Treating intestinal inflammation with anti-CD80 antibodies that do not inhibit CD80 binding to CTLA-4
View Patent ↗The present invention relates to the identification of antibodies which are specific to human B7.1 antigen (CD80) and which are capable of inhibiting the binding of B7.1 to a CD28 receptor and which are not capable of inhibiting the binding of B7.1 to a CTLA-4 receptor. Two of these antibodies, 16C10 and 7C10, significantly inhibit the production of IL-2, in spite of the existence of a second activating ligand B7.2 (CD86). Blocking of the primary activation signal between CD28 and B7.1 (CD80) with these antibodies while allowing the unimpaired or coincident interaction of CTLA-4 and B7.1 and/or B7.2 represents a combined antagonistic effect on positive co-stimulation with an agonistic effect on negative signalling. These antibodies, or B7.1-binding fragments thereof, may be used for the treatment of Crohn's disease.
1. A method for inhibiting or preventing T cell/B cell interactions associated with intestinal inflammation comprising administering an amount of a monoclonal anti-CD80 antibody or a CD80-binding fragment thereof sufficient to inhibit the binding of B cells and T cells via the CD80/CD28 pathway; wherein said monoclonal antibody or fragment thereof binds specifically to CD80 antigen without inhibiting the binding of CD80 antigen to CTLA-4.
2. The method of claim 1 , wherein said anti-CD80 antibody is a human monoclonal antibody, or a chimeric or humanized antibody comprising constant regions derived from human constant regions.
3. The method of claim 1 , wherein said anti-CD80 antibody competes for binding to CD80 antigen with antibody 7C10, produced by a hybridoma assigned ATCC accession no. HB-12117, or antibody 16C10, produced by a hybridoma assigned ATCC accession no. HB-12119.
4. The method of claim 2 , wherein said anti-CD80 antibody is a chimeric antibody comprising variable regions of an Old World monkey antibody and human constant regions.
5. A method of treating intestinal inflammation in a subject in need of such treatment by administering a therapeutically effective amount of a monoclonal anti-CD80 antibody or a CD80-binding fragment thereof that does not inhibit the CD80/CTLA-4 binding interaction.
6. The method of claim 5 , wherein said anti-C80 antibody is a human monoclonal anti-CD80 antibody, or a chimeric or humanized antibody comprising constant regions derived from human constant regions.
7. The method of claim 6 , comprising administering a chimeric anti-CD80 antibody comprising variable regions of an Old World monkey antibody and human constant regions.
8. The method of claim 1 , wherein said anti-CD80 antibody or CD80-binding fragment thereof is administered in combination with an immunomodulator selected from the group consisting of IL-7, IL-10, CTLA4-Ig, soluble CTLA-4, an anti-CD28 antibody, and a CD28-binding fragment of an anti-CD28 antibody.
9. The method of claim 5 , wherein said anti-CD80 antibody or CD80-binding fragment thereof is administered in combination with an immunomodulator selected from the group consisting of IL-7, IL-10, CTLA4-Ig, soluble CTLA-4, an anti-CD28 antibody, and a CD28-binding fragment of an anti-CD28 antibody.
10. The method of claim 1 , wherein said anti-CD80 antibody or CD80-binding fragment thereof is administered in combination with an immunosuppressant selected from the group consisting of cyclosporin A, FK506, anti-TNFα antibody, anti-CD54 antibody, anti-CD11 antibody anti-CD11a antibody, anti-IL-1 antibody, TNFα receptor, and IL-1 receptor.
11. The method of claim 5 , wherein said anti-CD80 antibody or CD80-binding fragment thereof is administered in combination with an immunosuppressant selected from the group consisting of cyclosporin A, FK506, anti-TNFα antibody, anti-CD54 antibody, anti-CD11 antibody, anti-CD11a antibody, anti-IL-1 antibody, TNFα receptor, and IL-1 receptor.
12. The method of claim 4 , wherein said anti-CD80 antibody competes for binding to CD80 antigen with antibody 7C10, produced by a hybridoma assigned ATCC accession no. HB-12117, or antibody 16C10, produced by a hybridoma assigned ATCC accession no. HB-12119.
13. The method of claim 4 , wherein said anti-CD80 antibody is a chimeric antibody comprising variable regions of antibody 7C10, produced by a hybridoma assigned ATCC accession no. HB-12117, or antibody 16C10, produced by a hybridoma assigned ATCC accession no. HB-12119.
14. The method of claim 13 , wherein said chimeric anti-CD80 antibody comprises a human constant region selected from the group consisting of human gamma 1 constant region, human gamma 4 constant region, and human gamma 4 PE constant region.
15. The method of claim 13 , wherein the light chain of said anti-CD80 antibody has the amino acid sequence shown in FIG. 3 a (SEQ ID NO:1) and the heavy chain of said anti-CD80 antibody has the amino acid sequence shown in FIGS. 3 b and 3 c (SEQ ID NO:3).
