Bispecific Molecules That Are Immunoreactive With Immune Effector Cells That Express An Activating Receptor And An Antigen Expressed By A Cell Infected By A Virus And Uses Thereof

Abstract

The present invention relates to bispecific molecules that are capable of localizing an immune effector cell that expresses an activating receptor to a virally infected cell, so as to thereby facilitate the killing of the virally infected cell. In a preferred embodiment, such localization is accomplished using bispecific molecules that are immunoreactive with an activating receptor of an immune effector cell and to an antigen expressed by a cell infected with a virus wherein the antigen is detectably present on the cell infected with the virus at a level that is greater than the level at which the antigen is detected on the virus by the bispecific molecules, and to the use of such bispecific molecules in the treatment of latent viral infections.

1 . A bispecific molecule comprising:
 a. a first epitope-binding domain, said first epitope-binding domain being capable of immunospecifically binding to an epitope of a protein expressed on the surface of an immune effector cell, wherein said immune effector cell expresses an activating receptor, and   b. a second epitope-binding domain, said second epitope-binding domain being capable of immunospecifically binding to an epitope of an antigen expressed by a cell infected with a virus; wherein said antigen is detectably present on said cell infected by said virus at a level that is greater than the level at which said antigen is detected on said virus by said bispecific molecule.   
     
     
         2 . The bispecific molecule of  claim 1 , wherein said first epitope-binding domain binds to an activating receptor of an immune effector cell. 
     
     
         3 . The bispecific molecule of  claim 2 , wherein said effector cell is a T-cell, a CD4+ T-cell, a CD8+ T-cell, a natural killer cell, a macrophage, a granulocyte, or a dendritic cell. 
     
     
         4 . The bispecific molecule of  claim 2 , wherein said virus is EBV, HSV, CMV, HIV, HBV, HCV, HPV, or influenza virus. 
     
     
         5 . The bispecific molecule of  claim 2 , wherein said cell is latently infected with said virus. 
     
     
         6 . The bispecific molecule of  claim 2 , wherein said antigen expressed by said cell infected with said virus is selected from the group consisting of LMP-1, LMP-2, influenza virus M2 protein, HIV env protein, HPV E6 and HPV E7. 
     
     
         7 . The bispecific molecule of  claim 2 , wherein said antigen expressed by said cell infected with said virus is detectably present on said cell and is not detected on said virus by said bispecific molecule. 
     
     
         8 . The bispecific molecule of  claim 2 , wherein said epitope on said effector cell is a CD3 epitope, a CD4 epitope, a CD8 epitope, a CD2 epitope, a CD16 epitope, or an NKG2D epitope. 
     
     
         9 . The bispecific molecule of  claim 2 , wherein said first epitope binding domain is an antigen binding domain from a CD3 antibody, a CD4 antibody, a CD8 antibody, a CD2 antibody, a CD16 antibody, an NKG2D antibody. 
     
     
         10 . The bispecific molecule of  claim 2 , wherein said antigen expressed by said cell infected with said virus is detectably present on said cell at a level that is at least 2 times greater than the level at which said antigen is detected on said virus by said bispecific molecule. 
     
     
         11 . The bispecific molecule of  claim 2 , wherein said antigen expressed by said cell infected with said virus is detectably present on said cell at a level that is at least 5 times greater than the level at which said antigen is detected on said virus by said bispecific molecule. 
     
     
         12 . The bispecific molecule of  claim 2 , wherein said antigen expressed by said cell infected with said virus is detectably present on said cell at a level that is at least 10 times greater than the level at which said antigen is detected on said virus by said bispecific molecule. 
     
     
         13 . The bispecific molecule of  claim 2 , wherein said antigen expressed by said cell infected with said virus is detectably present on said cell at a level that is at least 100 times greater than the level at which said antigen is detected on said virus by said bispecific molecule. 
     
     
         14 . The bispecific molecule of  claim 2 , wherein said antigen is detectably present on said cell infected by said virus at a level that is greater than the level at which said antigen is detected on a cell that is not infected by said virus by said bispecific molecule. 
     
     
         15 . The bispecific molecule of  claim 14 , wherein said wherein said antigen is detectably present on said cell infected by said virus at a level that is at least 2 times greater than the level at which said antigen is detected on a cell that is not infected by said virus by said bispecific molecule. 
     
     
         16 . The bispecific molecule of  claim 14 , wherein said wherein said antigen is detectably present on said cell infected by said virus at a level that is at least 5 times greater than the level at which said antigen is detected on a cell that is not infected by said virus by said bispecific molecule. 
     
     
         17 . The bispecific molecule of  claim 14 , wherein said wherein said antigen is detectably present on said cell infected by said virus at a level that is at least 10 times greater than the level at which said antigen is detected on a cell that is not infected by said virus by said bispecific molecule. 
     
     
         18 . The bispecific molecule of  claim 14 , wherein said wherein said antigen is detectably present on said cell infected by said virus at a level that is at least 100×greater than the level at which said antigen is detected on a cell that is not infected by said virus by said bispecific molecule. 
     
     
         19 . The bispecific molecule of  claim 14 , wherein said antigen expressed by said cell infected with said virus is detectably present on said cell and is not detected on a cell not infected by said bispecific molecule. 
     
     
         20 . A pharmaceutical composition comprising a bispecific molecule and a pharmaceutically acceptable carrier, said bispecific molecule comprising:
 a. a first epitope-binding domain, said first epitope-binding domain being capable of immunospecifically binding to an epitope of a protein expressed on the surface of an immune effector cell, wherein said immune effector cell expresses an activating receptor, and   b. a second epitope-binding domain, said second epitope-binding domain being capable of immunospecifically binding to an epitope of an antigen expressed by a cell infected with a virus; wherein said antigen is detectably present on said cell infected by said virus at a level that is greater than the level at which said antigen is detected on said virus by said bispecific molecule.   
     
