Antibody targeting compounds
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.
1. An antibody targeting compound comprising a therapeutic targeting agent at least 500 daltons in size covalently linked to the combining site of a catalytic antibody via a linker of the formula X—Y—Z, such that 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 Y is an optional recognition group; and Z is a reactive group
wherein the catalytic antibody is an aldolase antibody having a reactive lysine residue at its combining site;
wherein the targeting agent is linked to the X group of the linker; and whereby a side chain of the reactive lysine residue reacts with the beta lactam ring to form an amide linkage, and wherein the linkage forms an irreversible covalent bond.
2. The compound of claim 1 wherein antigen binding specificity of the antibody is substantially modified following the covalent linkage.
3. The compound of claim 1 wherein the combining site of said antibody is linked to the agent via a complementarity determining region.
4. The compound of claim 1 wherein said agent is linked to the combining site of said antibody via a variable framework region.
5. The compound of claim 1 wherein said antibody is full length.
6. The compound of claim 1 wherein said antibody is a fragment of a full length antibody.
7. The compound of claim 6 wherein said fragment of a full length antibody is Fab, Fab′ F(ab′) 2 , Fv or sFv.
8. The compound of claim 1 wherein said antibody is a human antibody, humanized antibody or chimeric human antibody.
9. The compound of claim 1 wherein the X group of said linker comprises a linear stretch of between 5-100 atoms.
10. The compound of claim 1 wherein the X group of 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.
11. The compound of claim 1 wherein said linker comprises a repeating ether unit of between 2-100 units.
12. The compound of claim 1 wherein the compound further comprises a therapeutic drug covalently attached to the X group.
13. The antibody targeting compound of claim 12 wherein said therapeutic drug is a prodrug.
14. The compound of claim 1 wherein the targeting agent is specific for a biological molecule.
15. The antibody targeting compound of claim 14 wherein said biological molecule is a cell surface expressed or particle surface expressed ligand or receptor.
16. The antibody targeting compound of claim 15 wherein said cell surface expressed ligand or receptor is an integrin, a folate receptor, a cytokine receptor, an interleukin receptor, a viral protein or an enzyme.
17. The antibody targeting compound of claim 15 wherein said biological molecule is a fluid phase biomolecule.
18. The antibody targeting compound of claim 15 wherein said biological molecule is an extracellular matrix biomolecule.
19. A method of delivering a biological activity to cells, tissue extracellular matrix biomolecule or a biomolecule in the fluid of an individual, said method comprising administering to the individual the antibody targeting compound of claim 1 wherein said antibody targeting compound is specific for said cells, tissue extracellular matrix biomolecule or fluid biomolecule and wherein said antibody targeting compound comprises a biological activity.
20. A method of imaging cells or tissue in an individual wherein said cells or tissue expresses a target molecule, said method comprising administering to the individual the antibody targeting 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, said method comprising contacting said surface with an effective amount of the antibody targeting compound of claim 1 wherein said antibody targeting compound comprises a therapeutic targeting agent specific for a receptor on said microbial cells or virus particles.
22. The compound of claim 1 wherein the Y-group has a formula that is either
wherein A, Z, Y, X or W are independently C or N, or
wherein A, Z, Y or X are independently C, O, N or S.
23. The compound of claim 1 wherein the X-group of said linker is branched.
24. The compound of claim 23 wherein the branched ends of the X-group are attached to different molecules.
25. The compound of claim 23 wherein the branched ends of the X-group are attached to identical molecules.
26. The compound of claim 1 wherein the targeting agent comprises a peptide that is covalently linked to the X group of said linker.
27. The compound of claim 1 wherein the aldolase antibody is mouse monoclonal antibody 38C2 or humanized 38C2 antibody.
28. The compound of claim 22 wherein the Y-group comprises phenyl.