16. The method of claim 13 , wherein the light chain of said anti-CD80 antibody has the amino acid sequence shown in FIG. 5 a (SEQ ID NO:9) and the heavy chain of said anti-CD80 antibody has the amino acid sequence shown in FIGS. 5 b and 5 c (SEQ ID NO:11).
17. The method of claim 14 , wherein said chimeric anti-CD80 antibody comprises variable regions of antibody 16C10, produced by a hybridoma assigned ATCC accession no. HB-12119, and a human gamma 1 constant region.
18. The method of claim 1 , comprising administering a CD80-binding fragment of a monoclonal antibody that binds specifically to CD80 antigen without inhibiting the binding of CD80 antigen to CTLA-4.
19. The method of claim 18 , wherein said CD80-binding antibody fragment is selected from the group consisting of Fab, F(ab′) 2 , and Fv.
20. The method of claim 18 , wherein said CD80-binding antibody fragment competes for binding to CD80 antigen with antibody 7C10, produced by a hybridoma assigned ATCC accession no. HB-12117, or antibody 16C10, produced by a hybridoma assigned ATCC accession no. HB-12119.
21. The method of claim 18 , wherein said CD80-binding antibody fragment comprises variable regions of an Old World monkey antibody.
22. The method of claim 21 , wherein said CD80-binding antibody fragment comprises variable regions of antibody 7C10, produced by a hybridoma assigned ATCC accession no. HB-12117, or antibody 16C10, produced by a hybridoma assigned ATCC accession no. HB-12119.
23. The method of claim 5 , wherein said anti-CD80 antibody competes for binding to CD80 antigen with antibody 7C10, produced by a hybridoma assigned ATCC accession no. HB-12117, or antibody 16C10, produced by a hybridoma assigned ATCC accession no. HB-12119.
24. The method of claim 7 , wherein said chimeric anti-CD80 antibody comprises variable regions of antibody 7C10, produced by a hybridoma assigned ATCC accession no. HB-12117, or antibody 16C10, produced by a hybridoma assigned ATCC accession no. HB-12119.
25. The method of claim 24 , wherein said chimeric anti-CD80 antibody comprises a human constant region selected from the group consisting of human gamma 1 constant region, human gamma 4 constant region, and human gamma 4 PE constant region.
26. The method of claim 24 , wherein the light chain of said anti-CD80 antibody has the amino acid sequence shown in FIG. 3 a (SEQ ID NO:1) and the heavy chain of said anti-CD80 antibody has the amino acid sequence shown in FIGS. 3 b and 3 c (SEQ ID NO:3).
27. The method of claim 24 , wherein the light chain of said anti-CD80 antibody has the amino acid sequence shown in FIG. 5 a (SEQ ID NO:9) and the heavy chain of said anti-CD80 antibody has the amino acid sequence shown in FIGS. 5 b and 5 c (SEQ ID NO:11).
28. The method of claim 25 , wherein said anti-CD80 antibody comprises variable regions of antibody 16C10, produced by a hybridoma assigned ATCC accession no. HB-12119, and a human gamma 1 constant region.
29. The method of claim 5 , comprising administering a CD80-binding fragment of a monoclonal antibody that does not inhibit the CD80/CTLA-4 binding interaction.
30. The method of claim 29 , wherein said CD80-binding antibody fragment is selected from the group consisting of Fab, F(ab′) 2 , and Fv.
31. The method of claim 29 , wherein said CD80-binding antibody fragment competes for binding to CD80 antigen with antibody 7C10, produced by a hybridoma assigned ATCC accession no. HB-12117, or antibody 16C10, produced by a hybridoma assigned ATCC accession no. HB-12119.
32. The method of claim 29 , wherein said CD80-binding antibody fragment comprises variable regions of an Old World monkey antibody.
33. The method of claim 32 , wherein said CD80-binding antibody fragment comprises variable regions of antibody 7C10, produced by a hybridoma assigned ATCC accession no. HB-12117, or antibody 16C10, produced by a hybridoma assigned ATCC accession no. HB-12119.
34. The method of claim 1 , wherein the intestinal inflammation is Crohn's disease.
35. The method of claim 1 , wherein the intestinal inflammation is ulcerative colitis.
36. The method of claim 1 , wherein the intestinal inflammation is Coeliac disease.
37. The method of claim 1 , wherein the intestinal inflammation is proctitis.
38. The method of claim 1 , wherein the intestinal inflammation is eosinophilia gastroenteritis.
39. The method of claim 1 , wherein the intestinal inflammation is mastocytosis.
40. The method of claim 5 , wherein the intestinal inflammation is Crohn's disease.
41. The method of claim 5 , wherein the intestinal inflammation is ulcerative colitis.
42. The method of claim 5 , wherein the intestinal inflammation is Coeliac disease.
43. The method of claim 5 , wherein the intestinal inflammation is proctitis.
44. The method of claim 5 , wherein the intestinal inflammation is eosinophilia gastroenteritis.
45. The method of claim 5 , wherein the intestinal inflammation is mastocytosis.