Antibody 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 . An integrin targeting compound comprising, an RGD peptidomimetic-antibody complex wherein: 
 a) said RGD peptidomimetic binds to one or both of α v β 3  and α v β 5 ;    b) said antibody does not bind to α v β 3  or α v β 5 ;    c) said complex results from an association between the RGD peptidomimetic and the combining site of the antibody; and    d) said integrin targeting compound competes for binding between one or both of α v β 3  and α v β 5  and a protein selected from the group consisting of vitronectin, and fibrinogen.    
     
     
         2 . The composition of  claim 1  wherein said association between the RGD peptidomimetic and the combining site of the antibody is covalent.  
     
     
         3 . The composition of  claim 2  wherein said covalent association is achieved by a linker that extends from the targeting agent to the protein.  
     
     
         4 . The integrin targeting compound of  claim 1  wherein said antibody is a catalytic antibody.  
     
     
         5 . The integrin targeting compound of  claim 4  wherein said catalytic antibody is selected from the group consisting of an aldolase antibody, a beta lactamase antibody and an esterase antibody or an amidase antibody.  
     
     
         6 . The integrin targeting compound of  claim 2  wherein said RGD peptidomimetic is linked to the combining site of said antibody via a complementarity determining region.  
     
     
         7 . The integrin targeting compound of  claim 2  wherein said RGD peptidomimetic is linked to the combining site of said antibody via a variable framework region.  
     
     
         8 . The integrin targeting compound of  claim 1  wherein said antibody is full length.  
     
     
         9 . The integrin targeting compound of  claim 1  wherein said antibody is a fragment of a full length antibody.  
     
     
         10 . The integrin targeting compound of  claim 9  wherein said fragment of a full length antibody is Fab, Fab′ F(ab′) 2 , Fv or sFv.  
     
     
         11 . The integrin targeting compound of  claim 1  wherein said antibody is a human antibody, humanized antibody or chimeric human antibody.  
     
     
         12 . The integrin targeting compound of  claim 2  wherein RGD peptidomimetic is linked covalently to a linear or branched linker which is linked covalently to the antibody combining site.  
     
     
         13 . The integrin targeting compound of  claim 12  wherein said linker comprises a linear stretch of between 5-100 atoms selected from the group consisting of C, H, N, O, P, S, Si, F, Cl, Br, and I, or a salt thereof.  
     
     
         14 . The integrin targeting compound of  claim 12  wherein said linker comprises one or more groups selected from alkyl, alkenyl, alkynyl, oxoalkyl, oxoalkenyl, oxoalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, sulfoalkyl, sulfoalkenyl, sulfoalkynyl group, phosphoalkyl, phosphoalkenyl, and phosphoalkynyl.  
     
     
         15 . The targeting agent-linker of  claim 12  wherein said linker comprises a repeating ether unit of between 2-100 units.  
     
     
         16 . The targeting agent-linker of  claim 12  wherein said linker comprises a heterocarbyl structure of the formula  
       
         
           
           
               
               
           
         
         wherein 
 R 2  to R 4  is C, H, N, O, P, S, Si, halogen (F, Cl, Br, I) or a salt thereof;  
 n is 1-100; and  
 m is 1-100.  
 
       
     
     
         17 . The integrin targeting compound of  claim 12  wherein said linker comprises one or more ring structures.  
     
     
         18 . The integrin targeting compound of  claim 17  wherein said one or more ring structures includes one or more six membered rings of the formula  
       
         
           
           
               
               
           
         
         wherein 
 A, Z, Y, X or W are independently C or N.  
 
       
     
     
         19 . The integrin targeting compound of  claim 18  wherein said one or more ring structures includes one or more five membered rings of the formula  
       
         
           
           
               
               
           
         
         wherein 
 A, Z, Y or X are independently C, O, N or S.  
 
       
     
     
         20 . The integrin targeting compound of  claim 1  further comprising a biological agent.  
     
     
         21 . The integrin targeting compound of  claim 2  wherein said covalent linkage is nonreversible.  
     
     
         22 . The integrin targeting compound of  claim 2  wherein said covalent linkage is reversible.  
     
     
         23 . The integrin targeting compound of  claim 2  wherein said covalent linkage is labile.  
     
     
         24 . The integrin targeting compound of  claim 2  wherein said labile linkage is a pH sensitive linkage, is a substrate for an enzyme or is susceptible to degradation by radiation.  
     
     
         25 . The integrin targeting compound of  claim 12  wherein said covalent linkage between said RGD peptidomimetic and said linker or between said linker and said antibody or both is nonreversible.  
     
     
         26 . The integrin targeting compound of  claim 12  wherein said covalent linkage between said RGD peptidomimetic and said linker or between said linker and said antibody or both is reversible.  
     
