Antibodies that bind IL-4 and/or IL-13 and their uses

1. A bispecific antibody or bispecific antibody fragment thereof that specifically binds IL-13 and IL-4, wherein the bispecific antibody or bispecific antibody fragment thereof comprises two light chains and two heavy chains, wherein the bispecific antibody or bispecific antibody fragment comprises a light chain variable domain VL hB-B13 , a light chain variable domain VL hBD4-8 , a heavy chain variable domain VH hB-B13 and a heavy chain variable domain VH hBD4-8 ; wherein:

said VL hB-B13 comprises CDRs comprising the amino acid sequences RASESVDSYGQSYMH (SEQ ID NO: 8), LASNLES (SEQ ID NO: 9), and QQNAEDSRT (SEQ ID NO: 10);

said VL hBD4-8 comprises CDRs comprising the amino acid sequences HASQNIDVWLS (SEQ ID NO: 14), KASNLHTG (SEQ ID NO: 15), and QQAHSYPFT (SEQ ID NO: 16),

said VH hB-B13 comprises CDRs comprising the amino acid sequences GFSLTDSSIN (SEQ ID NO: 11), DGRID (SEQ ID NO: 12), and DGYFPYAMDF (SEQ ID NO: 13), and

said VH hBD4-8 comprises CDRs comprising a) the amino acid sequences GYSFTSYWIH (SEQ ID NO: 17), IDPSDGETR (SEQ ID NO: 18) and LKEYGNYDSFYFDV (SEQ ID NO: 19) or b) the amino acid sequences GYSFTSYWIH (SEQ ID NO: 17), IDASDGETR (SEQ ID NO: 21), and LKEYGNYDSFYFDV (SEQ ID NO: 19); and wherein:

said VL hB-B13 comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:1,

said VL hBD4-8 comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:3,

said VH hB-B13 comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:2, and

said VH hBD4-8 comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:4 or SEQ ID NO:5.

2. The bispecific antibody or bispecific antibody fragment thereof of claim 1 , wherein the light chains comprise the structure amino terminus (N)-VL hB-B13 -linker-VL hBD4-8 -CL-carboxy terminus (C) and the heavy chains comprise the structure N-VH hB-B13 -linker-VH hBD4-8 -CH1-CH2-CH3-C.

3. The bispecific antibody or bispecific antibody fragment thereof of claim 2 , wherein the linker comprises the amino acid sequence of SEQ ID NO:6.

4. The bispecific antibody or bispecific antibody fragment thereof of claim 2 , wherein

said VL hB-B13 comprises the amino acid sequence of SEQ ID NO:1,

said VL hBD4-8 comprises the amino acid sequence of SEQ ID NO:3,

said VH hB-B13 comprises the amino acid sequence of SEQ ID NO:2, and

said VH hBD4-8 comprises the amino acid sequence of SEQ ID NO:4.

5. The bispecific antibody or bispecific antibody fragment thereof of claim 2 , wherein

said VL hB-B13 comprises the amino acid sequence of SEQ ID NO:1,

said VL hBD4-8 comprises the amino acid sequence of SEQ ID NO:3,

said VH hB-B13 comprises the amino acid sequence of SEQ ID NO:2, and

said VH hBD4-8 comprises the amino acid sequence of SEQ ID NO:5.

6. The bispecific antibody or bispecific antibody fragment thereof of claim 1 , wherein the light chains comprise the structure N-VL hBD4-8 -linker-VL hB-B13 -CL-C and the heavy chains comprise the structure N-VH hBD4-8 -linker-VH hB-B13 -CH1-CH2-CH3-C.

7. The bispecific antibody or bispecific antibody fragment thereof of claim 6 , wherein the linker comprises the amino acid sequence of SEQ ID NO:6.

8. The bispecific antibody or bispecific antibody fragment thereof of claim 6 , wherein

said VL hBD4-8 comprises the amino acid sequence of SEQ ID NO:3,

said VL hB-B13 comprises the amino acid sequence of SEQ ID NO:1,

said VH hBD4-8 comprises the amino acid sequence of SEQ ID NO:4, and

said VH hB-B13 comprises the amino acid sequence of SEQ ID NO:2.

