Anti-EDB antibody-targeted IL-10 cytokine for therapy of rheumatoid arthritis
The present invention relates to fusion proteins comprising an antibody, functional fragment or functional derivative thereof having specific binding affinity to either the extracellular domain of oncofetal fibronectin (ED-B) or at least one of the extracellular domains of oncofetal tenascin fused to a cytokine selected from the group consisting of IL-10, IL15, IL-24 and GM-CSF, functional fragments and functional derivatives thereof. The invention is also directed to the use of at least one of said fusion proteins for the manufacture of a medicament. In particular, the invention concerns the use of said medicament for the treatment of tumors or chronic inflammatory diseases such as atherosclerosis, arthritis and psoriasis.
1. A fusion protein comprising:
(i) an antibody, functional fragment or functional derivative thereof having specific binding affinity to the extracellular domain B of oncofetal fibronectin (ED-B) fused to
(ii) an IL-10 cytokine.
2. The fusion protein of claim 1 , wherein the antibody, functional fragment or functional derivative thereof is selected from the group consisting of polyclonal antibodies, monoclonal antibodies, chimeric antibodies, humanized antibodies, CDR-grafted antibodies, Fv-fragments, Fab-fragments, Fab 2 -fragments and antibody-like binding proteins.
3. The fusion protein according to claim 1 , wherein the functional derivative of the antibody is the diabody L19 (short) having the amino sequence set forth in SEQ ID NO: 7.
4. The fusion protein according to claim 1 , wherein a member of the group consisting of L19 (long) and L19 (short), is fused to an IL-10 cytokine.
5. The fusion protein according to claim 1 , wherein the IL-10 cytokine is a murine IL-10 cytokine or a human IL-10 cytokine.
6. The fusion protein according to claim 1 , wherein the IL-10 cytokine is fused N-terminally or C-terminally to the antibody, functional fragment or functional derivative thereof.
7. The fusion protein according to claim 1 , wherein the antibody fragment or functional derivative thereof is L19.
8. The fusion protein according to claim 1 , which is L19-IL-10.
9. The fusion protein according to claim 1 , having the amino acid sequence set forth in SEQ ID NO: 14.
10. A method for manufacturing a medicament, comprising:
preparing a pharmaceutical composition comprising:
a therapeutically effective amount of a fusion protein according to claim 1 , and
at least one pharmaceutically acceptable excipient selected from carriers, stabilizers, antioxidants, pH-regulating substances and controlled-release excipients;
wherein the medicament is for treating rheumatoid arthritis.
11. A pharmaceutical composition comprising at least one fusion protein according to claim 1 and optionally a pharmaceutically acceptable excipient.
12. A method of treating rheumatoid arthritis, comprising: administering an effective amount of the pharmaceutical composition according to claim 11 to a patient in need thereof.