Binding members for interleukin-4 receptor alpha (IL-4Rα)-173
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 antibody or fragment thereof that specifically binds 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.
2. The antibody or fragment thereof according to claim 1 , wherein the amino acid substitutions comprise one or more substitutions as shown in FIGS. 3 and 4 .
3. The antibody or fragment thereof according to claim 1 , 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.
4. The antibody or fragment thereof according to claim 1 , 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.
5. The antibody or fragment thereof according to claim 4 , wherein the amino acid substitutions in the framework regions comprise one or more substitutions as shown in FIGS. 3 and 4 .
6. 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.
7. The antibody or fragment thereof according to claims 1 or 6 , 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.
8. The antibody or fragment thereof according to claim 7 , wherein the antibody molecule is an scFv.
9. The antibody or fragment thereof according to claim 7 , wherein the antibody molecule comprises an antibody constant region.
10. The antibody or fragment thereof according to claim 7 , wherein the antibody molecule is an IgG1, IgG2 or IgG4 molecule.
11. A composition comprising an isolated antibody or fragment thereof according to claims 1 or 6 , and a pharmaceutically acceptable excipient.
12. An isolated nucleic acid molecule comprising a nucleotide sequence encoding the antibody or fragment thereof according to claims 1 or 6 .
13. A host cell in vitro transformed with the nucleic acid according to claim 12 .
14. An isolated antibody or fragment thereof for human interleukin-4 receptor alpha (hIL-4Rα), having at least 73% amino acid sequence identity with the 6xCDR composite score of any of Antibodies 1-42.
15. An isolated antibody or fragment thereof that specifically binds human interleukin-4 receptor alpha (hIL-4Rα), comprising a VH domain wherein:
(i) the VH domain has amino acid sequence SEQ ID NO: 192;
(ii) the VH domain has amino acid sequence SEQ ID NO: 362; or
(iii) the VH domain has amino acid sequence SEQ ID NO: 232;
and, wherein the VH domain 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; or
105, 108, 113 in HFW4.
16. The antibody or fragment thereof according to claim 15 , wherein the amino acid substitutions in the framework regions comprise one or more substitutions as shown in FIGS. 3 and 4 .
17. The antibody or fragment thereof according to claim 15 , wherein the antibody molecule is an scFv.
18. The antibody or fragment thereof according to claim 15 , wherein the antibody molecule comprises an antibody constant region.
19. The antibody or fragment thereof according to claim 15 , wherein the antibody molecule is an IgG1, IgG2 or IgG4 molecule.
20. A composition comprising an isolated antibody or fragment thereof according to claim 15 , and a pharmaceutically acceptable excipient.
21. An isolated nucleic acid molecule comprising a nucleotide sequence encoding the antibody or fragment thereof according to claim 15 .
22. A host cell in vitro transformed with the nucleic acid according to claim 21 .
23. An isolated antibody or fragment thereof that specifically binds human interleukin-4 receptor alpha (hIL-4Rα), comprising a VL domain wherein:
(i) the VL domain has amino acid sequence SEQ ID NO: 197;
(ii) the VL domain has amino acid sequence SEQ ID NO: 367; or
(iii) the VL domain has amino acid sequence SEQ ID NO: 237;
and, wherein the VL domain comprises one or more amino acid substitutions at the following residues within the framework regions, using the standard numbering of Kabat:
1, 2, 3, 9 in LFW1;
38, 42 in LFW2; or
58, 65, 66, 70, 74, 85, 87 in LFW3.
24. The antibody or fragment thereof according to claim 23 , wherein the amino acid substitutions in the framework regions comprise one or more substitutions as shown in FIGS. 3 and 4 .
25. The antibody or fragment thereof according to claim 23 , wherein the amino acid substitutions in the framework regions comprise one or more substitutions as shown in FIGS. 3 and 4 .
26. The antibody or fragment thereof according to claim 23 , wherein the antibody molecule is an scFv.
27. The antibody or fragment thereof according to claim 23 , wherein the antibody molecule comprises an antibody constant region.
28. The antibody or fragment thereof according to claim 23 , wherein the antibody molecule is an IgG1, IgG2 or IgG4 molecule.
29. A composition comprising an isolated antibody or fragment thereof according to claim 23 , and a pharmaceutically acceptable excipient.
30. An isolated nucleic acid molecule comprising a nucleotide sequence encoding the antibody or fragment thereof according to claim 23 .
31. A host cell in vitro transformed with the nucleic acid according to claim 30 .
32. An isolated antibody or fragment thereof that specifically binds human interleukin-4 receptor alpha (hIL-4Rα), comprising 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.
33. The antibody or fragment thereof according to claim 32 , wherein the amino acid substitutions in the framework regions comprise one or more substitutions as shown in FIGS. 3 and 4 .
34. The antibody or fragment thereof according to claim 32 , wherein the antibody molecule is an scFv.
35. The antibody or fragment thereof according to claim 32 , wherein the antibody molecule comprises an antibody constant region.
36. The antibody or fragment thereof according to claim 32 , wherein the antibody molecule is an IgG1, IgG2 or IgG4 molecule.
37. A composition comprising an isolated antibody or fragment thereof according to claim 32 , and a pharmaceutically acceptable excipient.
38. An isolated nucleic acid molecule comprising a nucleotide sequence encoding the antibody or fragment thereof according to claim 32 .
39. A host cell in vitro transformed with the nucleic acid according to claim 38 .