     
         27 . The integrin targeting compound of  claim 12  wherein said covalent linkage between said RGD peptidomimetic and said linker or between said linker and said antibody or both is labile.  
     
     
         28 . The integrin targeting compound of  claim 27  wherein said labile linkage is a pH sensitive linkage, is a substrate for an enzyme or is susceptible to degradation by radiation.  
     
     
         29 . An agent-linker-antigen compound for noncovalently linking to the combining site of an antibody, wherein: 
 a) said agent is an RGD peptidomimetic that binds to one or both of α v β 3  and α v β 5 ;    b) said antigen comprises at least one antigenic determinant recognized by the antibody combining site;    c) said said linker 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.    d) said agent-linker-antigen compound competes for binding between one or both of α v β 3  and α v β 5  and a protein selected from the group consisting of vitronectin and fibrinogen.    
     
     
         30 . The agent-linker-antigen compound of  claim 29  wherein said linker comprises one or more groups selected from alkyl, alkenyl, alkynyl, oxoalkyl, oxoalkenyl, oxoalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, sulfoalkyl, sulfoalkenyl, sulfoalkynyl group, phosphoalkyl, phosphoalkenyl, and phosphoalkynyl.  
     
     
         31 . The agent-linker-antigen compound of  claim 29  wherein said linker comprises one or more mono or fused homo or hetero saturated or unsaturated 5 to 7 membered carbocyclic ring.  
     
     
         32 . The agent-linker-antigen compound of  claim 29  wherein said linker is branched.  
     
     
         33 . The agent-linker-antigen compound of  claim 29  wherein at least two of said of said agents are linked to a different branch of said branched linker.  
     
     
         34 . An agent-linker compound for covalently linking to a combining site of an antibody, wherein: 
 a) said agent is an RGD peptidomimetic that binds to one or both of α v β 3  and α v β 5 ;    b) said linker is of the formula   X—Y—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,  
 Y if present is a single or fused 5 or 6 membered homo- or heterocarbocylic saturated or unsaturated ring; and  
 Z is a ketone, diketone, beta lactam, active ester, haloketone, lactone, anhydride, epoxide, aldehyde, maleimide disulfide, or aryl halide;  
 wherein Z is a reactive group for covalently linking the agent to a side chain of a reactive amino acid in the combining site of the antibody, said targeting agents or biological agents linked to X or Y if present or both X and Y if Y is present; and  
   c) said agent-linker compound competes for binding between one or both of α v β 3  and α v β 5  and a protein selected from the group consisting of vitronectin, and fibrinogen.    
     
     
         35 . The agent-linker of  claim 34  wherein said agents are linked in such a way as to retain the ability to bind a target or exhibit a biological activity.  
     
     
         36 . The agent-linker of  claim 34  wherein X comprises a linear stretch of between 5-200 atoms.  
     
     
         37 . The targeting agent-linker of  claim 34  wherein X is a heterocarbyl structure of the formula  
       
         
           
           
               
               
           
         
         wherein 
 R 2  to R 4  is C, H, N, O, P, S, Si, halogen (F, Cl, Br, I) or a salt thereof;  
 n is 1-100; and  
 m is 1-100.  
 
       
     
     
         38 . The agent-linker of  claim 34  wherein Y is a six membered ring of the formula  
       
         
           
           
               
               
           
         
         wherein 
 A, Z, Y, X or W are independently C or N.  
 
       
     
     
         39 . The agent-linker of  claim 34  wherein Y is a five membered ring of the formula  
       
         
           
           
               
               
           
         
         wherein 
 A, Z, Y or X are independently C, O, N or S.  
 
       
     
     
         40 . The agent-linker of  claim 34  wherein said linker is branched by addition of one or more connecting chains, said linker comprises more than one recognition group, said linker comprises more than one reactive group, or combinations thereof.  
     
     
         41 . The agent-linker of  claim 34  wherein said linker has the structure below wherein n is from 1-100.  
       
         
           
           
               
               
           
         
       
     
     
         42 . An integrin targeting agent comprising the agent-linker of  claim 34  covalently linked to the combining site of an antibody.  
     
     
         43 . An agent-linker compound for covalently linking to a combining site of an antibody, wherein: 
 a) said agent is an RGD peptidomimetic that binds to one or both of α v β 3  and α v β 5 ;    b) said linker of the formula   X—Y—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 comprising a repeating ether unit of between 0-100 units;  
 Y is a single or fused 5 or 6 membered homo- or heterocarbocylic saturated or unsaturated ring located within 1-20 atoms of Z; and  
 Z is a reactive group for covalently linking the agent to a side chain of a reactive amino acid in the combining site of the antibody; and  
   c) said agent-linker compound competes for binding between one or both of α v β 3  and α v β 5  and a protein selected from the group consisting of vitronectin and fibrinogen.    
     
