Dual il-2r and il-7r binding compounds

Abstract

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 having greater than 60% sequence similarity to 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 having greater than 60% sequence similarity to 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 having greater than 60% sequence similarity to 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 having greater than 60% sequence similarity to any one of SEQ ID NOS: 395 and 9301-9315;   the Rγc ligand comprises an amino acid sequence having greater than 60% sequence similarity to any one of SEQ ID NOS: 1204 and 9340-9353; and   the IL-7Rα ligand comprises an amino acid sequence having greater than 60% sequence similarity to 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 having greater than 60% sequence similarity to SEQ ID NO: 395;   the Rγc ligand comprises an amino acid sequence having greater than 60% sequence similarity to SEQ ID NO: 1204; and   the IL-7Rα ligand comprises an amino acid sequence having greater than 60% sequence similarity to 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 having greater than 60% sequence similarity to 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 a first Rγc ligand; and   an IL-7Rαγc ligand, wherein the IL-7Rαγc ligand comprises the IL-7Rα ligand and a second Rγc ligand.   
     
     
         8 . The dual receptor binding compound of  claim 7 , wherein:
 the IL-2Rβ ligand is bound to the first Rγc ligand through a peptidyl ligand linker; and   the IL-7Rα ligand is bond to the second Rγc ligand through a peptidyl ligand linker.   
     
     
         9 . The dual receptor binding compound of  claim 7 , wherein the first Rγc ligand and the second Rγc ligand have greater than 60% sequence similarity. 
     
     
         10 . The dual receptor binding compound of  claim 7 , wherein,
 the IL-2Rβγc ligand comprises an amino acid sequence having greater than 60% sequence similarity to 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 having greater than 60% sequence similarity to any one of SEQ ID NOS: 4021-4028.   
     
     
         11 . 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.   
     
     
         12 . The dual receptor binding compound of  claim 1 , wherein the dual receptor binding compound comprises a construct partner. 
     
     
         13 . The dual receptor binding compound of  claim 12 , 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. 
     
     
         14 . The dual receptor binding compound of  claim 12 , wherein the construct partner is selected from a polyethylene glycol, a hIgG-Fc recombinant fusion protein, and a hIgG1-Fc recombinant fusion protein. 
     
     
         15 . The dual receptor binding compound of  claim 12 , wherein the construct partner comprises an antibody and the antibody is directed to a tumor antigen. 
     
     
         16 . The dual receptor binding compound of  claim 12 , 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. 
     
     
         17 . The dual receptor binding compound of  claim 12 , wherein the dual receptor binding compound comprises a construct linker. 
     
     
         18 . The dual receptor binding compound of  claim 17 , wherein the construct linker comprises a peptidyl ligand linker. 
     
     
         19 . The dual receptor binding compound of  claim 1 , wherein the dual receptor binding compound comprises an amino acid sequence having greater than 60% sequence similarity to any one of SEQ ID NOS: 8001-8007, 8012-8052, 8061-8082, 8101, and 8102, and PEG-1 to PEG-7. 
     
     
         20 . 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.   
     
     
         21 . A pharmaceutical composition comprising a dual receptor binding compound of  claim 1 . 
     
     
         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 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.