Methods for treating viral infection using IL-28 and IL-29 cysteine mutants

Abstract

IL-28A, IL-28B, IL-29, and certain mutants thereof have been shown to have antiviral activity on a spectrum of viral species. Of particular interest is the antiviral activity demonstrated on viruses that infect liver, such as hepatitis B virus and hepatitis C virus. In addition, IL-28A, IL-28B, IL-29, and mutants thereof do not exhibit some of the antiproliferative activity on hematopoietic cells that is observed with interferon treatment. Without the immunosuppressive effects accompanying interferon treatment, IL-28A, IL-28B, and IL-29 will be useful in treating immunocompromised patients for viral infections.

1 . A method of treating a viral infection in a mammal, the method comprising: 
 administering to the mammal a therapeutically effective amount of an isolated polypeptide comprising an amino acid sequence having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs:2, 4, 6, 18, 20, 22, 24, 26, 28, 30, 32, 34, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, and 136, wherein after administration of the polypeptide the viral load is reduced.    
     
     
         2 . The method of  claim 1  wherein the polypeptide is a recombinant polypeptide.  
     
     
         3 . The method of  claim 1  wherein the viral infection is a virus selected from the group consisting of hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, human immunodeficiency virus, respiratory syncytial virus, herpes virus, Epstein-Barr virus, influenza virus, adenovirus, parainfluenza virus, rhino virus, coxsackie virus, vaccinia virus, west nile virus, severe acute respiratory syndrome, dengue virus, Venezuelan equine encephalitis virus, pichinde virus and polio virus.  
     
     
         4 . The method of  claim 1  wherein the polypeptide is conjugated to a polyalkyl oxide moiety.  
     
     
         5 . The method of  claim 4  wherein the polyalkyl oxide moiety is polyethylene glycol.  
     
     
         6 . The method of  claim 5  wherein the polyethylene glycol is monomethoxy-PEG propionaldehyde.  
     
     
         7 . The method of  claim 6  wherein the monomethoxy-PEG propionaldehyde has a molecular weight of about 20 Kd or 30 Kd.  
     
     
         8 . The method of  claim 6  wherein the monomethoxy-PEG propionaldehyde is linear or branched.  
     
     
         9 . The method of  claim 6  wherein the monomethoxy-PEG propionaldehyde is conjugated N-terminally to the polypeptide.  
     
     
         10 . A method of treating liver inflammation in a mammal, the method comprising: 
 administering to the mammal a therapeutically effective amount of an isolated polypeptide comprising an amino acid sequence having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs:2, 4, 6, 18, 20, 22, 24, 26, 28, 30, 32, 34, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, and 136, wherein after administration the liver inflammation is reduced.    
     
     
         11 . The method of  claim 10  wherein the polypeptide is a recombinant polypeptide.  
     
     
         12 . The method of  claim 10  wherein the liver inflammation is associated with a viral infection.  
     
     
         13 . The method of  claim 12  wherein the viral infection is a virus selected from the group consisting of hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, human immunodeficiency virus, respiratory syncytial virus, herpes virus, Epstein-Barr virus, influenza virus, adenovirus, parainfluenza virus, rhino virus, coxsackie virus, vaccinia virus, west nile virus, severe acute respiratory syndrome, dengue virus, Venezuelan equine encephalitis virus, pichinde virus and polio virus.  
     
     
         14 . The method of  claim 10  wherein the polypeptide is conjugated to a polyalkyl oxide moiety.  
     
     
         15 . The method of  claim 14  wherein the polyalkyl oxide moiety is polyethylene glycol.  
     
     
         16 . The method of  claim 15  wherein the polyethylene glycol is monomethoxy-PEG propionaldehyde.  
     
     
         17 . The method of  claim 16  wherein the monomethoxy-PEG propionaldehyde has a molecular weight of about 20 Kd or 30 Kd.  
     
     
         18 . The method of  claim 16  wherein the monomethoxy-PEG propionaldehyde is linear or branched.  
     
     
         19 . The method of  claim 16  wherein the monomethoxy-PEG propionaldehyde is conjugated N-terminally to the polypeptide.  
     
