BINDING MEMBERS OF INTERLEUKIN-4 RECEPTOR ALPHA (IL4-Ra)

Abstract

Binding members, especially antibody molecules, for interleukin (IL)-4 receptor alpha (IL-4Rα), and their therapeutic use e.g., in treating or preventing disorders associated with IL-4Rα, IL-4 and/or IL-13, examples of which are asthma and COPD.

1 . An isolated binding member for human interleukin-4 receptor alpha (hIL-4Rα), which binding member has an IC 50  geomean for inhibition of human IL-4 (hIL-4) induced cell proliferation of less than 50 pM in TF-1 proliferation assay using 18 pM soluble human IL-4 protein and which binding member is also capable of binding to cynomolgus monkey interleukin-4 receptor alpha (cyIL-4Rα). 
     
     
         2 . The binding member according to  claim 1 , wherein the ratio of binding of the binding member when as a scFv to hIL-4Rα and to cyIL-4Rα measured using the receptor-ligand binding assay is at least 6:1. 
     
     
         3 . An isolated binding member capable of binding to at least one amino acid residue selected from position 67, 68, 92 and 93 according to the position in SEQ ID NO: 460, of full length human interleukin-4 receptor alpha (hIL-4Rα). 
     
     
         4 . An isolated binding member for human interleukin-4 receptor alpha (hIL-4Rα), comprising a set of CDRs: HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the set of CDRs has 10 or fewer amino acid substitutions from a reference set of CDRs in which:
 HCDR1 has amino acid sequence SEQ ID NO: 193; 
 HCDR2 has amino acid sequence SEQ ID NO: 194; 
 HCDR3 has amino acid sequence SEQ ID NO: 195; 
 LCDR1 has amino acid sequence SEQ ID NO: 198; 
 LCDR2 has amino acid sequence SEQ ID NO: 199; and 
 LCDR3 has amino acid sequence SEQ ID NO: 200. 
 
     
     
         5 . A binding member according to  claim 4 , wherein the amino acid substitutions comprise one or more substitutions as shown in  FIGS. 3 and 4 . 
     
     
         6 . The binding member according to  claim 4 , wherein the amino acid substitutions comprise an amino acid substitution at one or more of the following residues within the CDRs, using the standard numbering of Kabat:
 53, 57, in HCDR2;   97, 98, 99, 101, 102 in HCDR3;   27, 27A, 27B, 31 in LCDR1;   56 in LCDR2; or 92, 93, 94, 95, 95A 95B, 95C, 96, 97 in LCDR3.   
     
     
         7 . The binding member according to  claim 4 , which in addition comprises one or more amino acid substitutions at the following residues within the framework regions, using the standard numbering of Kabat:
 11, 12 in HFW1;   37, 48 in HFW2;   68, 84, 85 in HFW3;   105, 108, 113 in HFW4;   1, 2, 3, 9 in LFW1;   38, 42 in LFW2; or   58, 65, 66, 70, 74, 85, 87 in LFW3.   
     
     
         8 . A binding member according to  claim 7 , wherein the amino acid substitutions in the framework regions comprise one or more substitutions as shown in  FIGS. 3 and 4 . 
     
     
         9 . An isolated binding member for human interleukin-4 receptor alpha (hIL-4Rα), wherein
 (i) the HCDR1 has amino acid sequence SEQ ID NO: 363; 
 the HCDR2 has amino acid sequence SEQ ID NO: 364; 
 the HCDR3 has amino acid sequence SEQ ID NO: 365; 
 the LCDR1 has amino acid sequence SEQ ID NO: 368; 
 the LCDR2 has amino acid sequence SEQ ID NO: 369; and 
 the LCDR3 has amino acid sequence SEQ ID NO: 370; or 
 (ii) the HCDR1 has amino acid sequence SEQ ID NO: 233; 
 the HCDR2 has amino acid sequence SEQ ID NO: 234; 
 the HCDR3 has amino acid sequence SEQ ID NO: 235; 
 the LCDR1 has amino acid sequence SEQ ID NO: 238; 
 the LCDR2 has amino acid sequence SEQ ID NO: 239; and 
 the LCDR3 has amino acid sequence SEQ ID NO: 240; 
 
     
     
         10 . A binding member according to  claim 1 ,  3 ,  4  or  9 , wherein the binding member is or comprises an antibody molecule comprising an antibody VH domain and an antibody VL domain, wherein the VH domain comprises HCDR1, HCDR2, HCDR3 and a first framework and the VL domain comprises LCDR1, LCDR2, LCDR3 and a second framework. 
     
     
         11 . A binding member according to  claim 10 , wherein the antibody molecule is an scFv. 
     
     
         12 . A binding member according to  claim 10 , wherein the antibody molecule comprises an antibody constant region. 
     
     
         13 . A binding member according to  claim 10 , wherein the antibody molecule is an IgG 1, IgG2 or IgG4 molecule. 
     
     
         14 . A composition comprising an isolated binding member according to  claim 1 ,  3 ,  4  or  9 , and a pharmaceutically acceptable excipient. 
     
     
         15 . A method of treating a disorder associated with aberrant IL-4Rα expression and/or IL-4Rα activity in an individual, comprising administering a binding member according to  claim 1 ,  3 ,  4  or  9  to the individual. 
     
     
         16 . A method according to  claim 15 , wherein the disorder is asthma. 
     
     
         17 . An isolated nucleic acid molecule comprising a nucleotide sequence encoding a binding member according to  claim 1 ,  3 ,  4  or  9 . 
     
     
         18 . A host cell in vitro transformed with the nucleic acid according to  claim 17 . 
     
     
         19 . An isolated binding member for human interleukin-4 receptor alpha (hIL-4Rα), having at least 73% amino acid sequence identity with the 6×CDR composite score of any of Antibodies 1-42.