
  • the anti-sense anticancer agents are strategies of using DNA fragments capable of complementally binding to cancer cell-specific mRNAs, to inhibit the processing of mRNAs or the expression of proteins, thus inducing the death of cancer cells.
  • As a result of the human genome project about 30,000 gene sequences were interpreted and about 100,000 mRNA sequences could be identified. With this, as a large amount of information for cancer cell-associated mRNA candidates are established, genes associated with signaling pathways and genes associated with apoptosis and cell proliferation are screened and now in clinical trials.
  • angiogenesis supplying oxygen and nutrients required therefor.
  • angiogenesis-associated factors e.g., VEGF, bFGF, IL-8, PDGF, PD-EGF, etc.
  • angiogenesis is a necessary process for the growth of tumors.
  • Angiogenesis inhibitors are used to interfere with angiogenesis caused by tumors so as to suppress the growth of tumors, thus treat cancer.
  • Direct angiogenesis inhibitors interfere with angiogenesis by inhibiting the proliferation or migration of vascular endothelial cells or by inhibiting reactions to angiogenesis factors.
  • the direct angiogenesis inhibitors have an advantage in that they cause less acquired drug resistance.
  • Indirect angiogenesis inhibitors suppress angiogenesis by inhibiting the expression of proteins in tumors activating angiogenesis or by blocking the binding between tumor proteins and vascular endothelial cell surface receptors.
  • the gene therapy which is a method of treating diseases by gene transfer and expression, is used to correct the genetic defect of a certain disordered gene, unlike the drug therapy.
  • the ultimate purpose of the gene therapy is to obtain useful therapeutic effects by genetically modifying a living gene.
  • the gene therapy has various advantages, such as the accurate transfer of a genetic factor into a disease site, the complete decomposition of the genetic factor in vivo, the absence of toxicity and immune antigenicity, and the long-term stable expression of the genetic factor and thus is being spotlighted as the best therapy for the treatment of diseases.
  • the main research field for gene therapy can be summarized in three fields of introducing a gene showing a therapeutic effect on a certain disease, increasing the resistant function of a normal cell so as to show resistance to an anticancer agent and the like, or substituting for a modified or deleted gene in patients with various genetic diseases.
  • the gene therapies are broadly classified into two categories, i.e., in vivo and in vitro therapies.
  • the in vivo gene therapy comprises introducing a therapeutic gene directly into the body, and the in vitro gene therapy comprises culturing a target cell in vitro, introducing a gene into the cell, and then, introducing the genetically modified cell into the body.
  • the in vitro therapy is more frequently used than the in vivo therapy.
  • the gene transfer technologies are broadly divided into a viral vector-based transfer method using virus as a carrier, a non-viral delivery method using synthetic phospholipid or synthetic cationic polymer, and a physical method, such as electroporation of introducing a gene by applying temporary electrical stimulation to a cell membrane.
  • the viral vector-based transfer method is considered to be preferable for the gene therapy because the transfer of a genetic factor can be efficiently made with a vector with the loss of a portion or whole of replicative ability, which has a gene having a therapeutic gene substituted.
  • virus used as the virus carrier or vector include RNA virus vectors (retrovirus vectors, lentivirus vector, etc.), and DNA virus vectors (adenovirus vectors, adeno-associated virus vectors, etc.).
  • virus vectors include RNA virus vectors (retrovirus vectors, lentivirus vector, etc.), and DNA virus vectors (adenovirus vectors, adeno-associated virus vectors, etc.).
  • its examples include herpes simplex viral vectors, alpha viral vectors, etc. Among them, retrovirus and adenovirus vectors are being particularly actively studied.
  • retrovirus acting to integrate into the genome of host cells are that it is harmless to the human body, but can inhibit the function of normal cells upon integration, also it infects various cells, proliferates easily, can receive about 1-7 kb of foreign genes, and is capable of producing replication-deficient virus.
  • it has disadvantages in that it is hard to infect cells after mitosis, it is difficult to transfer a gene in vivo, and the somatic cell tissue needs to be proliferated always in vitro.
  • since it can be integrated into a proto- oncogene it has the risk of mutation and can cause cell necrosis.
  • adenovirus has various advantages for use as a cloning vector; it has moderate size, can be replicated within a cell nucleus, and is clinically nontoxic. Also, it is stable even when inserted with a foreign gene, and does not cause the rearrangement or loss of genes, can transform eucaryotes, and is stably expressed at a high level even when it is integrated into the chromosome of host cells.
