Novel use of adenoviruses and nucleic acids coding therefor

Abstract

The invention relates to the use of a virus, preferably an adenovirus, for producing a medicament. Said virus is replication-deficient in cells which do not contain YB-1 in the core and codes for an oncogene or oncogene product, especially an oncogene protein, which transactivates at least one viral gene, preferably an adenoviral gene, said gene being selected among the group comprising E1B55kDa, E4orf6, E4orf3, and E3ADP.

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       56 . Use of a virus for the manufacture of a medicament, characterised in that the virus is replication deficient in cells which lack YB-1 in the nucleus, and whereby the virus encodes an oncogene protein which transactivates at least one viral gene, whereby the gene is selected from the group comprising E1B55kDa, E4orf6, E4orf3 and E3ADP.  
   
   
       57 . Use of a virus for replication in cells which exhibit YB-1 in the nucleus, characterised in that the virus is replication deficient in cells which lack YB-1 in the nucleus, and whereby the virus encodes an oncogene protein which transactivates at least one viral gene, whereby the gene is selected from the group comprising E1B55Da, E4orf6, E4orf3 and E3ADP.  
   
   
       58 . Use according to claims  56  or  57 , whereby the virus is an adenovirus.  
   
   
       59 . Use according to claims  58 , characterised in that the virus replicates in cells which have YB-1 in the nucleus.  
   
   
       60 . Use according to claims  56  or  57 , characterised in that the viral oncogene protein is E1A and/or the oncogene is the gene coding for E1A.  
   
   
       61 . Use according to  claim 60 , characterised in that the viral oncogene protein E1A does not induce nucleus localisation of YB-1.  
   
   
       62 . Use according to claims  56  or  57 , characterised in that the cells are Rb negative and the cells are YB-1 nucleus positive, preferably are YB-1 nucleus positive independent from the cell cycle.  
   
   
       63 . Use according to  claim 56 , characterised in that the medicament is for the treatment of tumors.  
   
   
       64 . Use according to  claim 63 , characterised in that the cells forming the tumor or parts thereof are resistant against pharmacologically effective agents.  
   
   
       65 . Use according to  claim 64 , characterised in that the cells show an overexpression of the membrane-bound transport protein P glycoprotein.  
   
   
       66 . Use according to claims  56  or  57 , characterised in that the viral oncogene protein is under the control of a tissue and/or tumor specific promoter.  
   
   
       67 . Use according to  claim 66 , characterised in that the viral oncogene is E1A.  
   
   
       68 . Use according to claims  56  or  57 , characterised in that the virus codes for YB-1.  
   
   
       69 . Use according to  claim 68 , characterised in that YB-1 is under the control of a tissue specific and/or tumor specific promoter.  
   
   
       70 . Use according to claims  56  or  57 , characterised in that the virus codes for at least one protein, whereby the protein is selected from the group comprising E4orf6, E4orf3, E1B55 and adenoviral E3ADP protein.  
   
   
       71 . Use according to claims  56  or  57 , characterised in that the cells forming the tumor or parts thereof have YB-1 in the nucleus.  
   
   
       72 . Use according to claims  56  or  57 , characterised in that the tumor comprises YB-1 in the nucleus after induction of the transport of YB-1 into the nucleus.  
   
   
       73 . Use according to claims  56  or  57 , characterised in that the virus is selected from the group comprising AdΔ24, dl922-947, E1Ad/01/07, dl1119/1131, CB 016, dl520 and viruses lacking an expressed viral oncogene which is capable of binding a functional Rb tumor suppressor gene product.  
   
   
       74 . Use of a virus for the manufacture of a medicament, whereby the virus is designed such that the replication is controlled by YB-1 through the activation of the E2-late promoter.  
   
   
       75 . Use of a virus for replication in cells which have YB-1 in the nucleus, characterised in that the virus is designed such that the replication is controlled by YB-1 through the activation of the E2-late promoter.  
   
   
       76 . Use according to claims  74  or  75 , characterised in that the virus is an adenovirus.  
   
   
       77 . Use according to claims  76 , characterised in that the replication is controlled by YB-1 predominantly through the activation of the E2-late promoter.  
   
   
       78 . Viral oncogene protein, characterised in that it comprises the following characteristics: 
 a) transactivating of at least one viral gene, whereby the viral gene is selected from the group comprising E1B-55k, E3ADP and E4orf6 and E4orf3; and    b) lacking induction of YB-1 in a nucleus, preferably in the nucleus of a cell, in which the viral oncogene protein is present.    
   
   
       79 . Viral oncogene protein according to  claim 78 , characterised in that the viral oncogene protein is E1A.  
   
   
       80 . Viral oncogene protein according to claims  78  or  79 , characterised in that the viral oncogene protein comprises one or several mutations or deletions compared to the wildtype oncogene protein.  
   
