Anti-OX40 antibodies
The present disclosure provides antibodies that specifically bind to human OX40 receptor (OX40) and compositions comprising such antibodies. In a specific aspect, the antibodies specifically bind to human OX40 and modulate OX40 activity, e.g., enhance, activate, or induce OX40 activity, or reduce, deactivate, or inhibit OX40 activity. The present disclosure also provides methods for treating disorders, such as cancer, by administering an antibody that specifically binds to human OX40 and modulates OX40 activity, e.g., enhances, activates, or induces OX40 activity. Also provided are methods for treating autoimmune or inflammatory diseases or disorders, by administering an antibody that specifically binds to human OX40 and modulates OX40 activity, e.g., reduces, deactivates, or inhibits OX40 activity.
1. An isolated antibody that specifically binds to human OX40, comprising:
(a) heavy chain variable region comprising
a heavy chain complementarity determining region 1 (CDR1) comprising the amino acid sequence of GSAMH (SEQ ID NO: 4),
a heavy chain CDR2 comprising the amino acid sequence of RIRSKANSYATAYAASVKG (SEQ ID NO: 5), and
a heavy chain CDR3 comprising the amino acid sequence of GIYDSSGYDY (SEQ ID NO: 6); and
(b) a light chain variable region comprising
a light chain CDR1 comprising the amino acid sequence of RSSQSLLHSNGYNYLD (SEQ ID NO: 1),
a light chain CDR2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO: 2), and a light chain CDR3 comprising the amino acid sequence of MQALQTPLT (SEQ ID NO: 3).
2. The antibody of claim 1 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 61, 62, or 63.
3. The antibody of claim 1 , wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain and the light chain, respectively, comprise the amino acid sequences set forth in SEQ ID NOs: 61 and 20; 62 and 20; or 63 and 20.
4. The antibody of claim 1 , wherein the antibody comprises a heavy chain and a light chain, wherein the amino acid sequences of the heavy chain and the light chain, respectively, consist of the amino acid sequences set forth in SEQ ID NOs: 61 and 20; 62 and 20; or 63 and 20.
5. The antibody of claim 1 , further comprising heavy and/or light chain constant regions.
6. The antibody of claim 5 , wherein the heavy chain constant region is selected from the group consisting of human immunoglobulins IgG 1 , IgG 2 , IgG 3 , IgG 4 , IgA 1 , and IgA 2 .
7. The antibody of claim 6 , wherein the IgG 1 is non-fucosylated IgG 1 .
8. The antibody of claim 6 , wherein the amino acid sequence of the IgG 1 comprises a N297A mutation or a mutation selected from the group consisting of D265A, P329A, and a combination thereof, numbered according to the EU index as in Kabat.
9. The antibody of claim 6 , wherein the amino acid sequence of the IgG 1 comprises a N297Q mutation, numbered according to the EU index as in Kabat.
10. The antibody of claim 6 , wherein the amino acid sequence of the IgG 4 comprises a S228P mutation, numbered according to the EU index as in Kabat.
11. The antibody of claim 6 , wherein the amino acid sequence of the IgG 2 comprises a C127S mutation, numbered according to the EU index as in Kabat.
12. The antibody of claim 6 , wherein the amino acid sequence of the IgG 1 comprises:
(a) a mutation selected from the group consisting of N297A, N297Q, D265A, and a combination thereof; or
(b) a mutation selected from the group consisting of D265A, P329A, and a combination thereof, numbered according to the EU index as in Kabat.
13. The antibody of claim 1 , wherein the antibody comprises a heavy chain constant region selected from the group consisting of human immunoglobulins IgG 1 , IgG 2 , IgG 3 , IgG 4 , IgA 1 , and IgA 2 ; and/or wherein the antibody comprises a light chain constant region selected from the group consisting of human immunoglobulins IgGκ and IgGλ.
