Hexon isolated from simian adenovirus serotype 19, hypervariable region thereof and chimeric adenovirus using the same

Abstract

Novel hexon isolated from simian adenovirus serotype 19 encoded in the polynucleotide defined as SEQ ID NO: 3, hepervariable region thereof, chimeric adenovirus comprising the same, and therapeutic use thereof provides a solution to the problem of safety and effective systemic treatment for developing gene therapeutic agents using adenovirus.

1 . A hexon isolated from simian adenovirus serotype 19 having the amino acid sequence of SEQ ID NO: 16. 
     
     
         2 . A DNA encoding the hexon of  claim 1 . 
     
     
         3 . The DNA of  claim 2  having the nucleotide sequence of SEQ ID NO: 3. 
     
     
         4 . A hypervariable region (HVR) having the amino acid sequence of SEQ ID NO: 21 isolated from simian adenovirus serotype 19. 
     
     
         5 . A DNA encoding the HVR of  claim 4 . 
     
     
         6 . The DNA of  claim 5  having the nucleotide sequence of SEQ ID NO: 20. 
     
     
         7 . A chimeric adenovirus having a normative amino acid sequence in the hexon by the substitution of the hexon protein having the amino acid sequence of SEQ ID NO: 16, or seven (7) or more consecutive residues therefrom. 
     
     
         8 . The chimeric adenovirus of  claim 7 , wherein the normative amino acid sequence is the HVR having the amino acid sequence of SEQ ID NO: 21. 
     
     
         9 . The chimeric adenovirus of  claim 7 , wherein the normative amino acid sequence is a fragment of the HVR selected from the group consisting of: amino acid residues 11 to 41 of SEQ ID NO: 21; amino acid residues 46 to 52 of SEQ ID NO: 21; amino acid residues 69 to 78 of SEQ ID NO: 21; amino acid residues 106 to 119 of SEQ ID NO: 21; amino acid residues 126 to 138 of SEQ ID NO: 21; amino acid residues 160 to 173 of SEQ ID NO: 21; and amino acid residues 275 to 303 of SEQ ID NO: 21. 
     
     
         10 . The chimeric adenovirus of  claim 7 , which is a human adenovirus. 
     
     
         11 . The chimeric adenovirus of  claim 10 , wherein the human adenovirus is selected from the group consisting of human adenovirus serotypes 2, 3, 5, 11, 24, 26, 30, 34, 35, 36, 41, 48, 49, and 50. 
     
     
         12 . The chimeric adenovirus of  claim 7 , wherein the chimeric adenovirus further comprises a therapeutic transgene. 
     
     
         13 . The chimeric adenovirus of  claim 12 , wherein the therapeutic transgene is selected from the group consisting of tumor suppressor gene, antigenic gene, cytotoxic gene, cytostatic gene, suicide gene, anti-angiogenic gene, and immune-modulatory gene. 
     
     
         14 . The chimeric adenovirus of  claim 13 , wherein
 the tumor suppressor gene is selected from the group consisting of p53 gene, APC gene, DPC-4/Smad-4 gene, BRCA-1 gene, BRCA-2 gene, WT-1 gene, retinoblastoma gene, MMAC-1 gene, adenomatous polyposis coil protein, DCC (deleted in colorectal cancer) gene, MMSC-2 gene, NF-1 gene, NF-2 gene, MTS1 gene, CDK4 gene, and VHL gene;   the antigenic gene is carcinoembryonic antigen (CEA), CD3, CD133, CD44, or p53;   the cytotoxic gene is selected from the group consisting of genes coding  Pseudomonas  exotoxin, ricin toxin, and diphtheria toxin;   the cytostatic gene is selected from the group consisting of p21, retinoblastoma gene, E2F-Rb fusion protein gene, a gene coding cyclin-dependent kinase inhibitor, and growth arrest specific homeobox (GAX) gene;   the suicide gene is selected from the group consisting of genes coding herpes simplex virus thymidine kinase, varicella thymidine kinase, cytosine deaminase, purine nucleoside phosphorylase, beta-lactanase, carboxypeptidase G2, cytochrome P450-2B1, nitroreductase, beta-glucuronidase and TRAIL (TNF related apoptosis-inducing ligand);   the anti-angiogenic gene is selected from the group consisting of genes coding vascular endothelial growth factor (VEGF), soluble VEGF receptor, angiostatin, endostatin, and apolipoprotein (a) kringle domain (LK8); and   the immune-modulatory gene is selected from the group consisting of genes coding CD16, CTLA-4, IL24 and GM-CSF.   
     
     
         15 . A composition comprising the chimeric adenovirus of  claim 7 . 
     
     
         16 . A method for delivering a therapeutic transgene to a mammalian cell comprising introducing into said cell the chimeric adenovirus of  claim 12 . 
     
     
         17 . A method for treating cancers comprising administering into a subject the chimeric adenovirus of  claim 12 . 
     
     
         18 . A method for preparing an adenoviral vector for gene therapy comprising substituting seven (7) or more amino acid residues in the hexon of a human adenovirus with seven (7) or more residues of the hexon protein having the amino acid sequence of SEQ ID NO: 16. 
     
     
         19 . An isolated host cell comprising the chimeric adenovirus of  claim 7 . 
     
     
         20 . The isolated host cell of  claim 19 , wherein the isolated host cell is a human cell.