   
       81 . Viral oncogene protein according to  claim 80 , characterised in that the deletion is selected from the group comprising deletion of the CR3 region, deletion of the N terminus and deletion of the C terminus.  
   
   
       82 . Use of a viral replication system comprising a nucleic acid coding for a virus as defined in claims  56  or  57 , and comprising a nucleic acid of the helper virus, whereby the nucleic acid of the helper virus comprises a nucleic acid sequence coding for YB-1.  
   
   
       83 . Use according to  claim 82 , characterised in that the replication system is an adenoviral replication system.  
   
   
       84 . Use of a nucleic acid coding for a virus as defined in claims  56 ,  57 ,  74  or  75 , for the manufacture of a medicament, preferably for the manufacture of a medicament for the treatment of tumors.  
   
   
       85 . Use according to  claim 84 , characterised in that the cells forming the tumor or parts thereof, have a resistance against pharmacologically active agents.  
   
   
       86 . Use according to  claim 85 , characterised in that the resistance is a multiple resistance.  
   
   
       87 . Use according to claims  85  or  86 , characterised in that the pharmacologically active agent is an antitumor agent.  
   
   
       88 . Use according to  claim 87 , characterised in that the antitumor agent is a cytostatic.  
   
   
       89 . Use of a nucleic acid coding for a virus as defined in claims  56 ,  57 ,  74  or  75 , for replication in cells which have YB-1 in the nucleus, characterised in that the virus is replication deficient in cells which do not have YB-1 in the nucleus, and the virus encodes an oncogene or oncogene product which transactivates at least one viral gene, whereby the gene is selected from the group comprising E1B55Da, E4orf6, E4orf3 and E3ADP.  
   
   
       90 . Use of a nucleic acid coding for a virus as defined in claims  56 ,  57 ,  74  or  75 , for the manufacture of a medicament, whereby the virus is designed such that the replication is controlled by YB-1 through the activation of the E2-late promoter.  
   
   
       91 . Use of a nucleic acid coding for a virus as defined in claims  56 ,  57 ,  74  or  75 , for replication in cells, whereby the virus is designed such that the replication is controlled by YB-1 through the activation of the E2-late promoter.  
   
   
       92 . Use according to claims  90  or  91 , characterised in that the replication is controlled by YB-1 predominantly through the activation of the E2-late promoter.  
   
   
       93 . Use of a vector comprising a nucleic acid as defined in  claim 89  or  90 , for the manufacture of a medicament or for replication in cells having YB-1 in the nucleus.  
   
   
       94 . Use of a compound interacting with YB-1 for the characterisation of cells, cells of a tumor tissue or patients, in order to determine whether these shall be contacted with and/or treated by a virus as defined in claims  56  or  57 , whereby the compound is selected from the group comprising antibodies, anticalines, aptamers, aptazymes and spiegelmers.  
   
   
       95 . Use of the viral oncogene protein as defined in  claim 78  or a nucleic acid coding therefor, for the manufacture of a virus which may be used in connection with the uses as specified in claims  56  or  57 .  
   
   
       96 . Use of a virus as defined in claims  56  or  57 , whereby the virus comprises a nucleic acid coding for a transgene.  
   
   
       97 . Use of a virus as defined in any of claims  56  or  57 , whereby the virus comprises the translation and/or transcription product of a transgene.  
   
   
       98 . Use of an adenoviral replication system as defined in  claim 82 , whereby the nucleic acid of the adenoviral replication system and/or the nucleic acid of the helper virus comprises a transgene or a nucleic acid coding for a transgene.  
   
   
       99 . Use of a nucleic acid as defined in  claim 84 , whereby the nucleic acid comprises a transgene or a nucleic acid coding for a transgene.  
   
   
       100 . Use according to  claim 96 , whereby the transgene is selected from the group comprising prodrug genes, cytokines, apoptose-inducing genes, tumor suppressor genes, genes for metalloproteinase inhibitors and genes for angiogenesis inhibitors.  
   
   
       101 . Use according to  claim 96 , whereby the transgene is selected from the group comprising nucleic acids for siRNA, for aptamers, for antisense molecules and for ribozymes, whereby the siRNA, the aptamer, the antisense molecule and/or the ribozyme are targeting a target molecule.  
   
   
       102 . Use according to  claim 101 , whereby the target molecule is selected from the group comprising resistance relevant factors, anti-apoptosis factors, oncogenes, angiogenesis factors, DNA synthesis enzymes, DNA repair enzymes, growth factors, receptors for growth factors, transcription factors, metalloproteinases, preferably matrix metalloprotein kinases, and plasminogen activator of the urokinase type.  
   
   
       103 . Use according to  claim 56 , whereby the medicament further comprises a pharmaceutically active compound.  
   
   
       104 . Use according to  claim 103 , whereby the pharmaceutically active compound is selected from the group comprising cytokines, metalloproteinase inhibitors, angiogenesis inhibitors, cytostatics and cell cycle inhibitors.