Binding molecules specific for il-21 and uses thereof

Abstract

This disclosure provides IL-21 binding molecules, e.g., anti-IL-21 antibodies and antigen-binding fragments thereof. In certain aspects the anti-IL-21 antibodies and fragments thereof can be hybridoma-derived murine monoclonal antibodies, and humanized versions thereof. In certain aspects the binding molecules, e.g., anti-IL-21 antibodies and antigen-binding fragments thereof provided herein inhibit, suppress, or antagonize IL-21 activity. In addition, this disclosure provides compositions and methods for diagnosing and treating diseases or disorders, e.g., inflammatory, immune-mediated, or autoimmune diseases or disorders associated with IL-21-mediated signal transduction. In a particular embodiment, the disclosure provides methods for treating or preventing Graft-versus-host disease (GVHD) using IL-21 binding molecules, e.g., anti-IL-21 antibodies and antigen-binding fragments thereof.

1 . An antibody or an antigen-binding fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein:
 (a) CDR1, CDR2, and CDR3 of the VH comprise SEQ ID NO: 43, SEQ ID NO: 44, and SEQ ID NO: 45, respectively and CDR1, CDR2, and CDR3 of the VL comprise SEQ ID NO: 48, SEQ ID NO: 49, and SEQ ID NO: 50 respectively; or   (b) CDR1, CDR2, and CDR3 of the VH comprise SEQ ID NO: 53, SEQ ID NO: 54, and SEQ ID NO: 55, respectively and CDR1, CDR2, and CDR3 of the VL comprise SEQ ID NO: 58, SEQ ID NO: 59, and SEQ ID NO: 60 respectively;   wherein the antibody or the antigen-binding fragment thereof specifically binds to IL-21.   
     
     
         2 . The antibody or antigen-binding fragment of  claim 1 , wherein
 (a) the VH comprises the amino acid sequence of SEQ ID NO: 42; and   (b) the VL comprises the amino acid sequence of SEQ ID NO: 47.   
     
     
         3 . The antibody or antigen-binding fragment of  claim 1 , wherein
 (a) the VH comprises the amino acid sequence of SEQ ID NO: 52; and   (b) the VL comprises the amino acid sequence of SEQ ID NO: 57.   
     
     
         4 . The antibody or antigen-binding fragment of  claim 1 , wherein the antibody or antigen-binding fragment comprises an IgG constant domain. 
     
     
         5 . The antibody or antigen-binding fragment of  claim 4 , wherein the IgG constant domain comprises one or more amino acid substitutions that increase the antibody or antigen-binding fragment half-life compared to that observed in the antibody or antigen-binding fragment having a wild-type IgG constant domain. 
     
     
         6 . The antibody or antigen-binding fragment of  claim 4 , wherein the IgG constant domain is human IgG1. 
     
     
         7 . The antibody of  claim 1 , wherein the antibody is a murine antibody, a humanized antibody, a chimeric antibody, or a recombinant antibody. 
     
     
         8 . The antigen-binding fragment of  claim 1 , wherein the antigen-binding fragment is Fv, Fab, F(ab′)2, Fab′, dsFv, scFv, and sc(Fv)2. 
     
     
         9 . The antibody or antigen-binding fragment of  claim 1 , wherein the antibody or antigen-binding fragment is conjugated to an agent selected from the group consisting of an antimicrobial agent, a therapeutic agent, a prodrug, a peptide, a protein, an enzyme, a lipid, a biological response modifier, a pharmaceutical agent, a lymphokine, a heterologous antibody or fragment thereof, a detectable label, a polyethylene glycol (PEG), and any combination thereof. 
     
     
         10 . A pharmaceutical composition comprising the antibody or antigen-binding fragment of  claim 1 , and one or more of a pharmaceutically acceptable carrier, or a diluent. 
     
     
         11 . A method for treating an autoimmune disease or disorder in a subject in need thereof comprising administering to the subject an effective amount of the antibody or antigen-binding fragment of  claim 1 , wherein the autoimmune disease is Sjögren's syndrome (SS), systemic sclerosis, ANCA-associated vasculitis (AAV), giant cell arteritis (GCA) vasculitis, systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis (RA), Crohn's disease, myasthenia gravis, Pemphigus vulgaris, idiopathic thrombocytopenic purpura (ITP), Type I Diabetes, IgG4-related disease, or any combination thereof. 
     
     
         12 . The method of  claim 11 , wherein the autoimmune disease is systemic lupus erythematosus. 
     
     
         13 . A method for detecting IL-21 expression levels in a sample comprising (a) contacting said sample with the antibody or antigen-binding fragment of  claim 1 ; and (b) detecting binding of the antibody to IL-21 in said sample. 
     
     
         14 . A method for treating Graft-versus-host disease (GVHD) in a subject in need thereof comprising administering to the subject an effective amount of the antibody or antigen-binding fragment of  claim 1 .