Methods of treatment utilizing binding proteins of the interleukin-21 receptor
View Patent ↗The present invention provides binding proteins and antigen-binding fragments thereof, including human antibodies, that specifically bind to the human interleukin-21 receptor (IL-21R), and methods of using them. The binding proteins can act as, e.g., antagonists of IL-21R activity, thereby modulating immune responses in general, and those mediated by IL-21R in particular. The disclosed compositions and methods may be used, e.g., in diagnosing, treating, and/or preventing IL-21R-associated disorders, e.g., inflammatory disorders, autoimmune diseases, allergies, transplant rejection, and other immune system disorders.
1. A method of treating lupus in a subject in need thereof, comprising administering to the subject a binding protein or antigen-binding fragment thereof that specifically binds to human interleukin-21 receptor (“IL-21R”) in an amount sufficient to inhibit or reduce immune cell activity in the subject thereby treating the lupus, wherein the binding protein or antigen-binding fragment thereof comprises the CDR sequences set forth in SEQ ID NOs:163, 164, 169, 194, 195, and 176.
2. The method of claim 1 , wherein the binding protein or antigen-binding fragment is an antibody.
3. The method of claim 1 , wherein the binding protein or antigen-binding fragment is an scFv.
4. A method of treating lupus in a subject in need thereof, comprising administering to the subject a binding protein or antigen-binding fragment thereof that specifically binds to human IL-21R in an amount sufficient to inhibit or reduce immune cell activity in the subject thereby treating the lupus, wherein the binding protein or antigen-binding fragment thereof comprises the CDR sequences encoded by the nucleotide sequences of:
(a) nucleotide 148 to 165 of SEQ ID NO:239;
(b) nucleotide 208 to 255 of SEQ ID NO:239;
(c) nucleotide 352 to 378 of SEQ ID NO:239;
(d) nucleotide 124 to 156 of SEQ ID NO:97;
(e) nucleotide 202 to 222 of SEQ ID NO:97; and
(f) nucleotide 319 to 354 of SEQ ID NO:97.
5. The method of claim 4 , wherein the binding protein or antigen-binding fragment is an antibody.
6. The method of claim 4 , wherein the binding protein or antigen-binding fragment is an scFv.
7. A method of treating lupus in a subject in need thereof, comprising administering to the subject a binding protein or antigen-binding fragment thereof that specifically binds to human IL-21R in an amount sufficient to inhibit or reduce immune cell activity in the subject thereby treating the lupus, wherein the binding protein or antigen-binding fragment thereof comprises a V L domain and a V H domain, and wherein the V L domain comprises
SEQ ID NO:221 and the V H domain comprises amino acid 1 to 118 of SEQ ID NO:219.
8. The method of claim 7 , wherein the binding protein or antigen-binding fragment is an antibody.
9. The method of claim 7 , wherein the binding protein or antigen-binding fragment is an scFv.
10. A method of treating lupus in a subject in need thereof, comprising administering to the subject a binding protein or antigen-binding fragment thereof that specifically binds to human IL-21R in an amount sufficient to inhibit or reduce immune cell activity in the subject thereby treating the lupus, wherein the binding protein or antigen-binding fragment thereof comprises a V L domain and a V H domain, and wherein the V L domain comprises an amino acid sequence encoded by nucleotide 58 to 384 of SEQ ID NO:97, and the V H domain comprises an amino acid sequence encoded by nucleotide 58 to 411 of SEQ ID NO:239.
11. The method of claim 10 , wherein the binding protein or antigen-binding fragment is an antibody.
12. The method of claim 10 , wherein the binding protein or antigen-binding fragment is an scFv.
13. The method of any one of claims 1 , 4 , 7 , and 10 , wherein the lupus is systemic lupus erythematosus.
14. The method of any one of claims 1 , 4 , 7 , and 10 , wherein the lupus is cutaneous lupus erythematosus.
15. The method of any one of claims 1 , 4 , 7 , and 10 , wherein the binding protein or antigen-binding fragment thereof has an association constant for human IL-21R of at least 10 5 M −1 s −1 .
16. The method of any one of claims 1 , 4 , 7 , and 10 , wherein the binding protein or antigen-binding fragment thereof inhibits interleukin-21 (“IL-21”)-mediated BAF3 cell proliferation with an IC 50 of about 1.75 nM or less, and wherein the BAF3 cells comprise a human IL-21 receptor.
17. The method of any one of claims 1 , 4 , 7 , and 10 , wherein the binding protein or antigen-binding fragment thereof inhibits IL-21-mediated proliferation of TF1 cells with an IC 50 of about 14 nM or less, and wherein the TF1 cells comprise a human IL-21 receptor.
18. The method of any one of claims 1 , 4 , 7 , and 10 , wherein the binding protein or antigen-binding fragment thereof inhibits IL-21-mediated proliferation of primary human B cells with an IC 50 of about 1.9 nM or less, and wherein the B cells comprise a human IL-21R.
19. The method of any one of claims 1 , 4 , 7 , and 10 , wherein the binding protein or antigen-binding fragment thereof inhibits IL-21-mediated proliferation of primary human CD4 + cells with an IC 50 of about 1.5 nM or less, and wherein the CD4 + cells comprise a human IL-21R.
20. The method of any one of claims 1 , 4 , 7 , and 10 , wherein the binding protein or antigen-binding fragment specifically binds to an amino acid sequence that is at least about 95% identical to any sequence of at least 100 contiguous amino acids of SEQ ID NO:2.
21. The method of any one of claims 1 , 4 , 7 , and 10 , wherein the binding protein or antigen-binding fragment inhibits the binding of IL-21 to IL-21R.
22. The method of any one of claims 1 , 4 , 7 , and 10 , wherein the binding protein or antigen-binding fragment is IgG1.
23. The method of any one of claims 1 , 4 , 7 , and 10 , wherein the binding protein or antigen-binding fragment is human.