  • Good host cells for adenovirus are cells causing human hematosis, lymphoma and myeloma. However, these cells are difficult to proliferate because they are linear DNAs, it is not easy to recover infected virus, and they have low virus infection rate. Also, the expression of a transferred gene is the highest after 1-2 weeks, and in some cells, the expression is kept only for about 3-4 weeks. In addition, these have the problem of high immune antigenicity.
  • Adeno-associated virus can overcome the above-described problems, at the same time, has many advantages for use as a gene therapeutic agent and thus is recently considered to be preferable.
  • AAV which is single-strand provirus, requires an assistant virus for replication, and the AAV genome is 4,680 bp in size and can be inserted into a certain site of chromosome 19 of infected cells.
  • a trans-gene is inserted into plasmid DNA linked with 145 bp of each of two inverted terminal repeat sequence (ITR) and a signal sequence. This gene is transfected with another plasmid DNA expressing AAV rep and cap genes, and adenovirus is added as an assistant virus.
  • ITR inverted terminal repeat sequence
  • AAV has advantages in that the range of its host cells to be transferred with a gene is wide, immune side effects due to repeated administration are little, and the gene expression time is long. Furthermore, it is stable even when the AAV genome is integrated into the chromosome of a host cell, and it does not cause the modification or rearrangement of gene expression in host cells.
  • an AAV vector containing a CFTR gene was approved by NIH for the treatment of cystic fibrosis in 1994, it has been used for the clinical treatment of various diseases.
  • An AAV vector containing a factor IX gene which is a blood coagulation factor, is used for the treatment of hemophilia B, and the development of a therapeutic agent for hemophilia A using the AAV vector is currently being conducted.
  • AAV vectors containing various kinds of anticancer genes were certified for use as tumor vaccines.
  • Gene therapies using VEGF can be exemplified by a recombinant deficient adenovirus containing a nucleic acid encoding an angiogenesis factor for the treatment of pulmonary hypertension (Korean patent application No. 10-2001- 7013633).
  • this therapy uses a VEGF sense base sequence, it can be used only for the treatment of ischemic diseases, and is unsuitable for the treatment of diseases caused by angiogenesis, particularly cancer.
  • adenovirus is unsuitable to use for treatment, because it has the disadvantages of high immune antigenicity, low infectivity towards host cells, and short gene expression time.
  • a rAAV-ASh VEGF-A vector containing the anti-sense cDNA of VEGF-A (Korean patent application No. 10- 2004-54043), and a rAAV-AShVEGF-ABC vector containing the anti-sense cDNAs of VEGF-A, VEGF-B and VEGF-C (PCT/KR2005/002435), are effective as gene therapeutic agents for cancer.
  • a gene therapeutic agent for cancer comprising a rAAV- AShVEGF-A vector containing the anti-sense cDNA of VEGF-A, a rAAV- TShVEGFR-I vector containing the truncated soluble cDNA of VEGFR-I, and a rAAV-TShVEGFR-2 containing the truncated soluble cDNA of VEGFR-2 (Korean patent application No. 10-2005-67661).
  • the present inventors have made extensive efforts to develop a more effective therapeutic agent for cancer, as a result, constructed a rAAV-TRh VEGFR-I vector and a rAAV-TRh VEGFR-2 vector containing truncated soluble cDNA of VEGFR, and found that said vectors inhibit the function of VEGF and also show excellent tumor inhibitory effects in vivo, thereby completing the present invention.
  • the present invention comprises following steps: (a) transfecting a pAAV vector containing truncated cDNA of VEGFR-I, AAV rep-cap plasmid DNA and an adeno-virus helper plasmid into an animal cell line; (b) culturing the transfected animal cell line; and (c) isolating and purifying recombinant rAAV particles after disrupting the cultured cell line; and provides a rAAV vector containing truncated cDNA of VEGFR- 1.
  • the present invention also comprises following steps: (a) transfecting a pAAV vector containing truncated cDNA of VEGFR-2, AAV rep-cap plasmid DNA and an adeno-virus helper plasmid into an animal cell line; (b) culturing the transfected animal cell line; and (c) isolating and purifying recombinant rAAV particles after disrupting the cultured cell line; and provides a rAAV vector containing truncated cDNA of VEGFR-2.
  • the present invention also provides a gene therapeutic agent specific to cancer, comprising the above rAAV vector containing truncated cDNA of VEGFR-I and the above rAAV vector containing truncated cDNA of VEGFR-2.