14. The antibody of claim 1 , wherein the antibody is a human antibody.
15. The antibody of claim 1 , wherein the antibody is agonistic.
16. The antibody of claim 1 , wherein the antibody activates, enhances, or induces an activity of human OX40.
17. The antibody of claim 1 , wherein the antibody induces CD4 + T cell proliferation.
18. The antibody of claim 17 , wherein the CD4 + T cell proliferation is a substantially increasing function of the concentration of the antibody.
19. The antibody of claim 17 , wherein the CD4 + T cell proliferation shows a sigmoidal dose response curve.
20. The antibody of claim 1 , wherein the antibody induces production of TNFα, TNFβ, IFNγ, GM-CSF, IL-2, IL-4, IL-10, IL-13, or a combination thereof by anti-CD3-stimulated peripheral blood mononuclear cells (PBMCs).
21. The antibody of claim 1 , wherein the antibody induces IL-2 production by SEA-stimulated PBMCs and suppresses IL-10 production by SEA-stimulated PBMCs.
22. The antibody of claim 1 , wherein the antibody relieves suppression of T effector cells by T regulatory cells.
23. The antibody of claim 1 , wherein the antibody:
(a) induces IL-2 production by a co-culture of T effector cells and T regulatory cells and
(b) suppresses IL-10 production by a co-culture of T effector cells and T regulatory cells.
24. An isolated antibody that specifically binds to human OX40, comprising the heavy chain variable region and the light chain variable region of claim 1 , wherein the antibody is selected from the group consisting of a Fab, Fab′, F(ab′) 2 , and scFv fragment.
25. An isolated antibody that specifically binds to human OX40, comprising one heavy chain and one light chain, wherein the heavy chain and light chain comprise the heavy chain variable region and the light chain variable region, respectively, of claim 1 .
26. The antibody of claim 1 , wherein the antibody is antagonistic to human OX40.
27. The antibody of claim 1 , wherein the antibody deactivates, reduces, or inhibits an activity of human OX40.
28. The antibody of claim 1 , wherein the antibody inhibits or reduces binding of human OX40 to human OX40 ligand.
29. The antibody of claim 1 , wherein the antibody inhibits or reduces human OX40 signaling.
30. The antibody of claim 1 , wherein the antibody inhibits or reduces human OX40 signaling induced by human OX40 ligand.
31. The antibody of claim 1 , wherein the antibody further comprises a detectable label.
32. A pharmaceutical composition comprising the antibody of claim 1 and a pharmaceutically acceptable excipient.
33. A kit comprising the antibody of claim 1 and a) a detection reagent, b) an OX40 antigen, c) a notice that reflects approval for use or sale for human administration, or d) a combination thereof.
34. A heavy chain comprising a heavy chain variable region, wherein the amino acid sequence of the heavy chain variable region consists of the amino acid sequence of SEQ ID NO: 16.
35. The heavy chain of claim 34 , wherein the heavy chain comprises a heavy chain constant region.
36. The heavy chain of claim 34 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 60, 61, 62, or 63.
37. The heavy chain of claim 34 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 60.
38. A light chain comprising a light chain variable region, wherein the amino acid sequence of the light chain variable region consists of the amino acid sequence of SEQ ID NO: 15.
39. The light chain of claim 38 , wherein the light chain comprises a light chain constant region.
40. The light chain of claim 38 , wherein the light chain comprises the amino acid sequence of SEQ ID NO: 20.
41. A pharmaceutical composition comprising the heavy chain of claim 34 and a pharmaceutically acceptable excipient.
42. The pharmaceutical composition of claim 41 , wherein the heavy chain comprises a heavy chain constant region.
43. The pharmaceutical composition of claim 41 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 60, 61, 62, or 63.
44. The pharmaceutical composition of claim 41 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 60.
45. A pharmaceutical composition comprising the light chain of claim 38 and a pharmaceutically acceptable excipient.
46. The pharmaceutical composition of claim 45 , wherein the light chain comprises a light chain constant region.
47. The pharmaceutical composition of claim 45 , wherein the light chain comprises the amino acid sequence of SEQ ID NO: 20.