9. The bispecific antibody or bispecific antibody fragment thereof of claim 6 , wherein

said VL hBD4-8 comprises the amino acid sequence of SEQ ID NO:3,

said VL hB-B13 comprises the amino acid sequence of SEQ ID NO:1,

said VH hBD4-8 comprises the amino acid sequence of SEQ ID NO:5, and

said VH hB-B13 comprises the amino acid sequence of SEQ ID NO:2.

10. The bispecific antibody or antibody fragment thereof of claim 1 , wherein the bispecific antibody neutralizes IL-4 and/or IL-13 activity.

11. The bispecific antibody or antibody fragment thereof of claim 1 , wherein the bispecific antibody neutralizes IL-4 and/or IL-13 mediated cell proliferation in TF-1 cells.

12. The bispecific antibody or antibody fragment thereof of claim 1 , wherein the bispecific antibody or antibody fragment thereof is conjugated to a second component.

13. The bispecific antibody or antibody fragment thereof of claim 12 , wherein the second component is a cell-binding agent, a cytotoxic agent, a radioisotope, an enzyme substrate, a fluorophore, a chromophore, an imaging agent or a metal ion.

14. A pharmaceutical composition comprising the bispecific antibody or bispecific antibody fragment thereof of claim 1 and a pharmaceutically acceptable carrier.

15. A kit comprising the bispecific antibody or antibody fragment thereof of claim 1 and a pharmaceutically acceptable carrier.

16. The bispecific antibody or bispecific antibody fragment thereof of claim 1 , wherein the light chains comprise the structure N-VL hB-B13 -L1-VL hBD4-8 -CL-C and the heavy chains comprise the structure N—VH hB-B13 -L2-VH hBD4-8 -CH1-C; wherein L1 and L2 are amino acid linkers.

17. The bispecific antibody or bispecific antibody fragment thereof of claim 16 , wherein

said VL hB-B13 comprises the amino acid sequence of SEQ ID NO:1,

said VL hBD4-8 comprises the amino acid sequence of SEQ ID NO:3,

said VH hB-B13 comprises the amino acid sequence of SEQ ID NO:2, and

said VH hBD4-8 comprises the amino acid sequence of SEQ ID NO:4.

18. The bispecific antibody or bispecific antibody fragment thereof of claim 16 , wherein

said VL hB-B13 comprises the amino acid sequence of SEQ ID NO:1,

said VL hBD4-8 comprises the amino acid sequence of SEQ ID NO:3,

said VH hB-B13 comprises the amino acid sequence of SEQ ID NO:2, and

said VH hBD4-8 comprises the amino acid sequence of SEQ ID NO:5.

19. The bispecific antibody or bispecific antibody fragment thereof of claim 16 that further comprises additional constant region domains.

20. The bispecific antibody or bispecific antibody fragment thereof of claim 19 , wherein the additional constant domains comprise CH2 and CH3.

21. The bispecific antibody or bispecific antibody fragment thereof of claim 16 , wherein L1 and L2 comprise the amino acid sequence of SEQ ID NO:6.

22. The bispecific antibody or bispecific antibody fragment thereof of claim 16 , wherein L1 and/or L2 is absent.

23. The bispecific antibody or bispecific antibody fragment thereof of claim 1 , wherein the light chains comprise the structure N-VL hBD4-8 -L1-VL hB-B13 -CL-C and the heavy chains comprise the structure N-VH hBD4-8 -L2-VH hB-B13 -CH1-C.

24. The bispecific antibody or bispecific antibody fragment thereof of claim 23 , wherein

said VL hBD4-8 comprises the amino acid sequence of SEQ ID NO:3,

said VL hB-B13 comprises the amino acid sequence of SEQ ID NO:1,

said VH hBD4-8 comprises the amino acid sequence of SEQ ID NO:4, and

said VH hB-B13 comprises the amino acid sequence of SEQ ID NO:2.

25. The bispecific antibody or bispecific antibody fragment thereof of claim 23 , wherein

said VL hBD4-8 comprises the amino acid sequence of SEQ ID NO:3,

said VL hB-B13 comprises the amino acid sequence of SEQ ID NO:1,

said VH hBD4-8 comprises the amino acid sequence of SEQ ID NO:5, and

said VH hB-B13 comprises the amino acid sequence of SEQ ID NO:2.

26. The bispecific antibody or bispecific antibody fragment thereof of claim 23 that further comprises additional constant region domains.