  • the truncated cDNA of VEGFR-I and truncated cDNA of VEGFR-2 preferably have SEQ ID NOs: 1 and 4, respectively.
  • the gene therapeutic agent according to the present invention is preferably specific to large intestine cancer, bladder cancer and lung cancer.
  • FIG. 1 is a gene map of p A AV-TRh VEGFR-I according to the present invention.
  • FIG. 2 is a gene map of pAAV-TRhVEGFR-2 according to the present invention.
  • FIG. 3A is a result showing the analysis of wound healing effect of rAAV- TRhVEGF-I and/or rAAV-TRhVEGF-2 according to the present invention
  • FIG. 3B is a microscopic photograph showing wound healing effect of rAAV- TRhVEGF-I and/or rAAV-TRhVEGF-2 according to the present invention.
  • FIG. 4 is a gene map of rAAV-AShVEGF-A.
  • FIG. 5 shows the change in tumor volume of nude mouse intra-abdominally injected with the rAAV vector according to the present invention.
  • cDNA was synthesized by the extraction of RNA from HUVEC (Cambrex Bio Science Walkersville, Inc., USA) cells, and 2,427b ⁇ of truncated human VEGFR-I receptor cDNA (SEQ ID NO: 1) was amplified by RT-PCR using the following primers, TRhVEGFR-I Fl and TRhVEGFR-I Rl.
  • the amplified fragment was digested with restriction enzymes Kpnl and Xhol and ligated with a pAAV-FIX cis plasmid DNA (US 6,093,292) digested with the same restriction enzymes, thus constructing pAAV-TRhVEGFR- 1 (FIG. 1).
  • TRhVEGFR-I Fl (SEQ ID NO: 2):
  • TRhVEGFR-I Rl (SEQ ID NO: 3):
  • TRhVEGFR-2 Fl (SEQ ID NO: 5): GGGGTACCGCCACCATGGAGAGCAAGGTGCT
  • Example 2 Construction of rAAV vector for use as gene therapeutic agent for inhibition of angiogenesis
  • AAV rep-cap plasmid DNA pAAV-RC plasmid; Stratagene Co., USA
  • pHelper plasmid adenovirus helper plasmid
  • HEK293 human embryonic kidney 293; ATCC CRL- 1573 cells
  • rAAV recombinant AAV particles
  • CsCl density gradient centrifugation three times, so as to collect a pure fraction with a RI (Refractive Index) of 1.37-1.41 g/ml, thus obtaining a rAAV-TRhVEGFR-1.
  • RI Refractive Index
  • the titration of the obtained rAAV-TRhVEGFR-1 and rAAV-TRhVEGFR-2 particles was performed by quantitative PCR using the following PCR primers constructed for a CMV promoter region:
  • CMV Fl (SEQ ID NO: 7): 5'-GGG CGT GGA TAG CGG TTT GAC TC-3' CMV Rl (SEQ ID NO: 8): 5'-CGG GGC GGG GTT ATT ACG ACA TT-3'.
  • each of pAAV plasmid DNAs with known concentrations was used as a standard substance, and it was found that the recombinant rAAV produced and isolated as described above generally had a rAAV particle titer of 10 12 ⁇ 10 13 viral particles/ml.
  • Example 3 Wound healing assay of the inventive rAAV vector
  • HUVEC cells cultured in a complete medium (EGM-2 BulletKit, Cat# CC-3162, Cambrex Bio Science Walkersville, Inc., USA) were treated with each or both of rAAV-TRhVEGFR-1 and rAAV-TRhVEGFR-2 to an M.O.I of 2 x 10 5 for 24 hours. After 48 hours, a plate where the cells have been grown was wounded with a cell scraper. The wounded plate was washed two times with collection medium [EBM-2 (Cat# CC-3156, Cambrex Bio Science Walkersville, Inc., USA) + 1% FBS] to remove detached cells. The plate was treated with 10 ng/ml of a VEGF protein (Calbiochem, Cat. #676472), and 24 hours later, migrated cells were photographed and analyzed.
  • EBM-2 Cat# CC-3156, Cambrex Bio Science Walkersville, Inc., USA
  • the inventive r AAV-TRhVEGFR-I vector and rAAV- TRhVEGFR-2 vector inhibited VEGF from causing angiogenesis by the migration of vascular endothelial cells, so as to prevent the proliferation of tumors, thus showing anticancer effects.
