Antigen associated with rheumatoid arthritis

1. An antibody conjugate comprising an antibody, or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment binds the Extra Domain-A (ED-A) of fibronectin and is conjugated to a molecule having anti-inflammatory activity, wherein

said antibody comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain,

said VH domain comprises a set of complementarity determining regions HCDR1, HCDR2 and HCDR3 that comprise the amino acid sequences of SEQ ID NOs: 83, 4, and 5, respectively, and

said VL domain comprises a set of complementarity determining regions LCDR1, LCDR2 and LCDR3 that comprise the amino acid sequences of SEQ ID NOs: 86, 7, and 8, respectively.

2. The antibody conjugate according to claim 1 , wherein said VH domain and/or said VL domain comprises a human framework.

3. The antibody conjugate according to claim 1 , wherein the VH domain comprises the amino acid sequence of SEQ ID NO: 81; or the amino acid sequence of SEQ ID NO: 81, wherein the amino acid at position 5 of SEQ ID NO: 81 is a leucine residue (L) rather than a valine residue (V).

4. The antibody conjugate according to claim 1 , wherein the VL domain comprises the amino acid sequence of SEQ ID NO: 82; or the amino acid sequence of SEQ ID NO: 82, wherein the amino acid at position 18 of SEQ ID NO: 82 is an arginine residue (R) rather than a lysine residue (K).

5. The antibody conjugate according to claim 1 , wherein the VH domain comprises the amino acid sequence of SEQ ID NO: 81, wherein the amino acid at position 5 of SEQ ID NO: 81 is a leucine residue (L) rather than a valine residue (V); and the VL domain comprises the amino acid sequence of SEQ ID NO: 82, wherein the amino acid at position 18 of SEQ ID NO: 82 is an arginine residue (R) rather than a lysine residue (K).

6. The antibody conjugate according to claim 5 , wherein said antigen-binding fragment comprises a single chain FV (scFv) or is a diabody.

7. The antibody conjugate according to claim 5 , wherein said antigen-binding fragment comprises a small immunoprotein (SIP).

8. The antibody conjugate according to claim 5 , wherein said antibody or antigen-binding fragment is conjugated to a detectable label.

9. The antibody conjugate according to claim 6 , wherein said molecule having anti-inflammatory activity is interleukin-10 (IL-10).

10. The antibody conjugate according to claim 9 , wherein said IL-10 is human IL-10.

11. The antibody conjugate according to claim 5 , wherein said antibody or antigen-binding fragment is conjugated to said molecule having anti-inflammatory activity via a peptide linker.

12. The antibody conjugate according to claim 11 , wherein said peptide linker comprises 15 amino acids.

13. The antibody conjugate according to claim 12 , wherein said peptide linker comprises the amino acid sequence (SSSSG) 3 (amino acid residues 243-257 of SEQ ID NO: 149).

14. The antibody conjugate according to claim 5 , wherein said antigen-binding fragment comprises a scFv or is a diabody, and wherein said VH domain is conjugated to said VL domain via an amino acid linker.

15. The antibody conjugate according to claim 14 , wherein said amino acid linker comprises 5 to 25 amino acids.

16. The antibody conjugate according to claim 15 , wherein said amino acid linker comprises 5 amino acids.

17. The antibody conjugate according to claim 1 , wherein the antibody conjugate comprises:

(i) the antigen-binding fragment, wherein the antigen-binding fragment comprises a scFv or is a diabody comprising said VH domain and said VL domain,

wherein said VH domain is conjugated to said VL domain via a 5 amino acid linker; and

(ii) human interleukin-10, wherein said VL domain is conjugated to said human interleukin-10 via a peptide linker comprising the amino acid sequence (SSSSG) 3 (amino acid residues 243-257 of SEQ ID NO: 149).

18. The antibody conjugate according to claim 1 , wherein the antibody conjugate comprises:

(i) the antigen-binding fragment, wherein the antigen-binding fragment comprises a scFv or is a diabody, wherein the VH domain comprises the amino acid sequence of SEQ ID NO: 81, wherein the amino acid at position 5 of SEQ ID NO: 81 is a leucine residue (L) rather than a valine residue (V); and the VL domain comprises the amino acid sequence of SEQ ID NO: 82, wherein the amino acid at position 18 of SEQ ID NO: 82 is an arginine residue (R) rather than a lysine residue (K);

wherein said VH domain is conjugated to said VL domain via a 5 amino acid linker; and

(ii) human interleukin-10, wherein said VL domain is conjugated to said human interleukin-10 via a peptide linker comprising the amino acid sequence (SSSSG) 3 (amino acid residues 243-257 of SEQ ID NO: 149).

19. The antibody conjugate according to claim 1 , wherein the antibody conjugate consists of:

(i) the antigen-binding fragment, wherein the antigen-binding fragment is a diabody comprising said VH domain and said VL domain,

(ii) a 5 amino acid linker, wherein said VH domain is conjugated to said VL domain via the 5 amino acid linker;

(iii) human interleukin-10; and

(iv) a peptide linker comprising the amino acid sequence (SSSSG) 3 (amino acid residues 243-257 of SEQ ID NO: 149), wherein said VL domain is conjugated to said human interleukin-10 via the peptide linker.

20. A pharmaceutical composition comprising the antibody conjugate according to claim 1 and a pharmaceutically acceptable carrier.

21. The antibody conjugate according to claim 1 , wherein the antibody conjugate consists of:

(i) the antigen-binding fragment, wherein the antigen-binding fragment is a diabody consisting of:

(a) a VH domain comprising the amino acid sequence of SEQ ID NO: 81, wherein the amino acid at position 5 of SEQ ID NO: 81 is a leucine residue (L) rather than a valine residue (V); and

(b) a VL domain comprising the amino acid sequence of SEQ ID NO: 82, wherein the amino acid at position 18 of SEQ ID NO: 82 is an arginine residue (R) rather than a lysine residue (K);

(ii) a 5 amino acid linker, wherein said VH domain is conjugated to said VL domain via the 5 amino acid linker;

(iii) human interleukin-10; and

(iv) a peptide linker consisting of the amino acid sequence (SSSSG) 3 (amino acid residues 243-257 of SEQ ID NO: 149), wherein said VL domain is conjugated to said human interleukin-10 via the peptide linker.

22. The antibody conjugate according to claim 2 , wherein said VH domain comprises a framework from the human germline DP47 gene.

23. The antibody conjugate according to claim 2 or 22 , wherein said VL domain comprises a framework from the human germline DPK22 gene.

24. The antibody conjugate according to claim 1 , wherein said antibody or antigen-binding fragment comprises a myc-tag sequence.

25. The antibody conjugate according to claim 1 , wherein said antibody or antigen-binding fragment is conjugated to a radioisotope.

26. The antibody conjugate according to claim 10 , wherein said human IL-10 comprises amino acid residues 258 to 417 of SEQ ID NO: 149.

27. The antibody conjugate according to claim 3 , wherein said molecule having anti-inflammatory activity is interleukin-10 (IL-10).

28. The antibody conjugate according to claim 27 , wherein said IL-10 is human IL-10.

29. The antibody conjugate according to claim 28 , wherein said human IL-10 comprises amino acid residues 258 to 417 of SEQ ID NO: 149.

30. The antibody conjugate according to claim 17 , wherein said human IL-10 comprises amino acid residues 258 to 417 of SEQ ID NO: 149.

31. The antibody conjugate according to claim 19 , wherein said human IL-10 comprises amino acid residues 258 to 417 of SEQ ID NO: 149.