27. The bispecific antibody or bispecific antibody fragment thereof of claim 26 , wherein the additional constant domains comprise CH2 and CH3.

28. The bispecific antibody or bispecific antibody fragment thereof of claim 23 , wherein L1 and L2 comprises the amino acid sequence of SEQ ID NO:6.

29. The bispecific antibody or bispecific antibody fragment thereof of claim 23 , wherein L1 and/or L2 is absent.

30. A bispecific antibody or bispecific antibody fragment thereof that specifically binds to IL-13 and IL-4;

wherein the bispecific antibody or bispecific antibody fragment thereof comprises an IgG molecule having two light chains and two heavy chains;

wherein each of the light chains is elongated at its N-terminus by an additional variable light chain domain, and each of the heavy chains is elongated at its N-terminus by an additional variable heavy chain domain; and

wherein:

(a) the light chains comprise the amino acid sequence of SEQ ID NO: 3, the additional variable light chain domain comprises the amino acid sequence of SEQ ID NO: 1, the heavy chains comprise the amino acid sequence of SEQ ID NO: 4, and the additional variable heavy chain domain comprises the amino acid sequence of SEQ ID NO: 2;

(b) the light chains comprise the amino acid sequence of SEQ ID NO: 3, the additional variable light chain domain comprises the amino acid sequence of SEQ ID NO: 1, the heavy chains comprise the amino acid sequence of SEQ ID NO: 5, and the additional variable heavy chain domain comprises the amino acid sequence of SEQ ID NO: 2;

(c) the light chains comprise the amino acid sequence of SEQ ID NO: 1, the additional variable light chain domain comprises the amino acid sequence of SEQ ID NO: 3, the heavy chains comprise the amino acid sequence of SEQ ID NO: 2, and the additional variable heavy chain domain comprises the amino acid sequence of SEQ ID NO: 4;

(d) the light chains comprise the amino acid sequence of SEQ ID NO: 1, the additional variable light chain domain comprises the amino acid sequence of SEQ ID NO: 3, the heavy chains comprise the amino acid sequence of SEQ ID NO: 2, and the additional variable heavy chain domain comprises the amino acid sequence of SEQ ID NO: 5;

(e) the light chains comprise the amino acid sequences HASQNIDVWLS (SEQ ID NO: 14), KASNLHTG (SEQ ID NO: 15), and QQAHSYPFT (SEQ ID NO: 16), the additional variable light chain domain comprises the amino acid sequences RASESVDSYGQSYMH (SEQ ID NO: 8), LASNLES (SEQ ID NO: 9), and QQNAEDSRT (SEQ ID NO: 10), the heavy chains comprise the amino acid sequences GYSFTSYWIH (SEQ ID NO: 17), IDPSDGETR (SEQ ID NO: 18), and LKEYGNYDSFYFDV (SEQ ID NO: 19), and the additional variable heavy chain domain comprises the amino acid sequences GFSLTDSSIN (SEQ ID NO: 11), DGRID (SEQ ID NO: 12), and DGYFPYAMDF (SEQ ID NO: 13);

(f) the light chains comprise the amino acid sequences HASQNIDVWLS (SEQ ID NO: 14), KASNLHTG (SEQ ID NO: 15), and QQAHSYPFT (SEQ ID NO: 16), the additional variable light chain domain comprises the amino acid sequences RASESVDSYGQSYMH (SEQ ID NO: 8), LASNLES (SEQ ID NO: 9), and QQNAEDSRT (SEQ ID NO: 10), the heavy chains comprise the amino acid sequences GYSFTSYWIH (SEQ ID NO: 20), IDASDGETR (SEQ ID NO: 21), and LKEYGNYDSFYFDV (SEQ ID NO: 22), and the additional variable heavy chain domain comprises the amino acid sequences GFSLTDSSIN (SEQ ID NO: 11), DGRID (SEQ ID NO: 12), and DGYFPYAMDF (SEQ ID NO: 13);

