IL-7R-ALPHA BINDING COMPOUNDS
IL-7Rα ligands and compounds comprising IL-7Rα ligands are disclosed. The IL-7Rα binding compounds include fusion proteins comprising the IL-7Rα ligands and can act as IL-7R agonists.
1 . An IL-7Rα ligand comprising:
the amino acid sequence of any of any one of SEQ ID NOS: 393-410, 520-596, and 605-655;
an amino acid sequence having greater than 60% sequence similarity to any one of SEQ ID NOS: 393-410, 520-596, and 605-655; or
an amino acid sequence of any one of SEQ ID NOS: 393-410, 520-596, and 605-655 having from 1 to 5 amino acid substitutions.
2 . The IL-7Rα ligand of claim 1 , wherein the IL-7Rα ligand has the amino acid sequence of any one of SEQ ID NOS: 393-410, 520-596, and 605-655.
3 . The IL-7Rα ligand of claim 1 , wherein the IL-7Rα ligand has an amino acid sequence having greater than 80% sequence similarity to any one of SEQ ID NOS: 393-410, 520-596, and 605-655.
4 . The IL-7Rα ligand of claim 1 , wherein the IL-7Rα ligand an amino acid sequence of any one of SEQ ID NOS: 393-410, 520-596, and 605-655 having from 1 to 3 amino acid substitutions.
5 . The IL-7Rα ligand of claim 1 , wherein the IL-7Rα ligand binds to the hu-IL-7Rα subunit with an IC50 less than 100 μM.
6 . The IL-7Rα ligand of claim 1 , wherein the IL-7Rα ligand comprises:
the amino acid sequence of SEQ ID NO: 407;
an amino acid sequence having greater than 60% sequence similarity to SEQ ID NO: 407; or
an amino acid sequence of SEQ ID NO: 407 having from 1 to 5 amino acid substitutions.
7 . The IL-7Rα ligand of claim 1 , wherein the IL-7Rα ligand comprises from 1 to 5 glycines on the carboxyl terminus, the amino terminus or on both the carboxyl terminus and the amino terminus.
8 . An IL-7Rα binding compound comprising the IL-7Rα ligand of claim 1 bound to an Rγc ligand.
9 . The IL-7Rα binding compound of claim 8 , wherein the IL-7Rα ligand is bound to the Rγc ligand through a peptidyl ligand linker.
10 . The IL-7Rα binding compound of claim 8 , wherein the Rγc ligand comprises:
an amino acid sequence of SEQ ID NO: 429;
an amino acid sequence having greater than 60% sequence similarity to SEQ ID NO: 429; or
an amino acid sequence of SEQ ID NO: 429 having from 1 to 5 amino acid substitutions.
11 . An IL-7Rα binding compound comprising the IL-7Rα ligand of claim 1 bound to a construct partner.
12 . The IL-7Rα binding compound of claim 11 , 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.
13 . The IL-7Rα binding compound of claim 11 , wherein the construct partner is selected from a polyethylene glycol, a hIgG-Fc recombinant fusion protein. and a hIgG1-Fc recombinant fusion protein.
14 . The IL-7Rα binding compound of claim 11 , wherein the construct partner comprises an antibody and the antibody is directed to a tumor antigen.
15 . The IL-7Rα binding compound of claim 11 , 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.
16 . The IL-7Rα binding compound of claim 11 , wherein the IL-7Rα binding compound comprises a construct linker.
17 . The IL-7Rα binding compound of claim 16 , wherein the construct linker comprises a peptidyl ligand linker.
18 . The IL-7Rα binding compound of claim 11 , wherein the IL-7Rα binding compound comprises an amino acid sequence of any one of SEQ ID NOS: 411-419 and 420-428.
19 . The IL-7Rα binding compound of claim 11 , wherein,
the IL-7Rα binding compound binds to hu-IL-2R with an IC50 less than 100 μM and binds to hu-IL-7R with an IC50 less than 100 μM; and
the IL-7Rα binding compound exhibits an EC 50 for STAT5 phosphorylation in TF-1β cells and/or NK-92 cells of less than 100 μM.
20 . A pharmaceutical composition comprising the IL-7Rα ligand of claim 1 .
21 . A pharmaceutical composition comprising the IL-7Rα binding compound of claim 11 .
22 . 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 IL-7Rα ligand of claim 1 , wherein the disease is selected from cancer, an autoimmune disease, an inflammatory disease, an infectious disease, and a viral disease.
23 . 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 IL-7Rα binding compound of claim 11 , wherein the disease is selected from cancer, an autoimmune disease, an inflammatory disease, an infectious disease, and a viral disease.