Binding members for interleukin-4 receptor alpha (IL-4Ra) - 173

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 - 19 . (canceled) 
     
     
         20 . A method of treating a disorder associated with aberrant IL-4Rα expression and/or IL-4Rα activity in an individual, comprising administering a therapeutically effective amount of an isolated antibody or fragment thereof that specifically binds human interleukin-4 receptor alpha (hIL-4Rα), wherein the isolated antibody or fragment thereof comprises 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. 
 
     
     
         21 . The method according to  claim 20 , wherein the disorder is selected from the group consisting of allergy, asthma, bronchitis, COPD, inflammatory bowel disease, fibrotic conditions, allergy, transplant rejection, delayed-type hypersensitivity or contact hypersensitivity reactions. 
     
     
         22 . The method according to  claim 20 , wherein the disorder is asthma. 
     
     
         23 . The method according to  claim 20 , wherein the isolated antibody or fragment thereof is an IgG1, IgG2 or IgG4 molecule. 
     
     
         24 . The method according to  claim 20  wherein the amino acid substitutions comprise one or more substitutions as shown in  FIGS. 3 and 4 . 
     
     
         25 . The method according to  claim 20  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. 
 
     
     
         26 . The method according to  claim 20  wherein the antibody or fragment thereof further 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. 
 
     
     
         27 . A method of treating a disorder associated with aberrant IL-4Rα expression and/or IL-4Rα activity in an individual, comprising administering a therapeutically effective amount of an isolated antibody or fragment thereof that specifically binds 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. 
 
     
     
         28 . The method according to  claim 20  or  27  wherein the antibody or fragment thereof comprises 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. 
     
     
         29 . The method according to  claim 27  wherein the isolated antibody or fragment thereof is an IgG1, IgG2 or IgG4 molecule. 
     
     
         30 . A method of treating a disorder associated with aberrant IL-4Rα expression and/or IL-4Rα activity in an individual, comprising administering a therapeutically effective amount of an isolated antibody or fragment thereof that specifically binds human interleukin-4 receptor alpha (hIL-4Rα), wherein the isolated antibody or fragment thereof comprises a VH and a VL domain wherein:
 (i) the VH domain has amino acid sequence SEQ ID NO: 192 and the VL domain has amino acid sequence SEQ ID NO: 197; 
 (ii) the VH domain has amino acid sequence SEQ ID NO: 362 and the VL domain has amino acid sequence SEQ ID NO: 367; or 
 (iii) the VH domain has amino acid sequence SEQ ID NO: 232 and the VL domain has amino acid sequence SEQ ID NO: 237; 
 and, wherein the VH domain and VL domain comprise 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. 
 
     
     
         31 . The method according to  claim 30  wherein the amino acid substitutions in the framework regions comprise one or more substitutions as shown in  FIGS. 3 and 4 . 
     
     
         32 . The method according to  claim 30  wherein the antibody molecule is an scFv. 
     
     
         33 . The method according to  claim 30  wherein the antibody molecule comprises an antibody constant region. 
     
     
         34 . The method according to  claim 30  wherein the antibody molecule is an IgG1, IgG2 or IgG4 molecule.