Treatment of B cell lymphoma using anti-CD80 antibodies that do not inhibit the binding of CD80 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 signaling. These antibodies may be used as specific immunosuppressants, e.g., for the treatment of autoimmune diseases and to prevent organ transplant rejection.
1. A method for treating B cell lymphoma 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 without inhibiting the binding of CD80 to CTLA-4.
2. The method of claim 1 , wherein said anti-CD80 antibody is a human monoclonal antibody, or a chimeric antibody comprising variable regions of a non-human anti-CD80 antibody and human constant regions.
3. The method of claim 2 , wherein said anti-CD80 antibody is a chimeric antibody comprising variable regions of a monkey antibody and human constant regions.
4. The method of claim 3 , 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.
5. The method of claim 2 , wherein said chimeric anti-CD80 antibody comprises light and heavy chain variable region amino acid sequences selected from the group consisting of:
the light and heavy chain variable region amino acid sequences of antibody 7C10 shown in FIG. 3A (SEQ ID NO:1) and in FIGS. 3 b and 3c (SEQ ID NO:2), respectively; and
the light and heavy chain variable region amino acid sequences of antibody 16C10 shown in FIG. 5 a (SEQ ID NO:5) and in FIGS. 5 b and 5 c (SEQ ID NO:6), respectively.
6. The method of claim 5 , 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.
7. The method of claim 6 , wherein said chimeric anti-CD80 antibody comprises the light and heavy chain variable region amino acid sequences of antibody 16C10 shown in FIG. 5 a (SEQ ID NO:5) and in FIGS. 5 b and 5 c (SEQ ID NO:6), respectively, and a human gamma 1 constant region.
8. The method of claim 1 , wherein said monoclonal anti-CD80 antibody or a CD80-binding fragment thereof competes for binding to CD80 with antibody 7C10 or antibody 16C10.
9. The method of claim 1 , comprising administering a CD80-binding fragment of a monoclonal antibody that binds specifically to CD80 without inhibiting the binding of CD80 to CTLA-4.
10. The method of claim 9 , wherein said CD80-binding antibody fragment is selected from the group consisting of Fab, F(ab′) 2 , and Fv.
11. The method of claim 9 , wherein said CD80-binding antibody fragment comprises variable regions of a monkey or human antibody.
12. The method of claim 11 , wherein said CD80-binding antibody fragment comprises light and heavy chain variable region amino acid sequences selected from the group consisting of:
the light and heavy chain variable region amino acid sequences of antibody 7C10 shown in FIG. 3A (SEQ ID NO:1) and in FIGS. 3 b and 3 c (SEQ ID NO:2), respectively; and
the light and heavy chain variable region amino acid sequences of antibody 1 6C10 shown in FIG. 5 a (SEQ ID NO:5) and in FIGS. 5 b and 5 c (SEQ ID NO:6), respectively.
13. The method of claim 1 , wherein said anti-CD80 antibody or CD80-binding fragment thereof is administered in combination with an anti-CD28 antibody or an anti-CD28 binding fragment thereof.
14. A method of treating B cell lymphoma 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.
15. The method of claim 14 , comprising administering a human monoclonal anti-CD80 antibody, or a chimeric anti-CD80 antibody comprising variable regions of a non-human anti-CD80 antibody and human constant regions.
16. The method of claim 15 , comprising administering a chimeric anti-CD80 antibody that comprises variable regions of a monkey antibody and human constant regions.
17. The method of claim 16 , comprising administering a chimeric anti-CD80 antibody that 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 PB constant region.
18. The method of claim 15 , comprising administering a chimeric anti-CD80 antibody that comprises light and heavy chain variable region amino acid sequences selected from the group consisting of:
the light and heavy chain variable region amino acid sequences of antibody 7C 10 shown in FIG. 3A (SEQ ID NO:1) and in FIGS. 3 b and 3 c (SEQ ID NO:2), respectively; and
the light and heavy chain variable region amino acid sequences of antibody 16C10 shown in FIG. 5 a (SEQ ID NO:5) and in FIGS. 5 b and 5 c (SEQ ID NO:6), respectively.
19. The method of claim 18 , comprising administering a chimeric anti-CD80 antibody that 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.
20. The method of claim 19 , comprising administering a chimeric anti-CD80 antibody that comprises the light and heavy chain variable region amino acid sequences of antibody 16C10 shown in FIG. 5 a (SEQ ID NO:5) and in FIGS. 5 b and 5 c (SEQ ID NO:6), respectively, and a human gamma 1 constant region.
21. The method of claim 14 , comprising administering a monoclonal anti-CD80 antibody or a CD80-binding fragment thereof that competes for binding to CD80 with antibody 7C10 or antibody 16C10.
22. The method of claim 14 , comprising administering a CD80-binding fragment of a monoclonal antibody that binds specifically to CD80 without inhibiting the binding of CD80 to CTLA-4.
23. The method of claim 22 , comprising administering a CD80-binding fragment selected from the group consisting of Fab, F(ab′) 2 , and Fv.
24. The method of claim 22 , comprising administering a CD80-binding antibody fragment that comprises variable regions of a monkey or human antibody.
25. The method of claim 24 , comprising administering a CD80-binding antibody fragment that comprises light and heavy chain variable region amino acid sequences selected from the group consisting of:
the light and heavy chain variable region amino acid sequences of antibody 7C10 shown in FIG. 3A (SEQ ID NO:1) and in FIGS. 3 b and 3 c (SEQ ID NO:2), respectively; and
the light and heavy chain variable region amino acid sequences of antibody 16C10 shown in FIG. 5 a (SEQ ID NO:5) and in FIGS. 5 b and 5 c (SEQ ID NO:6), respectively.
26. The method of claim 14 , comprising administering said anti-CD80 antibody or CD80-binding fragment in combination with an anti-CD28 antibody or an anti-CD28 binding fragment thereof.