     
         44 . The agent-linker of  claim 43  wherein said agents are linked in such a way as to retain the ability to bind a target or exhibit a biological activity.  
     
     
         45 . The agent-linker of  claim 43  wherein Z is selected from the group consisting of a ketone, diketone, beta lactam, active ester, haloketone, lactone, anhydride, epoxide, aldehyde, maleimide, disulfide, and aryl halide.  
     
     
         46 . The agent-linker of  claim 43  wherein X comprises a linear stretch of between 10-200 atoms.  
     
     
         47 . The agent-linker of claim  126  wherein X is a hetercarbyl of the formula  
       
         
           
           
               
               
           
         
         wherein 
 R 2  to R 4  is C, H, N, O, P, S, Si, halogen (F, Cl, Br, I) or a salt thereof  
 n is 1-100 and  
 m is 1-100  
 
       
     
     
         48 . The targeting agent-linker of  claim 43  wherein Y is a six membered ring of the formula  
       
         
           
           
               
               
           
         
         wherein 
 A, Z, Y, X or W are independently C or N.  
 
       
     
     
         49 . The targeting agent-linker of  claim 43  wherein Y is a five membered ring of the formula  
       
         
           
           
               
               
           
         
         wherein 
 A, Z, Y or X are independently C, O, N or S.  
 
       
     
     
         50 . The targeting agent-linker of  claim 43  wherein said linker comprises more than one connecting chain, more than one recognition group or more than one reactive group, or combinations thereof.  
     
     
         51 . An integrin targeting agent comprising the agent-linker of  claim 34  covalently linked to the combining site of an antibody.  
     
     
         52 . An integrin targeting agent comprising the agent-linker of  claim 43  covalently linked to the combining site of an antibody.  
     
     
         53 . A CCR5 targeting compound comprising, a CCR5 chemokine peptidomimetic-antibody complex wherein: 
 a) said CCR5 chemokine peptidomimetic binds to CCR5;    b) said antibody does not bind to CCR5    c) said complex results from an association between the CCR5 chemokine peptidomimetic and the combining site of the antibody; and    d) said CCR5 targeting compound competes for binding between CCR5 and a β-chemokine.    
     
     
         54 . An agent-linker compound for covalently linking to a combining site of an antibody, wherein: 
 a) said agent is a CCR5 peptidomimetic that binds to CCR5;    b) said linker is of the formula   X—Y—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,  
 Y if present is a single or fused 5 or 6 membered homo- or heterocarbocylic saturated or unsaturated ring; and  
 Z is a ketone, diketone, beta lactam, active ester, haloketone, lactone, anhydride, epoxide, aldehyde, maleimide disulfide, or aryl halide;  
 wherein Z is a reactive group for covalently linking the agent to a side chain of a reactive amino acid in the combining site of the antibody, said targeting agents or biological agents linked to X or Y if present or both X and Y if Y is present; and  
   c) said agent-linker compound competes for binding between CCR5 and a β-chemokine.    
     
     
         55 . An agent-linker compound for covalently linking to a combining site of an antibody, wherein: 
 a) said agent is a CCR5 peptidomimetic that binds to CCR5;    b) said linker of the formula   X—Y—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 comprising a repeating ether unit of between 0-100 units;  
 Y is a single or fused 5 or 6 membered homo- or heterocarbocylic saturated or unsaturated ring located within 1-20 atoms of Z; and  
 Z is a reactive group for covalently linking the agent to a side chain of a reactive amino acid in the combining site of the antibody; and  
   c) said agent-linker compound competes for binding between CCR5 and β-chemokine.    
     
     
         56 . A LHRH targeting compound comprising, an LHRH peptide-antibody complex wherein: 
 a) said LHRH peptide binds to the LHRH receptor;    b) said antibody does not bind to the LHRH receptor,    c) said complex results from an association between the LHRH peptide and the combining site of the antibody; and    d) said LHRH targeting compound competes for binding between LHRH and the LHRH receptor.    
     
     
         57 . An agent-linker compound for covalently linking to a combining site of an antibody, wherein: 
 a) said agent is an LRHR peptide that binds to the LHRH receptor;    b) said linker is of the formula   X—Y—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,  
 Y if present is a single or fused 5 or 6 membered homo- or heterocarbocylic saturated or unsaturated ring; and  
 Z is a ketone, diketone, beta lactam, active ester, haloketone, lactone, anhydride, epoxide, aldehyde, maleimide disulfide, or aryl halide;  
 wherein Z is a reactive group for covalently linking the agent to a side chain of a reactive amino acid in the combining site of the antibody, said targeting agents or biological agents linked to X or Y if present or both X and Y if Y is present; and  
   c) said agent-linker compound competes for binding between LHRH and the LHRH receptor.    
     
