Anti-S100A4 antibody molecules and their uses
Anti-S100A4 antibody molecules that are capable of inhibiting the biological activity of S100A4 in promoting tumor progression and/or in inducing tumor metastasis are described. The antibody molecules are also useful in the treatment of inflammatory conditions. The properties of the antibodies are demonstrated using in vitro and in vivo assays.
1. An isolated antibody molecule which specifically binds to human S100A4 polypeptide of SEQ ID NO: 11, wherein the antibody molecule comprises:
(a) a heavy chain variable domain comprising a CDR-H1 having the amino acid sequence of SEQ ID NO: 1; a CDR-H2 having the amino acid sequence of SEQ ID NO: 2; and a CDR-H3 having the amino acid sequence of SEQ ID NO: 3; and
(b) a light chain variable domain comprising a CDR-L1 having the amino acid sequence of SEQ ID NO: 4; a CDR-L2 having the amino acid sequence of SEQ ID NO: 5; and a CDR-L3 having the amino acid sequence of SEQ ID NO: 6.
2. An isolated antibody molecule which specifically binds to human S100A4 polypeptide, wherein the antibody molecule comprises (a) a heavy chain variable (VH) domain comprising a CDR-H1, a CDR-H2 and a CDR-H3 having the amino acid sequences of the CDR-H1, CDR-H2, and CDR-H3 set out in SEQ ID NO: 7 and (b) a light chain variable (VL) domain comprising a CDR-L1, a CDR-L2 and a CDR-L3 having the amino acid sequences of the CDR-L1, CDR-L2, and CDR-L3 set out in SEQ ID NO: 9.
3. The antibody molecule of claim 2 which comprises a VH domain comprising a CDR-H1, CDR-H2 and CDR-H3 having the sequences of SEQ ID NOs 1, 2 and 3, respectively, and/or a VL domain comprising a CDR-L1, CDR-L2 and CDR-L3 having the sequences of SEQ ID NOs 4, 5 and 6, respectively.
4. The antibody molecule of claim 2 which comprises a VH domain having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 7 and/or a VL domain having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 9.
5. The antibody molecule of claim 2 , which is capable of binding a S100A4 polypeptide comprising a polypeptide having amino acids 1 to 101 as set out in SEQ ID NO: 11 or 12.
6. An isolated antibody molecule which specifically binds to S100A4 polypeptide, wherein the antibody binds an epitope at least partially contained within the S100A4 amino acid sequence between amino acids 66 and 89 of SEQ ID NO: 11 or SEQ ID NO: 12.
7. The antibody molecule of claim 1 , wherein the antibody binds an epitope contained within the S100A4 amino acid sequence between amino acids 66 and 89 of SEQ ID NO: 11 or SEQ ID NO: 12.
8. The antibody molecule of claim 1 , wherein the antibody molecule is capable of binding to S100A4 peptides having the amino acid sequence RDNEVDFQEYCV (SEQ ID NO: 13) and/or FLSCIAMMCNEF (SEQ ID NO: 14).
9. The antibody molecule of claim 1 , wherein the antibody is capable of binding to an epitope defined by SEQ ID NO: 15.
10. The antibody molecule of claim 1 , wherein the antibody molecule is a complete antibody, a Fab fragment, a F(ab′)2 fragment, a scFv, a diabody, or a triabody.
11. The antibody molecule of claim 1 , wherein the antibody molecule is a humanised antibody, a chimeric antibody or a humaneered antibody.
12. The antibody molecule of claim 1 , wherein the antibody molecule is a bispecific antibody.
13. An antibody molecule which is a humanised antibody of an antibody molecule according to claim 1 .
14. The antibody molecule of claim 1 , wherein the antibody is capable of neutralizing a biological activity of S100A4.
15. The antibody molecule of claim 1 , wherein the antibody is capable of binding to native conformation S100A4 protein.
16. The antibody molecule of claim 1 , wherein the antibody is capable of binding to murine and human S100A4.
17. The antibody molecule of claim 1 , wherein the antibody is capable of binding to dimeric, oligomeric and/or multimeric forms of S100A4 protein.
18. The antibody molecule of claim 1 , wherein the antibody is capable of inhibiting T-cell recruitment mediated by S100A4.
19. The antibody molecule of claim 1 , wherein the antibody is capable of inhibiting the biological activity of S100A4 protein in stimulating cell invasion.
20. The antibody molecule of claim 19 , wherein the biological activity of S100A4 protein in stimulating cell invasion is determined in a 3D Matrigel matrix assay or a T cell invasion assay where S100A4 stimulates T cell infiltration into a fibroblasts monolayer or wherein the biological activity of S100A4 in inducing tumour metastasis is determined in an in vivo mouse xenograft model.
21. An antibody molecule conjugate comprising an antibody molecule of claim 1 , directly or indirectly linked or associated with a drug, a toxin, a nanoparticle, a radioisotope and/or a fluorescent label.
22. The antibody molecule conjugate of claim 21 , wherein the nanoparticle is a gold nanorod or nanoparticle.
23. The antibody molecule conjugate of claim 21 , wherein the antibody molecule is directly or indirectly conjugated or linked to one or more drugs or toxins that is a cytotoxic moiety or an agent capable of converting a prodrug to a cytotoxic moiety.
24. A pharmaceutical composition comprising an antibody molecule according to claim 1 , and a pharmaceutically acceptable excipient.
25. A pharmaceutical composition comprising an antibody molecule conjugate of claim 21 and a pharmaceutically acceptable excipient.
26. The antibody molecule conjugate of claim 23 , wherein the cytotoxic moiety is selected from the group consisting of a chemotherapeutic agent, a cytotoxic polypeptide, a radiosensitiser or a radioactive atom.