Complex of bi-specific antibody and digoxigenin conjugated to a therapeutic or diagnostic agent
The present invention relates to complexes of a) bi-specific antibodies and antibody fragments against a target protein and b) a digoxigenin conjugated to a therapeutic or diagnostic agent, methods for their production, their use as a delivery platform for therapeutic or diagnostic agents, pharmaceutical compositions containing said antibodies, and uses thereof.
1. A complex comprising:
a bi-specific antibody specific against digoxigenin (DIG) and a target protein, comprising a first antigen-binding site that binds to the digoxigenin, comprising a heavy chain variable domain of SEQ ID NO:3 and a light chain variable domain of SEQ ID NO:5,
wherein the heavy chain variable domain of SEQ ID NO:3 has mutations S49A, I57A and A60P, and a second antigen-binding site that binds to the target protein; and
digoxigenin, wherein the digoxigenin is conjugated to a therapeutic or a diagnostic agent selected from the group consisting of a peptide, a small compound, a radioactively labeled small compound, and an imaging reagent.
2. The complex according to claim 1 , wherein the bispecific antibody comprises
a) a monospecific bivalent antibody consisting of two full length antibody heavy chains and two full length antibody light chains whereby each chain comprises only one variable domain,
b) two peptide-linkers, and
c) two monospecific monovalent single chain antibodies each consisting of an antibody heavy chain variable domain, an antibody light chain variable domain, and a single-chain-linker between said antibody heavy chain variable domain and said antibody light chain variable domain.
3. The complex according to claim 1 , wherein said antigen-binding site specifically binding to DIG further comprises a heavy chain Fd-Fragment (V H and CH 1 ) of SEQ ID NO: 36, and an L-chain of SEQ ID NO: 6.
4. The complex according to claim 1 , wherein the antibody is humanized.
5. The complex according to claim 1 , wherein the target protein is a cell surface antigen.
6. The complex according to claim 5 , wherein the cell surface antigen is a tumor antigen.
7. The complex according to claim 5 , wherein the target protein is Her2.
8. The complex according to claim 5 , wherein the target protein is IGF1R.
9. The complex according to claim 5 , wherein the target protein is CD22.
10. The complex according to claim 1 , wherein the therapeutic or diagnostic agent is a peptide.
11. The complex according to claim 1 , wherein the therapeutic or diagnostic agent is a small compound.
12. The complex according to claim 11 , wherein the small compound is radioactively labeled.
13. The complex according to claim 1 , wherein the diagnostic agent is an imaging reagent.
14. The complex according to claim 1 , wherein the diagnostic agent is a digoxygenated Cy5.
15. A composition comprising the complex of claim 1 .
16. The composition of claim 15 , wherein the composition is a diagnostic composition.
17. The composition of claim 15 , wherein the composition is a pharmaceutical composition.