(g) the light chains comprise the amino acid sequences RASESVDSYGQSYMH (SEQ ID NO: 8), LASNLES (SEQ ID NO: 9), and QQNAEDSRT (SEQ ID NO: 10), the additional light chain domain comprises the amino acid sequences HASQNIDVWLS (SEQ ID NO: 14), KASNLHTG (SEQ ID NO: 15), and QQAHSYPFT (SEQ ID NO: 16), the heavy chains comprise the amino acid sequences GFSLTDSSIN (SEQ ID NO: 11), DGRID (SEQ ID NO: 12), and DGYFPYAMDF (SEQ ID NO: 13), and the additional variable heavy chain domain comprises the amino acid sequences GYSFTSYWIH (SEQ ID NO: 17), IDPSDGETR (SEQ ID NO: 18), and LKEYGNYDSFYFDV (SEQ ID NO: 19); or

(h) the light chains comprise the amino acid sequences RASESVDSYGQSYMH (SEQ ID NO: 8), LASNLES (SEQ ID NO: 9), and QQNAEDSRT (SEQ ID NO: 10), the additional variable light chain domain comprises the amino acid sequences HASQNIDVWLS (SEQ ID NO: 14), KASNLHTG (SEQ ID NO: 15), and QQAHSYPFT (SEQ ID NO: 16), the heavy chains comprise the amino acid sequences GFSLTDSSIN (SEQ ID NO: 11), DGRID (SEQ ID NO: 12), and DGYFPYAMDF (SEQ ID NO: 13), and the additional variable heavy chain domain comprises the amino acid sequences GYSFTSYWIH (SEQ ID NO: 20), IDASDGETR (SEQ ID NO: 21), and LKEYGNYDSFYFDV (SEQ ID NO: 22).

31. The bispecific antibody or bispecific antibody fragment thereof of claim 30 , wherein the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 3 are linked together with a peptide linker, and the amino acid sequences of SEQ ID NO: 2 and SEQ ID NO: 4 or SEQ ID NO: 5 are linked together with a peptide linker.

32. The bispecific antibody or bispecific antibody fragment thereof of claim 30 , wherein the peptide linker consists of the amino acid sequence of SEQ ID NO: 6.

33. A bispecific antibody or bispecific antibody fragment thereof that specifically binds to IL-13 and IL-4,

wherein the bispecific antibody or bispecific antibody fragment thereof comprises two light chains and two heavy chains;

wherein the light chains comprise an outer variable light chain domain linked to an inner variable light chain domain which is linked to a constant light chain domain (CL), and the heavy chains comprise an outer variable heavy chain domain linked to an inner variable heavy chain domain which is linked to a constant heavy chain domain (CH1); and

wherein:

(a) the outer variable light chain domain comprises the amino acid sequence of SEQ ID NO: 1, the inner variable light chain domain comprises the amino acid sequence of SEQ ID NO: 3, the outer variable heavy chain domain comprises the amino acid sequence of SEQ ID NO: 2, and the inner variable heavy chain domain comprises the amino acid sequence of SEQ ID NO: 4;

(b) the outer variable light chain domain comprises the amino acid sequence of SEQ ID NO: 1, the inner variable light chain domain comprises the amino acid sequence of SEQ ID NO: 3, the outer variable heavy chain domain comprises the amino acid sequence of SEQ ID NO: 2, and the inner variable heavy chain domain comprises the amino acid sequence of SEQ ID NO: 5;

(c) the outer variable light chain domain comprises the amino acid sequence of SEQ ID NO: 3, the inner variable light chain domain comprises the amino acid sequence of SEQ ID NO: 1, the outer variable heavy chain domain comprises the amino acid sequence of SEQ ID NO: 4, and the inner variable heavy chain domain comprises the amino acid sequence of SEQ ID NO: 2;

(d) the outer variable light chain domain comprises the amino acid sequence of SEQ ID NO: 3, the inner variable light chain domain comprises the amino acid sequence of SEQ ID NO: 1, the outer variable heavy chain domain comprises the amino acid sequence of SEQ ID NO: 5, and the inner variable heavy chain domain comprises the amino acid sequence of SEQ ID NO: 2;

(e) the outer variable light chain domain comprises the amino acid sequences RASESVDSYGQSYMH (CDR1; SEQ ID NO: 8), LASNLES (CDR2; SEQ ID NO: 9), and QQNAEDSRT (CDR3; SEQ ID NO: 10), the inner variable light chain domain comprises the amino acid sequences HASQNIDVWLS (CDR1; SEQ ID NO: 14), KASNLHTG (CDR2; SEQ ID NO: 15), and QQAHSYPFT (CDR3; SEQ ID NO: 16), the outer variable heavy chain domain comprises the amino acid sequences GFSLTDSSIN (CDR1; SEQ ID NO: 11), DGRID (CDR2; SEQ ID NO: 12), and DGYFPYAMDF (CDR3; SEQ ID NO: 13), and the inner variable heavy chain domain comprises the amino acid sequences GYSFTSYWIH (CDR1; SEQ ID NO: 17), IDPSDGETR (CDR2; SEQ ID NO: 18), and LKEYGNYDSFYFDV (CDR3; SEQ ID NO: 19);