  • Table 1 Delaying effect of wound-healing by treatment of rAAV vector according to this invention
  • tumor model was prepared by injecting 5 x 10 NCI-H460 human lung cancer cell line (ATCC HTB- 177) to BABL/c nude mice (BABL/c nu/nu mouse, Central Experiment Animal Inc., Japan SLC, Inc.) by hypodermic injection.
  • the rAAV- ASh VEGF-A vector (FIG. 4) used as a control group in this Example was constructed by following method.
  • cDNA was synthesized by the extraction of RNA from HUVEC (Cambrex Bio Science Walkersville, Inc., USA) cells, and 429bp of human VEGF-A isoform antisense cDNA (1025-1453 region) was amplified by RT-PCR using the following AShVEGF-A primer.
  • the amplified fragment was digested with restriction enzymes Kpnl and Xhol and ligated with pAAV-FIX cis plasmid DNA digested with the same restriction enzymes, thus constructing pAAV-AShVEGF-A.
  • AShVEGF-A F2 (SEQ ID NO: 9): GGGG ⁇ 4CCGTCTTGCTCTATCTTTC Kpnl
  • AShVEGF-A Rl (SEQ ID NO: 10):CCCJC£4(7GGCCTCCGAAACCATGAACT
  • taxol paclitaxel
  • DMSO dimethyl methyl sulfoxide
  • 0.2ml 200 ⁇ g/mouse dose
  • the volume of tumors was measured at an interval of 3 days with Vernier calipers for 3 weeks.
  • the group administered with [rAAV-TRhVEGFR-1 + rAAV-TRhVEGFR-2] which is a gene therapeutic agent according to the present invention, showed excellent tumor inhibitory effect as compared to the group administered with rAAV- AShVEGF-A and the group administered with taxol.
  • the present invention provides the rAAV vector for gene therapy containing truncated cDNA of VEGFR-I and truncated cDNA of VEGFR-2.
  • the present invention also provides a gene therapeutic agent specific to cancer, comprising the rAAV vector containing truncated cDNA of VEGFR-I and/or the rAAV vector containing truncated cDNA of VEGFR-2.
  • the gene therapeutic agent according to the present invention reduces the growth of tumors by inhibiting the expression and function of VEGF involved in angiogenesis necessary for the proliferation and metastasis of tumors.
  • the inventive gene therapeutic agent can be effectively used to treat cancer at a gene level.

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Abstract

L'invention concerne un agent thérapeutique génique utilisant un ADN tronqué de protéine du récepteur VEGF (VEGFR) et un système de virus adéno-associé (AVV) et, plus particulièrement, un agent thérapeutique génique spécifique du cancer, comprenant un vecteur rAAV contenant un ADNc tronqué de VEGFR-1, un vecteur rAAV contenant un ADNc tronqué de VEGFR-2 et ledit vecteur. L'agent thérapeutique génique de l'invention permet de limiter la croissance tumorale par inhibition de l'expression et de la fonction de VEGF impliqué dans l'angiogénèse nécessaire à la prolifération et à la métastase des tumeurs. En conséquence, on peut utiliser efficacement l'agent thérapeutique génique de l'invention pour traiter un cancer au niveau génique.
PCT/KR2005/002881 2005-08-31 2005-08-31 Virus adeno-associe de recombinaison contenant un adnc tronque de vegfr et agent therapeutique genique permettant de traiter le cancer renfermant ledit virus WO2007026973A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5851999A (en) * 1992-11-13 1998-12-22 Max-Planck-Gesellschaft zur Forderung der Wissenschaften ev. FLK-1 is a receptor for vascular endothelial growth factor

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5851999A (en) * 1992-11-13 1998-12-22 Max-Planck-Gesellschaft zur Forderung der Wissenschaften ev. FLK-1 is a receptor for vascular endothelial growth factor

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
DAVIS-SMYTH T. ET AL., EMBO J., vol. 15, no. 18, 16 September 1996 (1996-09-16), pages 4919 - 4927, XP000611912 *
EBOS J.M. ET AL., MOL. CANCER RES., vol. 2, no. 6, June 2004 (2004-06-01), pages 315 - 326, XP003013242 *
GERBER H.P. ET AL., DEVELOPMENT, vol. 126, no. 6, March 1999 (1999-03-01), pages 1149 - 1159, XP003008580 *
STRECK C.J. ET AL., J. AM. COLL. SURG., vol. 199, no. 1, July 2004 (2004-07-01), pages 78 - 86, XP003013241 *
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