Antibody Derivatives with Conditionally Enabled Effector Function

Abstract

Antibody derivatives that have diminished effector function in the initial state owing to the presence of one or more disabling moieties that substantially prevent engagement of the antibody regions responsible for interaction with humoral and cellular immune system effector molecules, and methods of use thereof.

What is claimed is: 
     
         1 . A disabled antibody derivative comprising:
 a target recognition moiety;   an antibody effector region, optionally comprising an IgG CH2 domain, an IgM CH3 domain, or IgG CH2 and CH3 domains;   a disabling moiety cleavable linker, and   an effector region disabling moiety.   
     
     
         2 . The disabled antibody derivative of  claim 1 , wherein the target recognition moiety comprises an antigen-binding antibody variable region; an artificially diversified polypeptide binder; or a peptide that binds to a cell surface protein. 
     
     
         3 . The disabled antibody derivative of  claim 1 , wherein the target recognition moiety binds to target on a cancer cell or on an immune system cell. 
     
     
         4 . The disabled antibody derivative of  claim 1 , wherein the antibody effector region comprises an IgG CH2 domain. 
     
     
         5 . The disabled antibody derivative of  claim 1 , wherein the disabling moiety cleavable linker comprises a polypeptide sequence containing a protease cleavage site. 
     
     
         6 . The disabled antibody derivative of  claim 1 , wherein the disabling moiety cleavable linker comprises a post-translationally modified protease cleavage site. 
     
     
         7 . The disabled antibody derivative of  claim 1 , wherein the effector region disabling moiety comprises an extracellular soluble portion of an Fc receptor. 
     
     
         8 . The disabled antibody derivative of  claim 8 , wherein the effector region disabling moiety comprises an extracellular soluble domain of a human Fc receptor, optionally of CD16, CD32, or CD64. 
     
     
         9 . The disabled antibody derivative of  claim 1 , wherein the effector region disabling moiety comprises an antibody-binding portion of an Fc-gamma receptor. 
     
     
         10 . The disabled antibody derivative of  claim 1 , wherein the target recognition moiety and the antibody effector region comprise a variable region and constant region of an antibody. 
     
     
         11 . The disabled antibody derivative of  claim 1 , wherein the target recognition moiety and the antibody effector region comprise a variable region and constant region of a human IgG antibody. 
     
     
         12 . The disabled antibody derivative of  claim 1 , wherein the target recognition moiety and the antibody effector region comprise a variable region and constant region of a human IgG antibody, and the disabling moiety cleavable linker is coupled to either the C terminus of the light chain or the C terminus of the heavy chain. 
     
     
         13 . The disabled antibody derivative of  claim 1 , wherein the target recognition moiety and the antibody effector region comprise a variable region and constant region of a human IgG antibody, the disabling moiety cleavable linker is coupled to either the C terminus of the light chain or the C terminus of the heavy chain, and the effector region disabling moiety comprises an antibody portion of an Fc gamma receptor. 
     
     
         14 . The disabled antibody derivative of  claim 1 , wherein the target recognition moiety and the antibody effector region comprise a variable region and constant region of a human IgG antibody, the disabling moiety cleavable linker is coupled to the C terminus of the light chain, and the effector region disabling moiety comprises an extracellular domain of human CD32. 
     
     
         15 . A nucleic acid encoding the disabled antibody derivative of  claim 1 . 
     
     
         16 . A vector comprising the nucleic acid of  claim 15 . 
     
     
         17 . A host cell expressing the disabled antibody derivative of  claim 1 . 
     
     
         18 . A kit comprising:
 the disabled antibody derivative of  claim 1 , and   an activator comprising a second target recognition moiety and an activation domain that cleaves the disabling moiety cleavable linker.   
     
     
         19 - 21 . (canceled) 
     
     
         22 . A method of directing immune effector function against a cell, the method comprising:
 contacting the cell with a disabled antibody derivative of  claim 1 ,   an activator comprising a second target recognition moiety and an activation domain that cleaves the disabling moiety cleavable linker, wherein the target recognition domain and the second target recognition domain bind to targets present on the cell, thereby inducing one or both of a humoral immune response or a cellular immune response against that cell.   
     
     
         23 . A method of directing immune effector function against a cell, the method comprising contacting the cell with a disabled antibody derivative of  claim 1 , wherein the target recognition domain binds to a target present on the cell, and the disabling moiety cleavable linker is cleaved by an endogenous activator, to thereby induce one or both of a humoral immune response or a cellular immune response against that cell. 
     
     
         24 - 25 . (canceled)