Antibodies that bind interleukin-2 and uses thereof
The present disclosure relates, in general, to human antibodies against human interleukin 2 (IL-2) and methods of use of such antibodies for modulating IL-2 activity and use in the treatment of conditions such as cancer, autoimmune disease, or infection.
1. A human or humanized antibody that binds human interleukin-2 (IL-2) with an affinity K D of 1×10 −10 M or less and inhibits binding of IL-2 with an IL-2 receptor alpha (IL-2 Rα) subunit,
wherein the antibody inhibits IL-2 signaling through IL-2 Rαβγ and through IL-2 Rβγ, and
wherein the antibody inhibits IL-2 signaling through IL-2 Rαβγ to a greater extent than through IL-2 Rβγ.
2. The antibody of claim 1 wherein the antibody does not completely block binding of human IL-2 to cells expressing human or mouse IL-2 Rβ or IL-2 Rβγ complex.
3. The antibody of claim 1 , wherein the antibody binds at a site allosteric to binding of IL-2 to IL-2 Rα, IL-2 Rβγ or IL-2 Rαβγ.
4. The antibody of claim 1 , wherein the antibody is a negative modulator antibody, optionally wherein the antibody is capable of weakening the binding affinity between IL-2 with IL-2 receptor α (IL-2 Rα) by at least about 2-fold, optionally up to 1000-fold.
5. The antibody of claim 1 wherein IL-2 complexed to the antibody binds to CHO cells expressing IL-2 Rβ and γc with an EC50 of 5 nM or less or wherein IL-2 complexed to the antibody binds to CHO cells expressing IL-2 Rβ (but not γc) with an EC50 of 100 nM or less.
6. The antibody of claim 1 wherein the antibody binds to human IL-2 and one or more of mouse, rat or rabbit IL-2.
7. The antibody of claim 1 , wherein the antibody inhibits IL-2 stimulation of STAT5 activation in cells expressing IL-2 Rα, IL-2 Rβ, and γc to a greater extent than cells expressing IL-2 Rβ and γc, but not IL-2 Rα.
8. The antibody of claim 1 , wherein the antibody inhibits IL-2 stimulation of STAT5 activation in cells that express IL-2 Rα, IL-2 Rβ, and γc by 200-fold or greater.
9. The antibody of claim 1 , wherein the antibody inhibits IL-2 stimulation of STAT5 activation in cells that express IL-2 Rβ and γc, but not IL-2 Rα by 10-fold or less.
10. The antibody of claim 1 , wherein the antibody inhibits IL-2 stimulation of proliferation in cells expressing IL-2 Rα, IL-2 Rβ, and γc to a greater extent than cells expressing IL-2 Rβ and γc, but not IL-2 Rα.
11. The antibody of claim 1 , wherein the antibody inhibits IL-2 stimulation of proliferation of NK cells that express IL-2 Rα, IL-2 Rβ, and γc, by greater than 15-fold.
12. The antibody of claim 1 , wherein the antibody inhibits IL-2 stimulation of proliferation of BaF3 cells that express IL-2 Rβ and γc, but not IL-2 Rα, by less than 10-fold.
13. The antibody of claim 1 , further comprising a heavy chain constant region, wherein the heavy chain constant region is a modified or unmodified IgG, IgM, IgA, IgD, IgE, a fragment thereof, or combinations thereof.
14. The antibody of claim 1 , further comprising a human light chain constant region attached to said light chain variable region.
15. A sterile pharmaceutical composition comprising the antibody of claim 1 and a pharmaceutically acceptable carrier.
16. An antibody that binds human interleukin-2 (IL-2) comprising
i).
(a) a heavy chain CDR1 amino acid sequence set forth in SEQ ID NOs: 17, 20, 23, or 26;
(b) a heavy chain CDR2 amino acid sequence set forth in SEQ ID NOs: 18, 21, 24, or 27 that is from the same heavy chain variable region as (a); and
(c) a heavy chain CDR3 amino acid sequence set forth SEQ ID NOs: 19, 22, 25, or 28 that is from the same heavy chain variable region as (a); and
ii).
(a) a light chain CDR1 amino acid sequence set forth in SEQ ID NOs: 29, 32, 35, or 38;
(b) a light chain CDR2 amino acid sequence set forth in SEQ ID NOs: 30, 33, 36, or 39 that is from the same light chain variable region as (a); and
(c) a light chain CDR3 amino acid sequence set forth in SEQ ID NOs: 31, 34, 37, or 40 that is from the same light chain variable region as (a).
17. An antibody of claim 16 , that comprises an amino acid sequence at least 90% identical to a heavy chain variable region amino acid sequence set forth in SEQ ID NOs: 1, 3, 5, or 7.
18. An antibody of claim 16 , in which one or more heavy chain framework amino acids have been replaced with corresponding amino acid(s) from another human antibody amino acid sequence.
19. An antibody of claim 16 , comprising an amino acid sequence at least 90% identical to a light chain variable region amino acid sequence set forth in any one of SEQ ID NOs: 9, 11, 13, or 15.
20. An antibody of claim 16 wherein the antibody
i) inhibits binding of IL-2 to an IL-2 receptor alpha (IL-2 R-α) subunit; and/or
ii) partially inhibits binding of IL-2 to an IL-2 Rβγ complex; and/or
iii) binds at a site allosteric to binding of IL-2 to IL-2 Rα, IL-2 Rβγ or IL-2 Rαβγ.
21. An antibody of claim 16 , wherein the antibody is a negative modulator antibody, optionally wherein the antibody is capable of weakening the binding affinity between IL-2 with IL-2 receptor α (IL-2 Rα) by at least about 2-fold, optionally up to 1000-fold.
22. An antibody of claim 16 , wherein the antibody does not shift the EC50 of binding of IL-2 to IL-2 Rβγ complex by more than 3-fold.
23. An antibody of claim 16 wherein the antibody binds to human IL-2 and one or more of mouse, rat or rabbit IL-2.
24. An antibody of claim 16 , wherein the antibody inhibits STAT5 activation in a cell in response to stimulation of the IL-2 R with IL-2.
25. An antibody of claim 16 that is a human antibody or a humanized antibody.
26. An antibody of claim 16 , in which one or more light chain framework amino acids have been replaced with corresponding amino acid(s) from another human antibody amino acid sequence.
27. An antibody of claim 16 that binds human interleukin-2 (IL-2) with an affinity K D of 10 −10 M or less.
28. An antibody of claim 16 comprising
(a) heavy chain HCDR1-HCDR3 amino acid sequences set forth in SEQ ID NOs: 17-19; and
(b) light chain LCDR1-LCDR3 amino acid sequences set forth in SEQ ID NOs: 29-31.
29. An antibody of claim 28 comprising a heavy chain variable region amino acid sequence set forth in SEQ ID NO: 1 and a light chain variable region amino acid sequence set forth in SEQ ID NO: 9.
30. An antibody of claim 16 comprising
(a) heavy chain HCDR1-HCDR3 amino acid sequences set forth in SEQ ID NOs: 26-28; and
(b) light chain LCDR1-LCDR3 amino acid sequences set forth in SEQ ID NOs: 38-40.
31. An antibody of claim 30 comprising a heavy chain variable region amino acid sequence set forth in SEQ ID NO: 7 and a light chain variable region amino acid sequence set forth in SEQ ID NO: 15.