Antagonist anti-il-7 receptor antibodies and methods

Abstract

The present invention provides antagonizing antibodies that bind to interleukin-7 receptor (IL-7R). The invention further provides a method of obtaining such antibodies and antibody-encoding nucleic acids. The invention further relates to therapeutic methods for use of these antibodies and antigen-binding portions thereof for the treatment and/or prevention of type 2 diabetes and immunological disorders, including type 1 diabetes, multiple sclerosis, rheumatoid arthritis, graft-versus-host disease, and lupus.

It is claimed: 
     
         1 . An isolated interleukin-7 receptor (IL-7R) antibody which specifically binds to interleukin-7 receptor alpha (IL-7Rα) and comprises an antigen binding region that cross-competes with a monoclonal antibody selected from the group consisting of P3A9, P4B3, P2D2, P2E11, HAL403a, HAL403b, C1GM and C2M3, for binding to IL-7Rα. 
     
     
         2 . The antibody of  claim 1 , wherein the antibody binds to an epitope comprising residues I82, K84, K100, T105, and Y192 of human IL-7Rα. 
     
     
         3 . An isolated antibody which specifically binds to interleukin-7 receptor alpha (IL-7Rα), wherein the antibody comprises a heavy chain variable region (VH) complementary determining region one (CDR1) having the amino acid sequence X 1 X 2 VMH, wherein X 1  is D or N; X 2  is S or Y (SEQ ID NO: 50), a VH CDR2 having the amino acid sequence X 1 X 2 X 3 X 4 X 5 GX 6 X 7 TYYADSVKG, wherein X 1  is L or A; X 2  is V or I; X 3  is G or S, X 4  is W or G, X 5  is D or S, X 6  is F, G or S, X 7  is F, A or S (SEQ ID NO: 51), and a VH CDR3 having the amino acid sequence X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 , wherein X 1  is Q or D; X 2  is G or I; X 3  is D or S, X 4  is Y or G, X 5  is M, V or G; X 6  is G or F; X 7  is N, D or M; X 8  is N, Y or D (SEQ ID NO: 52), a light chain variable region (VL) CDR1 having the amino acid sequence TX 1 SSGX 2 IX 3 SSYVQ wherein X 1  is R or G; X 2  is S or R X 3  is D or A (SEQ ID NO: 53), a VL CDR2 having the amino acid sequence EDX 1 QRPS wherein X 1  is D or N (SEQ ID NO: 54), and a VL CDR3 having the amino acid sequence X 1 X 2 YX 3 X 4 X 5 X 6 LX 7  wherein X 1  is Q or M; X 2  is S or Q; X 3  is D or A; X 4  is F or S, X 5  is H or S, X 6  is H or S, X 7  is V or W (SEQ ID NO: 55), wherein the antibody blocks STAT5 phosphorylation in a STAT5 activation assay. 
     
     
         4 . An isolated antibody which specifically binds to interleukin-7 receptor alpha (IL-7Rα), wherein the antibody comprises:
 a heavy chain variable region (VH) comprising the following complementarity determining regions (CDRs): a VH CDR1 that is a VH CDR1 in SEQ ID NO: 40; a VH CDR2 that is a VH CDR2 in SEQ ID NO: 40; and a VH CDR3 that is a VH CDR3 in SEQ ID NO: 40; and 
 light chain variable region (VL) comprising the following CDRs: a VL CDR1 that is a VL CDR1 in SEQ ID NO: 41; a VL CDR2 that is a VL CDR2 in SEQ ID NO: 41; and a VL CDR3 that is a VL CDR3 in SEQ ID NO: 41. 
 
     
     
         5 . The isolated antibody of  claim 4 , wherein the VH region comprises a VH CDR1 having the amino acid sequence DSVMH (SEQ ID NO: 19), GFTFDDS (SEQ ID NO: 46), or GFTFDDSVMH (SEQ ID NO: 47), a VH CDR2 having the amino acid sequence LVGWDGFFTYYADSVKG (SEQ ID NO: 23) or GWDGFF (SEQ ID NO: 48), and a VH CDR3 having the amino acid sequence QGDYMGNN (SEQ ID NO: 49). 
     
     
         6 . The isolated antibody of  claim 5 , wherein the VL region comprises a VL CDR1 having the amino acid sequence TRSSGSIDSSYVQ (SEQ ID NO: 29), a VL CDR2 having the amino acid sequence EDDQRPS (SEQ ID NO: 31), and a VL CDR3 having the amino acid sequence QSYDFHHLV (SEQ ID NO: 36). 
     
     
         7 . The antibody of  claim 4 , wherein the VH region comprises the amino acid sequence shown in SEQ ID NO: 40 and the VL region comprises the amino acid sequence shown in SEQ ID NO: 41. 
     
     
         8 . The antibody of  claim 7 , wherein said antibody comprises a light chain having the amino acid sequence shown in SEQ ID NO: 43 and a heavy chain having the amino acid sequence shown in SEQ ID NO: 42, with or without the C-terminal lysine of SEQ ID NO: 42. 
     
     
         9 . The isolated antibody of  claim 4 , wherein each CDR is defined in accordance with the Kabat definition, the Chothia definition, the combination of the Kabat definition and the Chothia definition, the AbM definition, or the contact definition of CDR. 
     
     
         10 . The antibody of any  claim 4 , wherein the antibody further comprises a constant region. 
     
     
         11 . The antibody of  claim 10 , wherein the antibody is of the human IgG1 or IgG2Δa subclass. 
     
     
         12 . A pharmaceutical composition comprising the antibody of  claim 4 . 
     
     
         13 . A cell line that recombinantly produces the antibody of  claim 4 . 
     
     
         14 . A nucleic acid encoding the antibody of  claim 4 . 
     
     
         15 . A method for treating and/or preventing an autoimmune disorder in an individual, the method comprising administering a therapeutically effective amount of an antagonist IL-7R antibody to an individual suffering from or at risk for an autoimmune disorder, thereby ameliorating and/or preventing one or more symptoms of the autoimmune disorder, wherein the autoimmune disorder is selected from the group consisting of type 1 diabetes, rheumatoid arthritis, lupus and multiple sclerosis. 
     
     
         16 . The method of  claim 15 , wherein administration of the antagonist IL-7R antibody results in reduced naïve and activated T cell populations in the individual compared to before administration. 
     
     
         17 . The method of  claim 16 , wherein the reduced T cell populations in the individual comprise T H 1 and/or T H 17 cells. 
     
     
         18 . A method of treating and/or preventing type 2 diabetes in an individual, the method comprising administering a therapeutically effective amount of an IL-7R antagonist to an individual suffering from or at risk for type 2 diabetes, thereby ameliorating and/or preventing one or more symptoms of type 2 diabetes. 
     
     
         19 . The method of  claim 18 , wherein the IL-7R antagonist is an antagonist IL-7R antibody. 
     
     
         20 . A method for treating and/or preventing graft-versus-host disease (GVHD) in an individual, comprising administering a therapeutically effective amount of an antagonist IL-7R antibody to an individual suffering from GVHD, thereby ameliorating one or more symptoms of GVHD.