Methods of treatment utiliziing binding proteins of the interleukin-21 receptor

Abstract

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 or preventing an IL-21R-associated disorder in a subject, 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 or preventing the disorder, wherein the binding protein or antigen-binding fragment thereof comprises at least one amino acid sequence that is at least about 95% identical to an amino acid sequence(s) selected from the group consisting of:
 (a) SEQ ID NO:163;   (b) SEQ ID NO:164;   (c) SEQ ID NO:169;   (d) SEQ ID NO:194;   (e) SEQ ID NO:195;   (f) SEQ ID NO:176;   (g) SEQ ID NO:219;   (h) SEQ ID NO:219 from amino acid 1 to 118;   (i) SEQ ID NO:220; and   (j) SEQ ID NO:221.   
     
     
         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 - 6 . (canceled) 
     
     
         7 . A method of treating or preventing an IL-21R-associated disorder in a subject, 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 or preventing the disorder, wherein the binding protein or antigen-binding fragment thereof comprises at least one amino acid sequence encoded by a nucleotide sequence that is at least about 95% identical to a nucleotide sequence(s) selected from the group consisting of:
 (a) SEQ ID NO:239 from nucleotide 148 to 165;   (b) SEQ ID NO:239 from nucleotide 208 to 255;   (c) SEQ ID NO:239 from nucleotide 352 to 378;   (d) SEQ ID NO:97 from nucleotide 124 to 156;   (e) SEQ ID NO:97 from nucleotide 202 to 222;   (f) SEQ ID NO:97 from nucleotide 319 to 354;   (g) SEQ ID NO:239 from nucleotide 58 to 1401;   (h) SEQ ID NO:239 from nucleotide 58 to 411;   (i) SEQ ID NO:97 from nucleotide 58 to 702; and   (j) SEQ ID NO:97 from nucleotide 58 to 384.   
     
     
         8 - 12 . (canceled) 
     
     
         13 . A method of treating or preventing an IL-21R-associated disorder in a subject, comprising administering to the subject a binding protein or antigen-binding fragment thereof that specifically binds to IL-21R, wherein the binding protein or antigen-binding fragment thereof comprises a light chain and a heavy chain, and wherein the light chain comprises at least one amino acid sequence selected from the group consisting of:
 (a) SEQ ID NO:194;   (b) SEQ ID NO:195;   (c) SEQ ID NO:176;   (d) SEQ ID NO:220; and   (e) SEQ ID NO:221.   
     
     
         14 - 16 . (canceled) 
     
     
         17 . A method of treating or preventing an IL-21R-associated disorder in a subject, comprising administering to the subject a binding protein or antigen-binding fragment thereof that specifically binds to a human IL-21R epitope that is recognized by AbS, wherein the binding protein or antigen-binding fragment competitively inhibits the binding of AbS to human IL-21R, in an amount sufficient to inhibit or reduce immune cell activity in the subject thereby treating or preventing the disorder. 
     
     
         18 - 20 . (canceled) 
     
     
         21 . The method of  claim 1 , wherein the IL-21R-associated disorder is selected from the group consisting of autoimmune disorders, inflammatory conditions, allergies, transplant rejections, and hyperproliferative disorders of the blood. 
     
     
         22 . The method of  claim 21 , wherein the IL-21R-associated disorder is selected from the group consisting of multiple sclerosis, systemic lupus erythematosus, psoriasis, transplant rejection, rheumatoid arthritis, and other arthritic disorders. 
     
     
         23 . The method of  claim 1 , 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 . 
     
     
         24 . The method of  claim 1 , wherein the binding protein or antigen-binding fragment thereof inhibits 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. 
     
     
         25 . The method of  claim 1 , 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. 
     
     
         26 . The method of  claim 1 , 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. 
     
     
         27 . The method of  claim 1 , 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. 
     
     
         28 . A method of determining whether an anti-IL-21R antibody is a therapeutic anti-IL-21R antibody comprising the steps of:
 (a) contacting a first blood sample from a subject with an IL-21 ligand;   (b) determining a level of expression of at least one IL-21-responsive gene in the first blood sample contacted with the IL-21 ligand;   (c) contacting a second blood sample from the subject with the IL-21 ligand in the presence of an anti-IL-21R antibody;   (d) determining the level of expression of the at least one IL-21-responsive gene in the second blood sample contacted with the IL-21 ligand in the presence of the anti-IL-21R antibody; and   (e) comparing the levels of expression of the at least one IL-21-responsive gene determined in steps (b) and (d),   wherein a change in the level of expression of the at least one IL-21-responsive gene indicates that the anti-IL-21R antibody is a therapeutic antibody.   
     
     
         29 - 30 . (canceled) 
     
     
         31 . A method of determining the pharmacodynamic activity of an anti-IL-21R antibody comprising detecting a modulation in a level of expression of at least one IL-21-responsive gene in a blood sample of a subject. 
     
     
         32 - 35 . (canceled)