IL-2R-βγ binding compounds
IL-2Rβγc binding compounds, and pharmaceutical compositions comprising the IL-2Rβγc binding compounds are disclosed. IL-2Rβγc binding compounds can act as IL-2R agonists and are useful in treating cancer, autoimmune diseases and inflammatory diseases.
1. An IL-2Rβγc binding compound, wherein the IL-2Rβγc binding compound comprises an IL-2Rβγc ligand, wherein the IL-2Rβγc ligand comprises:
a ligand linker;
an IL-2Rβ ligand bound to the ligand linker, wherein the IL-2Rβ ligand comprises any one of SEQ ID NOS: 805-903, 911-913, 915-930, 2575-2655, 2661-2853, 2855-2891, 2900-2926, 2929-2939, 9301, and 9308; and
an IL-2Rγc ligand bound to the ligand linker, wherein the IL-2Rγc ligand comprises any one of SEQ ID NOS: 944-1028, 1032, 1034, 1042, 1044, 1051-1060, and 1601-1613.
2. The IL-2Rβγc binding compound of claim 1 , wherein the IL-2Rβ ligand comprises any one of SEQ ID NOS: 911-913, 915-930, 2929-2939, 9301 and 9308.
3. The IL-2Rβγc binding compound of claim 1 , wherein,
the IL-2Rβ ligand comprises SEQ ID NO: 865; and
the IL-2Rγc ligand comprises SEQ ID NO: 965.
4. The IL-2Rβγc binding compound of claim 1 , wherein the IL-2Rβγc ligand comprises a disulfide bond between two cysteines of the IL-2Rβγc ligand.
5. The IL-2Rβγc binding compound of claim 1 , wherein the ligand linker comprises a peptidyl ligand linker.
6. The IL-2Rβγc binding compound of claim 1 , wherein the IL-2Rβγc ligand comprises any one of SEQ ID NOS: 1263-1270, 4070-4085, and 4090-4099.
7. The IL-2Rβγc binding compound of claim 1 , wherein the IL-2Rβγc ligand comprises SEQ ID NO: 1263.
8. The IL-2Rβγc binding compound of claim 1 , wherein the IL-2Rβγc ligand is a full IL-2R agonist or a partial IL-2R agonist.
9. The IL-2Rβγc binding compound of claim 1 , wherein,
the IL-2Rβγc ligand exhibits an EC 50 for STAT5 phosphorylation in TF-1β cells and/or NK-92 cells of less than 100 μM; and
the IL-2Rβγc ligand binds to hIL-2R with an IC50 less than 100 μM as determined using phage ELISA competition assays.
10. The IL-2Rβγc binding compound of claim 1 , wherein the IL-2Rβγc binding compound comprises a construct partner, wherein the IL-2Rβγc ligand is bound to the construct partner.
11. The IL-2Rβγc binding compound of claim 10 , wherein in the IL-2Rβγc ligand is bound to the construct partner through a construct linker.
12. The IL-2Rβγc binding compound of claim 11 , wherein the construct linker comprises a peptidyl ligand linker.
13. The IL-2Rβγc binding compound of claim 10 , wherein the construct partner is selected from a polymer, a polypeptide, an Fc-fragment, an immunoglobulin fragment, an antibody, a viral surface antigen or a virus-like particle, a cytokine, and a recombinant fusion protein.
14. The IL-2Rβγc binding compound of claim 10 , wherein the IL-2Rβγc binding compound is selected from a polyethylene glycol, a hIgG-Fc recombinant fusion protein, and a hIgG1-Fc recombinant fusion protein.
15. The IL-2Rβγc binding compound of claim 10 , wherein the construct partner comprises an antibody and the antibody is directed to a tumor antigen.
16. The IL-2Rβγc binding compound of claim 10 , wherein the construct partner comprises a cell-targeting moiety.
17. The IL-2Rβγc binding compound of claim 16 , wherein cell-targeting moiety comprises a tumor-targeting moiety, an immune cell-targeting moiety, or a combination thereof.
18. The IL-2Rβγc binding compound of claim 1 , wherein the IL-2Rβ ligand comprises any one of SEQ ID NO: 2818, 2819, 2856, 2859, 2862, and 2934.
19. The IL-2Rβγc binding compound of claim 1 , wherein,
the IL-2Rβ ligand comprises any one of SEQ ID NO: 2818, 2819, 2856, 2859, 2862, and 2934; and
the IL-2Rγc ligand comprises SEQ ID NO: 965.
20. The IL-2Rβγc binding compound of claim 1 , wherein the ligand linker comprises (G) n (SEQ ID NO: 9380), (GS) n (SEQ ID NO: 9381), (GGS) n (SEQ ID NO: 9382), (GGGS) n (SEQ ID NO: 9383), (GGGGS) n (SEQ ID NO: 9384), or a combination of any of the foregoing, wherein n is an integar from 1 to 20.
21. The IL-2Rβγc binding compound of claim 1 , wherein the ligand linker comprises (GGGGS) (SEQ ID NO: 9395), (GGGGS)2 (SEQ ID NO: 9396), (GGGGS)3 (SEQ ID NO: 9397), (GGGGS)4 (SEQ ID NO: 9398), (GG) (SEQ ID NO: 9399), (GGG) (SEQ ID NO: 9400), (GGGGG) (SEQ ID NO: 9401), (GGS) (SEQ ID NO: 9402), (GGGS) (SEQ ID NO: 9403), (GGGGSGG) (SEQ ID NO: 9404), (GGS)2 (SEQ ID NO: 9405), (G)5 (SEQ ID NO: 9406), or (GS)10 (SEQ ID NO: 9407).
22. A pharmaceutical composition comprising the IL-2Rβγc binding compound of claim 1 .