     
         20 . A method of treating a viral infection in a mammal, the method comprising: 
 administering to the mammal a composition comprising: 
 a therapeutically effective amount of an isolated polypeptide comprising an amino acid sequence having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs:2, 4, 6, 18, 20, 22, 24, 26, 28, 30, 32, 34, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, and 136; and  
 a pharmaceutically acceptable vehicle; and  
   wherein after administration of the composition the viral load is reduced.    
     
     
         21 . The method of  claim 20  wherein the viral infection is a virus selected from the group consisting of hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, human immunodeficiency virus, respiratory syncytial virus, herpes virus, Epstein-Barr virus, influenza virus, adenovirus, parainfluenza virus, rhino virus, coxsackie virus, vaccinia virus, west nile virus, severe acute respiratory syndrome, dengue virus, venezuelan equine encephalitis virus, pichinde virus and polio virus.  
     
     
         22 . The method of  claim 20  wherein the polypeptide is conjugated to a polyalkyl oxide moiety.  
     
     
         23 . The method of  claim 22  wherein the polyalkyl oxide moiety is polyethylene glycol.  
     
     
         24 . The method of  claim 23  wherein the polyethylene glycol is monomethoxy-PEG propionaldehyde.  
     
     
         25 . The method of  claim 24  wherein the monomethoxy-PEG propionaldehyde has a molecular weight of about 20 Kd or 30 Kd.  
     
     
         26 . The method of  claim 24  wherein the monomethoxy-PEG propionaldehyde is linear or branched.  
     
     
         27 . The method of  claim 24  wherein the monomethoxy-PEG propionaldehyde is conjugated N-terminally to the polypeptide.  
     
     
         28 . A method of treating liver inflammation in a mammal, the method comprising: 
 administering to the mammal a therapeutically effective amount of a composition comprising: 
 an isolated polypeptide comprising an amino acid sequence having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs:2, 4, 6, 18, 20, 22, 24, 26, 28, 30, 32, 34, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, and 136; and  
 a pharmaceutically acceptable vehicle; and  
   wherein after administration of the composition the liver inflammation is reduced.    
     
     
         29 . A method of treating a viral infection comprising administering to an immunocompromised mammal with a viral infection a therapeutically effective amount of an isolated polypeptide comprising an amino acid sequence having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs:2, 4, 6, 18, 20, 22, 24, 26, 28, 30, 32, 34, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, and 136, wherein after administration of the polypeptide the viral infection is reduced.  
     
     
         30 . The method of  claim 29  wherein the immunocompromised mammal is infected with a virus selected from the group consisting of hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, human immunodeficiency virus, respiratory syncytial virus, herpes virus, Epstein-Barr virus, influenza virus, adenovirus, parainfluenza virus, rhino virus, coxsackie virus, vaccinia virus, west nile virus, severe acute respiratory syndrome, dengue virus, Venezuelan equine encephalitis virus, pichinde virus and polio virus.  
     
     
         31 . A method of treating a viral infection in an immunocompromised mammal, the method comprising; 
 administering to the immunocompromised mammal a composition comprising: 
 a therapeutically effective amount of an isolated polypeptide comprising an amino acid sequence having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs:2, 4, 6, 18, 20, 22, 24, 26, 28, 30, 32, 34, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, and 136; and  
 a pharmaceutically acceptable vehicle; and  
   wherein after administration of the composition the viral infection is reduced.    
     
     
         32 . A kit comprising: 
 a composition comprising: 
 a therapeutically effective amount of an isolated polypeptide comprising an amino acid sequence having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs:2, 4, 6, 18, 20, 22, 24, 26, 28, 30, 32, 34, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, and 136; and  
 a pharmaceutically acceptable vehicle.  
   
     
     
         33 . The kit of  claim 32  further comprising an antiviral agent.  
     
     
         34 . The kit of  claim 33  wherein the antiviral agent is selected from the group of Interferon alpha, Serine Protease Inhibitor, Polymerase Inhibitor, Antisense Inhibitor, and combinations thereof.  
     
     
         35 . The kit of  claim 34  wherein the antiviral agent is RIBAVIRIN.  
     
     
         36 . The kit of  claim 34  wherein the antiviral agent is PEG-INTRON.  
     
     
         37 . The kit of  claim 34  wherein the antiviral agent is PEGASYS.