Method of reducing an immune response to a recombinant virus

Abstract

A method of reducing immune response during gene therapy is provided which involves co-administration of the viral vector bearing a therapeutic transgene and a selected immune modulator capable of inhibiting the formation of neutralizing antibodies and/or CTL elimination of the vectors upon repeated administration.

What is claimed is:  
     
         1 . A method of inhibiting in a mammal formation of neutralizing antibodies directed against a recombinant virus comprising the step of co-administering to said mammal said virus and an immune modulator which inhibits the formation of neutralizing antibodies to the recombinant virus.  
     
     
         2 . The method according to  claim 1 , further comprising the step of re-administering said virus.  
     
     
         3 . The method according to  claim 1 , wherein said immune modulator is administered simultaneously with said virus.  
     
     
         4 . The method according to  claim 1 , wherein said immune modulator is administered prior to administration of said virus.  
     
     
         5 . The method according to  claim 1 , wherein said immune modulator is administered subsequently to administration of said virus.  
     
     
         6 . The method according to  claim 1 , wherein said immune modulator is interleukin-12.  
     
     
         7 . The method according to  claim 1 , wherein said immune modulator comprises an anti-CD4 antibody.  
     
     
         8 . The method according to  claim 1 , wherein said agent is selected from the group consisting of a soluble CD40 molecule and an anti-CD40 ligand antibody.  
     
     
         9 . The method according to  claim 1 , wherein said agent is selected from the group consisting of a soluble CD28 and an anti-CD28 antibody.  
     
     
         10 . The method according to  claim 1 , wherein said immune modulator is gamma-interferon.  
     
     
         11 . The method according to  claim 1 , wherein said immune modulator is selected from the group consisting of a soluble CTLA4 and an anti-CTLA4 antibody.  
     
     
         12 . In a method for repeated delivery of a recombinant virus to a mammal, said method comprising the step of administering to said mammal a recombinant virus comprising a transgene, wherein the improvement comprises the steps of 
 co-administering with said recombinant virus an immune modulator which inhibits the formation of neutralizing antibodies against said virus; and    re-administering the recombinant virus to said mammal, whereby the inhibition of formation of neutralizing antibodies to the recombinant virus by the immune modulator permits re-administration of the recombinant virus.    
     
     
         13 . The method according to  claim 12 , wherein said immune modulator is selected from the group consisting of: 
 an agent which inhibits the formation of neutralizing antibodies by depleting or inhibiting CD4+ cells;    an anti-T cell antibody which inhibits the formation of neutralizing antibodies;    an agent which inhibits the formation of neutralizing antibodies by blocking the interaction between CD40 ligand on a T cell and CD40 on a B cell; and    an agent which inhibits the formation of neutralizing antibodies by blocking the interaction between the CD28 molecule or CTLA4 ligand on a T cell and B7 on a B cell.    
     
     
         14 . The method according to  claim 12 , wherein said immune modulator is a cytokine which inhibits a T H1 -mediated neutralizing antibody or T H2 -mediated neutralizing antibody.  
     
     
         15 . The method according to  claim 12  wherein said immune modulator is interleukin-12.  
     
     
         16 . The method according to  claim 12  wherein said immune modulator comprises an anti-CD4 antibody.  
     
     
         17 . The method according to  claim 12 , wherein said immune modulator binds to the CD40 ligand on a T cell.  
     
     
         18 . The method according to  claim 12 , wherein said immune modulator is selected from the group consisting of a soluble CD40 molecule and an anti-CD40 ligand antibody.  
     
     
         19 . The method according to  claim 12 , wherein said immune modulator binds to the CD28 molecule or CTLA4 ligand on a T cell.  
     
     
         20 . The method according to  claim 19 , wherein said immune modulator is selected from the group consisting of a soluble CD28 molecule and an anti-CD28 antibody.  
     
     
         21 . The method according to  claim 13  wherein said immune modulator comprises a DNA molecule.  
     
     
         22 . The method according to  claim 13  wherein said immune modulator comprises a protein.  
     
     
         23 . A method of inhibiting in a mammal formation of neutralizing antibodies directed against a recombinant virus comprising the step of co-administering to said mammal said recombinant virus and an agent which deplete or inhibits CD4+ cells.  
     
     
         24 . The method according to  claim 23 , further comprising the step of re-administering said recombinant virus.  
     
     
         25 . A method of inhibiting in a mammal formation of neutralizing antibodies directed against a recombinant virus comprising the step of co-administering to said mammal said recombinant virus and an anti-T cell antibody.  
     
     
         26 . The method according to  claim 25 , further comprising the step of re-administering said recombinant virus.  
     
     
         27 . A method of inhibiting in a mammal formation of neutralizing antibodies directed against a recombinant virus comprising the step of co-administering to said mammal said recombinant virus and an agent which blocks the interaction between CD40 ligand on a T cell and CD40 on a B cell.  
     
     
         28 . A method of inhibiting in a mammal formation of neutralizing antibodies directed against a recombinant virus comprising the step of co-administering to said mammal said recombinant virus and an immune modulator which binds to the CD40 ligand on the T cell, thereby inhibiting formation of neutralizing antibodies.  
     
     
         29 . The method according to  claim 28 , further comprising the step of re-administering said recombinant virus.  
     
     
         30 . A method of inhibiting in a mammal formation of neutralizing antibodies directed against a recombinant virus comprising the step of co-administering to said mammal said recombinant virus and an immune modulator which binds to the CD28 or CTLA4 ligand on a T cell, thereby inhibiting formation of neutralizing antibodies.  
     
     
         31 . The method according to  claim 30 , wherein said agent binds to the CD28 or CTLA4 ligand on the T cell.  
     
     
         32 . The method according to  claim 31 , wherein said immune modulator is selected from the group consisting of soluble CD28, a soluble CTLA4, an anti-CD28 antibody and an anti-CTLA4 antibody.  
     
     
         33 . The method according to  claim 30 , further comprising the step of re-administering said recombinant virus.  
     
     
         34 . A method of inhibiting in a mammal formation of neutralizing antibodies directed against a recombinant adeno-associated virus comprising the step of co-administering to said mammal said recombinant adeno-associated virus and a cytokine which inhibits the formation of neutralizing antibodies against said virus.  
     
     
         35 . The method according to  claim 34 , further comprising the step of re-administering said recombinant virus.  
     
     
         36 . A method of inhibiting in a mammal formation of neutralizing antibodies directed against a recombinant adeno-associated virus comprising the step of co-administering to said mammal said recombinant adeno-associated virus and an agent which depletes or inhibits CD4+ cells.  
     
     
         37 . A method of inhibiting in a mammal formation of neutralizing antibodies directed against a recombinant adeno-associated virus comprising the step of co-administering to said mammal said recombinant adeno-associated virus and an anti-T cell antibody.  
     
     
         38 . A method of inhibiting in a mammal formation of neutralizing antibodies directed against a recombinant adeno-associated virus comprising the step of co-administering to said mammal said recombinant adeno-associated virus and an immune modulator which binds to the CD40, thereby inhibiting formation of neutralizing antibodies.  
     
     
         39 . A method of inhibiting in a mammal formation of neutralizing antibodies directed against a recombinant adeno-associated virus comprising the step of co-administering to said mammal said recombinant adeno-associated virus and an immune modulator which binds the CD28 or CTLA4 ligand on a T cell, thereby inhibiting formation of neutralizing antibodies.  
     
     
         40 . The method according to  claim 39 , wherein said immune modulator is selected from the group consisting of a soluble CD28, a soluble CTLA4, an anti-CD28 antibody and an anti-CTLA4 antibody.