Dual IL-2R and IL-7R binding compounds
Dual receptor binding compounds comprising IL-2Rβ, IL-7Rα, and Rγc ligands, and pharmaceutical compositions comprising the dual receptor binding compounds are disclosed. The dual receptor binding compounds can act as IL-2R and IL-7R agonists and are useful in treating cancer, viral diseases, autoimmune diseases, and inflammatory diseases.
1. A dual receptor binding compound, wherein the dual receptor binding compound comprises:
an IL-2Rβ ligand, wherein the IL-2Rβ ligand comprises an amino acid sequence of any one of SEQ ID NOS: 1-572, 574-655, 661-891, 900-926, 930-937, or 9301-9315;
an Rγc ligand, wherein the Rγc ligand comprises an amino acid sequence of any one of SEQ ID NOS: 1001-1215, 1601-1613, or 9340-9353; and
an IL-7Rα ligand, wherein the IL-7Rα ligand comprises an amino acid sequence of any one of SEQ ID NOS: 2001-2410, 2601, 2602, or 9320-9332.
2. The dual receptor binding compound of claim 1 , wherein,
the IL-2Rβ ligand comprises an amino acid sequence of any one of SEQ ID NOS: 395 and 9301-9315;
the Rγc ligand comprises an amino acid sequence of any one of SEQ ID NOS: 1204 and 9340-9353; and
the IL-7Rα ligand comprises an amino acid sequence of any one of SEQ ID NOS: 2047 and 9320-9332.
3. The dual receptor binding compound of claim 1 , wherein,
the IL-2Rβ ligand comprises an amino acid sequence of SEQ ID NO: 395;
the Rγc ligand comprises an amino acid sequence of SEQ ID NO: 1204; and
the IL-7Rα ligand comprises an amino acid sequence of SEQ ID NO: 2407.
4. The dual receptor binding compound of claim 1 , wherein the dual receptor binding ligand has the structure of Formula (104a)-(104f).
5. The dual receptor binding compound of claim 1 , wherein the dual receptor binding compound comprises an amino acid sequence of any one of SEQ ID NOS: 4041-4058.
6. The dual receptor binding compound of claim 1 , wherein the dual receptor binding ligand has the structure of Formula (105a)-(105d), Formula (106a)-(106b), or Formula (107).
7. The dual receptor binding compound of claim 1 , wherein the dual receptor binding compound comprises:
an IL-2Rβγc ligand, wherein the IL-2Rβγc ligand comprises the IL-2Rβ ligand and the Rγc ligand; and
an IL-7Rαγc ligand, wherein the IL-7Rαγc ligand comprises the IL-7Rα ligand and the Rγc ligand.
8. The dual receptor binding compound of claim 7 , wherein,
the IL-2Rβγc ligand comprises an amino acid sequence of any one of SEQ ID NOS: 4001-4007, 4070-4085, 4090-4094, or 4095-4099; and
the IL-7Rαγc ligand comprises an amino acid sequence of any one of SEQ ID NOS: 4021-4028.
9. The dual receptor binding compound of claim 7 , wherein,
the IL-2Rβγc ligand is a full IL-2R agonist or a partial IL-2R agonist; and
the IL-7Rαγc ligand is a full IL-7R agonist or a partial IL-7R agonist.
10. The dual receptor binding compound of claim 1 , wherein the dual receptor binding compound comprises a construct partner.
11. The dual receptor binding compound of claim 10 , wherein the construct partner is selected from a polymer, a polypeptide, an Fc-fragment, an immunoglobulin fragment, antibody, a viral surface antigen or a virus-like particle, a cytokine and a recombinant fusion protein.
12. The dual receptor binding compound of claim 10 , wherein the construct partner is selected from a polyethylene glycol, a hIgG-Fc recombinant fusion protein, and a hIgG-Fc recombinant fusion protein.
13. The dual receptor binding compound of claim 10 , wherein the construct partner comprises an antibody and the antibody is directed to a tumor antigen.
14. The dual receptor binding compound of claim 10 , wherein the construct partner comprises a cell-targeting moiety, wherein cell-targeting moiety comprises a tumor-targeting moiety, an immune cell-targeting moiety, or a combination thereof.
15. The dual receptor binding compound of claim 10 , wherein the dual receptor binding compound comprises a construct linker.
16. The dual receptor binding compound of claim 15 , wherein the construct linker comprises a peptidyl ligand linker.
17. The dual receptor binding compound of claim 1 , wherein the dual receptor binding compound comprises an amino acid sequence of any one of SEQ ID NOS: 8001-8007, 8012-8052, 8061-8082, 8101, and 8102, and PEG-1 to PEG-7.
18. The dual receptor binding compound of claim 1 , wherein,
the dual receptor binding compound binds to hIL-2R with an IC50 less than 100 μM and binds to hIL-7R with an IC50 less than 100 μM; and
the dual receptor binding compound exhibits an EC 50 for STAT5 phosphorylation in TF-1β cells and/or NK-92 cells of less than 100 μM.
19. A pharmaceutical composition comprising a dual receptor binding compound of claim 1 .
20. A method of treating a disease in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the dual receptor binding compound of claim 1 , wherein the disease is selected from cancer, an autoimmune disease, an inflammatory disease, an infectious disease, and a viral disease.