(f) the outer variable light chain domain comprises the amino acid sequences RASESVDSYGQSYMH (CDR1; SEQ ID NO: 8), LASNLES (CDR2; SEQ ID NO: 9), and QQNAEDSRT (CDR3; SEQ ID NO: 10), the inner variable light chain domain comprises the amino acid sequences HASQNIDVWLS (CDR1; SEQ ID NO: 14), KASNLHTG (CDR2; SEQ ID NO: 15), and QQAHSYPFT (CDR3; SEQ ID NO: 16), the outer variable heavy chain domain comprises the amino acid sequences GFSLTDSSIN (CDR1; SEQ ID NO: 11), DGRID (CDR2; SEQ ID NO: 12), and DGYFPYAMDF (CDR3; SEQ ID NO: 13), and the inner variable heavy chain domain comprises the amino acid sequences GYSFTSYWIH (CDR1; SEQ ID NO: 20), IDASDGETR (CDR2; SEQ ID NO: 21), and LKEYGNYDSFYFDV (CDR3; SEQ ID NO: 22);

(g) the outer variable light chain domain comprises the amino acid sequences HASQNIDVWLS (CDR1; SEQ ID NO: 14), KASNLHTG (CDR2; SEQ ID NO: 15), and QQAHSYPFT (CDR3; SEQ ID NO: 16), the inner variable light chain domain comprises the amino acid sequences RASESVDSYGQSYMH (CDR1; SEQ ID NO: 8), LASNLES (CDR2; SEQ ID NO: 9), and QQNAEDSRT (CDR3; SEQ ID NO: 10), the outer variable heavy chain domain comprises the amino acid sequences GYSFTSYWIH (CDR1; SEQ ID NO: 17), IDPSDGETR (CDR2; SEQ ID NO: 18), and LKEYGNYDSFYFDV (CDR3; SEQ ID NO: 19), and the inner variable heavy chain domain comprises the amino acid sequences GFSLTDSSIN (CDR1; SEQ ID NO: 11), DGRID (CDR2; SEQ ID NO: 12), and DGYFPYAMDF (CDR3; SEQ ID NO: 13); or

(h) the outer variable light chain domain comprises the amino acid sequences HASQNIDVWLS (CDR1; SEQ ID NO: 14), KASNLHTG (CDR2; SEQ ID NO: 15), and QQAHSYPFT (CDR3; SEQ ID NO: 16), the inner variable light chain domain comprises the amino acid sequences RASESVDSYGQSYMH (CDR1; SEQ ID NO: 8), LASNLES (CDR2; SEQ ID NO: 9), and QQNAEDSRT (CDR3; SEQ ID NO: 10), the outer variable heavy chain domain comprises the amino acid sequences GYSFTSYWIH (CDR1; SEQ ID NO: 20), IDASDGETR (CDR2; SEQ ID NO: 21), and LKEYGNYDSFYFDV (CDR3; SEQ ID NO: 22), and the inner variable heavy chain domain comprises the amino acid sequences GFSLTDSSIN (CDR1; SEQ ID NO: 11), DGRID (CDR2; SEQ ID NO: 12), and DGYFPYAMDF (CDR3; SEQ ID NO: 13).

34. The bispecific antibody or bispecific antibody fragment thereof of claim 33 that further comprises additional constant region domains.

35. The bispecific antibody or bispecific antibody fragment thereof of claim 34 , wherein the additional constant region domains are CH2 and CH3.

36. The bispecific antibody or bispecific antibody fragment thereof of claim 33 , wherein a peptide linker links the outer variable light chain domain to the inner variable light chain domain, and a peptide linker links the outer variable heavy chain domain to the inner variable heavy chain domain.

37. The bispecific antibody or bispecific antibody fragment thereof of claim 36 , wherein the peptide linker consists of the amino acid sequence of SEQ ID NO: 6.