Methods for treating inflammatory bowel disease
View Patent ↗Methods of treating inflammatory disorders, such as rheumatoid arthritis, by modulating TWEAK and TNF-α are disclosed, as are other methods.
1. A method for treating inflammatory bowel disease comprising: administering to a human subject who has inflammatory bowel disease, a TWEAK (TNF-like weak inducer of apoptosis) blocking agent selected from the group consisting of a monoclonal, chimeric, human, or humanized antibody that binds to TWEAK, and a soluble form of a TWEAK receptor, in combination with a TNF-α blocking agent selected from the group consisting of a monoclonal, chimeric, human, or humanized antibody that binds to TNF-α, and a soluble form of a TNF-α receptor, in amounts and for a time to provide a therapeutic effect.
2. The method of claim 1 , wherein the inflammatory bowel disease is ulcerative colitis.
3. The method of claim 1 , wherein the inflammatory bowel disease is Crohn's disease.
4. The method of claim 1 , wherein the TWEAK blocking agent and the TNF-α blocking agent are administered in an amount effective to inhibit TWEAK and TNF-α pathways in cells that generate inflammatory signals.
5. The method of claim 1 , wherein the TWEAK blocking agent and the TNF-α blocking agent are administered in an amount effective to reduce transcription of genes induced by TWEAK and TNF-α in cells that generate inflammatory signals.
6. The method of claim 5 , wherein the genes induced by TWEAK and TNF-α are synergistically activated by TWEAK and TNF-α.
7. The method of claim 1 , wherein the TWEAK blocking agent is administered at a dosage that is equal to or less than an amount required for efficacy with the TWEAK blocking agent monotherapy.
8. The method of claim 7 , wherein the TWEAK blocking agent is administered at a dosage that is at least 10% less than an amount required for efficacy with the TWEAK blocking agent monotherapy.
9. The method of claim 1 , wherein the TNF-α blocking agent is administered at a dosage that is equal to or less than an amount required for efficacy with the TNF-α blocking agent monotherapy.
10. The method of claim 9 , wherein the TNF-α blocking agent is administered at a dosage that is at least 10% less than an amount required for efficacy with TNF-α blocking agent monotherapy.
11. The method of claim 1 , wherein the TWEAK blocking agent reduces the ability of TWEAK to bind to a TWEAK receptor.
12. The method of claim 1 , wherein the TWEAK blocking agent is a monoclonal, chimeric, human, or humanized antibody that binds to TWEAK.
13. The method of claim 12 , wherein the antibody that binds to TWEAK comprises a heavy chain variable domain comprising:
a) a complementarity determining region (CDR) 1 set forth as the amino acid sequence of amino acids 26 to 35 of SEQ ID NO:3 (GFTFSRYAMS);
b) a CDR 2 set forth as the amino acid sequence of amino acids 50 to 66 of SEQ ID NO:3 (EISSGGSYPYYPDTVTG); and
c) a CDR 3 set forth as the amino acid sequence of amino acids 99 to 114 of SEQ ID NO:3 (VLYYDYDGDRIEVMDY);
and a light chain variable domain comprising:
a) a CDR 1 set forth as the amino acid sequence of amino acids 24 to 39 of SEQ ID NO:4 (RSSQSLVSSKGNTYLH);
b) a CDR 2 set forth as the amino acid sequence of amino acids 55 to 61 of SEQ ID NO:4 (KVSNRFS); and
c) a CDR 3 set forth as the amino acid sequence of amino acids 94 to 102 of SEQ ID NO:4 (SQSTHFPRT).
14. The method of claim 13 , wherein the antibody comprises a first amino acid sequence set forth in SEQ ID NO:5 and a second amino acid sequence set forth in SEQ ID NO:6 or SEQ ID NO:7.
15. The method of claim 1 , wherein the TWEAK blocking agent is a soluble form of a TWEAK receptor.
16. The method of claim 15 , wherein the soluble form of the TWEAK receptor comprises an antibody Fc region.
17. The method of claim 1 , wherein the TNF-α blocking agent reduces the ability of TNF-α to bind to a TNF-α receptor.
18. The method of claim 1 , wherein the TNF-α blocking agent is a monoclonal, chimeric, human, or humanized antibody that binds to TNF-α.
19. The method of claim 18 , wherein the TNF-α blocking agent is infliximab or adalimumab.
20. The method of claim 1 , wherein the TNF-α blocking agent is a soluble form of a TNF-α receptor.
21. The method of claim 1 , wherein the TNF-α blocking agent is etanercept.
22. The method of claim 1 , wherein the TWEAK blocking agent and the TNF-α blocking agent are administered to the subject at the same time.
23. The method of claim 22 , wherein the TWEAK blocking agent and the TNF-α blocking agent are administered as a co-formulation.
24. The method of claim 1 , wherein the TWEAK blocking agent and the TNF-α blocking agent are administered sequentially.
25. The method of claim 24 , wherein the TWEAK blocking agent is administered to a patient who has already received the TNF-α blocking agent, wherein the TNF-α blocking agent is present at a therapeutic level in the subject.
26. The method of claim 24 , wherein the TNF-α blocking agent is administered to a patient who has already received the TWEAK blocking agent, wherein the TWEAK blocking agent is present at a therapeutic level in the subject.