     
         21 . The pharmaceutical composition of  claim 20 , wherein said first epitope-binding domain of said bispecific molecule binds to an activating receptor of an immune effector cell. 
     
     
         22 . A method of treating a latent virus infection in an individual in need of such treatment, said method comprising the step of administering a therapeutically effective amount of a bispecific molecule to said individual, said bispecific molecule comprising:
 a. a first epitope-binding domain, said first epitope-binding domain being capable of immunospecifically binding to an epitope of a protein expressed on the surface of an immune effector cell, wherein said immune effector cell expresses an activating receptor, and   b. a second epitope-binding domain, said second epitope-binding domain being capable of immunospecifically binding to an epitope of an antigen expressed by a cell infected with a virus; wherein said antigen is detectably present on said cell infected by said virus at a level that is greater than the level at which said antigen is detected on said virus by said bispecific molecule.   
     
     
         23 . A method of treating a persistent virus infection in an individual in need of such treatment, said method comprising the step of administering a therapeutically effective amount of a bispecific molecule to said individual, said bispecific molecule comprising:
 a. a first epitope-binding domain, said first epitope-binding domain being capable of immunospecifically binding to an epitope of a protein expressed on the surface of an immune effector cell, wherein said immune effector cell expresses an activating receptor, and   b. a second epitope-binding domain, said second epitope-binding domain being capable of immunospecifically binding to an epitope of an antigen expressed by a cell infected with a virus; wherein said antigen is detectably present on said cell infected by said virus at a level that is greater than the level at which said antigen is detected on said virus by said bispecific molecule.   
     
     
         24 . A method of treating an inactive virus infection in an individual in need of such treatment, said method comprising the step of administering a therapeutically effective amount of a bispecific molecule to said individual, said bispecific molecule comprising:
 a. a first epitope-binding domain, said first epitope-binding domain being capable of immunospecifically binding to an epitope of a protein expressed on the surface of an immune effector cell, wherein said immune effector cell expresses an activating receptor, and   b. a second epitope-binding domain, said second epitope-binding domain being capable of immunospecifically binding to an epitope of an antigen expressed by a cell infected with a virus; wherein said antigen is detectably present on said cell infected by said virus at a level that is greater than the level at which said antigen is detected on said virus by said bispecific molecule.   
     
     
         25 . A method of killing a cell containing a viral genome, said method comprises the step of contacting said cell with a bispecific molecule, said bispecific molecule comprising:
 a. a first epitope-binding domain, said first epitope-binding domain being capable of immunospecifically binding to an epitope of a protein expressed on the surface of an immune effector cell, wherein said immune effector cell expresses an activating receptor, and   b. a second epitope-binding domain, said second epitope-binding domain being capable of immunospecifically binding to an epitope of an antigen expressed by a cell infected with a virus; wherein said antigen is detectably present on said cell infected by said virus at a level that is greater than the level at which said antigen is detected on said virus by said bispecific molecule;   whereby said cell containing said viral genome is killed.   
     
     
         26 . A method of killing a cell expressing a viral protein, said method comprises the step of contacting said cell with a bispecific molecule, said bispecific molecule comprising:
 (A) a first epitope-binding domain, said first epitope-binding domain being capable of immunospecifically binding to an epitope of a protein expressed on the surface of an immune effector cell, wherein said immune effector cell expresses an activating receptor, and   (B) a second epitope-binding domain, said second epitope-binding domain being capable of immunospecifically binding to an epitope of said viral protein; wherein said viral protein is detectably present on said cell expressing said viral protein at a level that is greater than the level at which said viral protein is detected on a virus capable of expressing said viral protein;
 whereby said cell expressing said viral protein is killed. 
   
     
     
         27 . The method of  claim 22 , wherein said first epitope-binding domain of said bispecific molecule binds to an activating receptor of an immune effector cell. 
     
     
         28 . The method of  claim 22 , wherein said effector cell is a T-cell, a CD4+ T-cell, a CD8+ T-cell, a natural killer cell, a macrophage, a granulocyte, or a dendritic cell. 
     
     
         29 . The method of  claim 22 , wherein said virus is EBV, HSV, CMV, HIV, HBV, HCV, HPV, or influenza virus. 
     
     
         30 . The method of  claim 22 , wherein said cell is latently infected with said virus. 
     
     
         31 . The method of  claim 23 , wherein said first epitope-binding domain of said bispecific molecule binds to an activating receptor of an immune effector cell. 
     
     
         32 . The method of  claim 23 , wherein said effector cell is a T-cell, a CD4+ T-cell, a CD8+ T-cell, a natural killer cell, a macrophage, a granulocyte, or a dendritic cell. 
     
     
         33 . The method of  claim 23 , wherein said virus is EBV, HSV, CMV, HIV, HBV, HCV, HPV, or influenza virus. 
     
     
         34 . The method of  claim 23 , wherein said cell is latently infected with said virus. 
     
     
         35 . The method of  claim 24 , wherein said first epitope-binding domain of said bispecific molecule binds to an activating receptor of an immune effector cell. 
     
     
         36 . The method of  claim 24 , wherein said effector cell is a T-cell, a CD4+ T-cell, a CD8+ T-cell, a natural killer cell, a macrophage, a granulocyte, or a dendritic cell. 
     
     
         37 . The method of  claim 24 , wherein said virus is EBV, HSV, CMV, HIV, HBV, HCV, HPV, or influenza virus. 
     
     
         38 . The method of  claim 24 , wherein said cell is latently infected with said virus.