Targeting compounds

Abstract

The present invention provides antibody targeting compounds in which the specificity of the antibody has been reprogrammed by covalently or noncovalently linking a targeting agent to the combining site of an antibody. By this approach, the covalently modified antibody takes on the binding specificity of the targeting agent. The compound may have biological activity provided by the targeting agent or by a separate biological agent. Various uses of the invention compounds are provided.

What is claimed is: 
     
         1 . A targeting compound comprising an antibody or an antigen binding fragment thereof and a therapeutic targeting agent at least 300 Daltons in size linked to a side chain of a reactive lysine residue in the combining site of the antibody or antigen binding fragment thereof via a linker comprising X, wherein a precursor of the linker comprises the formula X—Z, wherein X is a linear or branched connecting chain of atoms comprising any of C, H, N, O, P, S, Si, F, Cl, Br, and I, or a salt thereof, and wherein Z is a group that competes for reaction with the side chain of the reactive lysine residue in the combining site of the antibody or antigen binding fragment thereof with a reactive group having the structure: 
       
         
           
           
               
               
           
         
         wherein the therapeutic targeting agent is linked via X to the side chain of the reactive lysine residue in the combining site of the antibody or antigen binding fragment thereof by an amine or amide linkage formed by contacting Z and the side chain of the reactive lysine residue in the combining site of the antibody or antigen binding fragment thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein the linker further comprises a recognition group Y, such that Y is located between X and Z. 
     
     
         3 . The compound of  claim 1 , wherein antigen binding specificity of the targeting compound is substantially modified compared to the antibody or antigen binding fragment thereof. 
     
     
         4 . The compound of  claim 1 , wherein the antibody or antigen binding fragment thereof is a human antibody, a humanized antibody, or a chimeric human antibody. 
     
     
         5 . The compound of  claim 1 , wherein the antibody or antigen binding fragment thereof is mouse monoclonal antibody 33F12 or 38C2 or humanized 33F12 or 38C2 antibody. 
     
     
         6 . The compound of  claim 1 , wherein X is a linear stretch of between 5-100 atoms. 
     
     
         7 . The compound of  claim 1 , wherein X is a linear stretch of 5 atoms. 
     
     
         8 . The compound of  claim 1 , wherein X comprises one or more groups selected from alkyl, alkenyl, alkynyl, oxoalkyl, oxoalkenyl, oxoalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, sulfoalkyl, sulfoalkenyl, sulfoalkynyl group, phosphoalkyl, phosphoalkenyl, and phosphoalkynyl. 
     
     
         9 . The compound of  claim 1 , wherein X is a branched connecting chain of atoms, and wherein the branched end of the chain is linked to identical therapeutic targeting agents. 
     
     
         10 . The compound of  claim 1 , wherein X is a branched connecting chain of atoms and wherein the branched end of the chain is linked to distinct therapeutic targeting agents. 
     
     
         11 . The compound of  claim 1 , wherein the linker comprises a repeating ether unit of between 2-100 units. 
     
     
         12 . The compound of  claim 1 , wherein the targeting compound further comprises a therapeutic drug linked to X. 
     
     
         13 . The targeting compound of  claim 12 , wherein the therapeutic drug is a prodrug. 
     
     
         14 . The compound of  claim 1 , wherein Z is an electrophilic group. 
     
     
         15 . The compound of  claim 14 , wherein Z is a ketone, diketone, beta lactam, active ester, haloketone, lactone, anhydride, epoxide, aldehyde, maleimide disulfide, or aryl halide. 
     
     
         16 . The compound of  claim 1 , wherein the therapeutic targeting agent comprises a growth factor. 
     
     
         17 . The compound of  claim 1 , wherein the therapeutic targeting agent is specific for a biological molecule. 
     
     
         18 . A method of producing the targeting compound of  claim 1 , comprising:
 obtaining an antibody or antigen binding fragment thereof and contacting the antibody or antigen binding fragment thereof with a precursor comprising the formula X—Z, wherein X is linked to a therapeutic targeting agent, and wherein the contacting covalently links a side chain of a reactive lysine residue in the combining site of the antibody or antigen binding fragment thereof to the Z group of the precursor via an amine or amide linkage; or obtaining a therapeutic targeting agent and contacting the therapeutic targeting agent with an antibody or antigen binding fragment thereof covalently linked via an amine or amide linkage to a linker comprising X, wherein the contacting links the therapeutic targeting agent to X.   
     
     
         19 . A method of delivering a biological activity to cells, tissue extracellular matrix biomolecule or a biomolecule in the fluid of an individual, wherein the method comprises administering to the individual the targeting compound of  claim 1 , wherein the targeting compound is specific for the cells, tissue extracellular matrix biomolecule or fluid biomolecule and wherein the targeting compound comprises a biological activity. 
     
     
         20 . A method of imaging cells or tissue in an individual wherein the cells or tissue expresses a target molecule, the method comprising administering to the individual the targeting compound of  claim 1  linked to a detectable label. 
     
     
         21 . A method of reducing the infectivity of microbial cells or viral particles present on a surface, the method comprising contacting the surface with an effective amount of the targeting compound of  claim 1 , wherein the targeting compound comprises a targeting agent or biological agent specific for a receptor on the microbial cells or virus particles.