     
         58 . An agent-linker compound for covalently linking to a combining site of an antibody, wherein: 
 a) said agent is an LHRH peptide that binds to the LHRH receptor;    b) said linker of the formula   X—Y—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 comprising a repeating ether unit of between 0-100 units;  
 Y is a single or fused 5 or 6 membered homo- or heterocarbocylic saturated or unsaturated ring located within 1-20 atoms of Z; and  
 Z is a reactive group for covalently linking the agent to a side chain of a reactive amino acid in the combining site of the antibody; and  
   c) said agent-linker compound competes for binding between LHRH and the LHRH receptor.    
     
     
         59 . An HIV-1 membrane fusion inhibiting compound-antibody complex wherein: 
 a) said HIV-1 membrane fusion inhibiting compound inhibits fusion of HIV-1 to a target cell;    b) said antibody does not inhibit fusion of HIV-1 to a target cell; and    c) said complex results from an association between the HIV-1 membrane fusion inhibiting compound and the combining site of the antibody.    
     
     
         60 . The HIV-1 membrane fusion inhibiting compound-antibody complex of  claim 59  wherein said HIV-1 membrane fusion inhibiting compound comprises a peptide or peptidomimetic of an HIV-1 envelope protein.  
     
     
         61 . The HIV-1 membrane fusion inhibiting compound-antibody complex of  claim 59  wherein said HIV-1 membrane fusion inhibiting compound comprises a small molecular weight organic molecule that binds to an HIV-1 envelope protein.  
     
     
         62 . An agent-linker compound for covalently linking to a combining site of an antibody, wherein: 
 a) said agent is an HIV-1 membrane fusion inhibiting compound;    b) said linker is of the formula   X—Y—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,  
 Y if present is a single or fused 5 or 6 membered homo- or heterocarbocylic saturated or unsaturated ring; and  
 Z is a ketone, diketone, beta lactam, active ester, haloketone, lactone, anhydride, epoxide, aldehyde, maleimide disulfide, or aryl halide;  
 wherein Z is a reactive group for covalently linking the agent to a side chain of a reactive amino acid in the combining site of the antibody, said targeting agents or biological agents linked to X or Y if present or both X and Y if Y is present; and  
   c) said agent-linker compound inhibits HIV-1 fusion to a cell membrane.    
     
     
         63 . An agent-linker compound for covalently linking to a combining site of an antibody, wherein: 
 a) said agent is HIV-1 membrane fusion inhibiting compound;    b) said linker of the formula   X—Y—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 comprising a repeating ether unit of between 0-100 units;  
 Y is a single or fused 5 or 6 membered homo- or heterocarbocylic saturated or unsaturated ring located within 1-20 atoms of Z; and  
 Z is a reactive group for covalently linking the agent to a side chain of a reactive amino acid in the combining site of the antibody; and  
   c) said agent-linker compound inhibits HIV-1 fusion to a cell membrane.    
     
     
         64 . A thrombopoietin (TPO) receptor targeting compound comprising, a TPO peptide or peptidomimetic-antibody complex wherein: 
 a) said peptide or peptidomimetic binds to the TPO receptor;    b) said antibody does not bind to the TPO receptor;    c) said complex results from an association between the peptide or peptidomimetic and the combining site of the antibody; and    d) said TPO receptor targeting compound competes for binding between TPO and the TPO receptor.    
     
     
         65 . An agent-linker compound for covalently linking to a combining site of an antibody, wherein: 
 a) said agent is a thrombopoietin (TPO) receptor peptide or peptidomimetic that binds to the TPO receptor;    b) said linker is of the formula   X—Y—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, ora salt thereof,  
 Y if present is a single or fused 5 or 6 membered homo- or heterocarbocylic saturated or unsaturated ring; and  
 Z is a ketone, diketone, beta lactam, active ester, haloketone, lactone, anhydride, epoxide, aldehyde, maleimide disulfide, or aryl halide;  
 wherein Z is a reactive group for covalently linking the agent to a side chain of a reactive amino acid in the combining site of the antibody, said targeting agents or biological agents linked to X or Y if present or both X and Y if Y is present; and  
   c) said agent-linker compound competes for binding between TPO and the TPO receptor.    
     
     
         66 . An agent-linker compound for covalently linking to a combining site of an antibody, wherein: 
 a) said agent is a thrombopoietin (TPO) receptor peptide or peptidomimetic that binds to the TPO receptor;    b) said linker of the formula   X—Y—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 comprising a repeating ether unit of between 0-100 units;  
 Y is a single or fused 5 or 6 membered home or heterocarbocylic saturated or unsaturated ring located within 1-20 atoms of Z; and  
 Z is a reactive group for covalently linking the agent to a side chain of a reactive amino acid in the combining site of the antibody; and  
   c) said agent-linker compound competes for binding between TPO and the TPO receptor.