Antibodies that bind IL-4 and/or IL-13 and their uses
View Patent ↗The present invention relates to novel humanized anti-IL-4 and IL-13 antibodies and fragments thereof and novel bispecific antibodies and fragments thereof that specifically bind to IL-4 and IL-13. The invention also includes uses of the antibodies to treat or prevent IL-4 and/or IL-13 mediated diseases or disorders, including allergic asthma and dermatitis.
1. A method of treating asthma or idiopathic pulmonary fibrosis in a mammal comprising the step of administering to the mammal a therapeutically effective amount of 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 chain polypeptides and two heavy chain polypeptides;
wherein each of the light chain polypeptides comprises an outer (N-terminal) variable light chain domain linked to an inner (C-terminal) variable light chain domain which is linked to a constant light chain domain (CL), and each of the heavy chain polypeptides comprises an outer (N-terminal) variable heavy chain domain linked to an inner (C-terminal) variable heavy chain domain which is linked to a constant heavy chain domain (CH1); and
wherein:
(a) the outer (N-terminal) 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 (C-terminal) 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 (N-terminal) 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 (C-terminal) 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); or
(b) the outer (N-terminal) 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 (C-terminal) 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 (N-terminal) 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 (C-terminal) 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).
2. The method of claim 1 , wherein the outer (N-terminal) 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 (C-terminal) 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 (N-terminal) 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 (C-terminal) 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).
3. The method of claim 1 , wherein the outer (N-terminal) 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 (C-terminal) 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 (N-terminal) 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 (C-terminal) 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).
4. The method of claim 1 , wherein the outer (N-terminal) variable light chain domain comprises an amino acid sequence that has 95% identity to the amino acid sequence of SEQ ID NO: 1, the inner (C-terminal) variable light chain domain comprises an amino acid sequence that has 95% identity to the amino acid sequence of SEQ ID NO: 3, the outer (N-terminal) variable heavy chain domain comprises an amino acid sequence that has 95% identity to the amino acid sequence of SEQ ID NO: 2, and the inner (C-terminal) variable heavy chain domain comprises an amino acid sequence that has 95% identity to the amino acid sequence of SEQ ID NO: 4.
5. The method of claim 1 , wherein the outer (N-terminal) variable light chain domain comprises an amino acid sequence that has 95% identity to the amino acid sequence of SEQ ID NO: 1, the inner (C-terminal) variable light chain domain comprises an amino acid sequence that has 95% identity to the amino acid sequence of SEQ ID NO: 3, the outer (N-terminal) variable heavy chain domain comprises an amino acid sequence that has 95% identity to the amino acid sequence of SEQ ID NO: 2, and the inner (C-terminal) variable heavy chain domain comprises an amino acid sequence that has 95% identity to the amino acid sequence of SEQ ID NO: 5.
6. The method of claim 1 , wherein the outer (N-terminal) variable light chain domain comprises the amino acid sequence of SEQ ID NO: 1, the inner (C-terminal) variable light chain domain comprises the amino acid sequence of SEQ ID NO: 3, the outer (N-terminal) variable heavy chain domain comprises the amino acid sequence of SEQ ID NO: 2, and the inner (C-terminal) variable heavy chain domain comprises the amino acid sequence of SEQ ID NO: 4.
7. The method of claim 1 , wherein the outer (N-terminal) variable light chain domain comprises the amino acid sequence of SEQ ID NO: 1, the inner (C-terminal) variable light chain domain comprises the amino acid sequence of SEQ ID NO: 3, the outer (N-terminal) variable heavy chain domain comprises the amino acid sequence of SEQ ID NO: 2, and the inner (C-terminal) variable heavy chain domain comprises the amino acid sequence of SEQ ID NO: 5.
8. The method of any one of claim 1 , or 4 - 7 , wherein the outer variable light chain and the inner variable light chain are linked by a peptide linker and the outer variable heavy chain and the inner variable heavy chain are linked by a peptide linker.
9. The method of claim 8 , wherein the linker comprises the amino acid sequence of SEQ ID NO:6.
10. The method of claim 1 , wherein the heavy chain polypeptides further comprises CH2 and CH3 domains.
11. The method of claim 1 , wherein the method is for treating asthma.
12. The method of claim 1 , wherein the method is for treating idiopathic pulmonary fibrosis.
13. The method of claim 1 , wherein the mammal is a human.
14. A method of treating asthma or idiopathic pulmonary fibrosis in a mammal comprising the step of administering to the mammal a therapeutically effective amount of 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 chain polypeptides and two heavy chain polypeptides;
wherein each of the light chain polypeptides comprises an outer (N-terminal) variable light chain domain linked to an inner (C-terminal) variable light chain domain which is linked to a constant light chain domain (CL), and each of the heavy chain polypeptides comprises an outer (N-terminal) variable heavy chain domain linked to an inner (C-terminal) variable heavy chain domain which is linked to a constant heavy chain domain (CH1); and
wherein:
(a) the outer (N-terminal) 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 (C-terminal) 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 (N-terminal) 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 (C-terminal) 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
(b) the outer (N-terminal) 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 (C-terminal) 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 (N-terminal) 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 (C-terminal) 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).
15. The method of claim 14 , wherein the outer (N-terminal) 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 (C-terminal) 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 (N-terminal) 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 (C-terminal) 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).
16. The method of claim 14 , wherein the outer (N-terminal) 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 (C-terminal) 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 (N-terminal) 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 (C-terminal) 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).
17. The method of claim 14 , wherein the outer (N-terminal) variable light chain domain comprises an amino acid sequence that has 95% identity to the amino acid sequence of SEQ ID NO: 3, the inner (C-terminal) variable light chain domain comprises an amino acid sequence that has 95% identity to the amino acid sequence of SEQ ID NO: 1, the outer (N-terminal) variable heavy chain domain comprises an amino acid sequence that has 95% identity to the amino acid sequence of SEQ ID NO: 4, and the inner (C-terminal) variable heavy chain domain comprises an amino acid sequence that has 95% identity to the amino acid sequence of SEQ ID NO: 2.
18. The method of claim 14 , the outer (N-terminal) variable light chain domain comprises an amino acid sequence that has 95% identity to the amino acid sequence of SEQ ID NO: 3, the inner (C-terminal) variable light chain domain comprises an amino acid sequence that has 95% identity to the amino acid sequence of SEQ ID NO: 1, the outer (N-terminal) variable heavy chain domain comprises an amino acid sequence that has 95% identity to the amino acid sequence of SEQ ID NO: 5, and the inner (C-terminal) variable heavy chain domain comprises an amino acid sequence that has 95% identity to the amino acid sequence of SEQ ID NO: 2.
19. The method of claim 14 , wherein the outer (N-terminal) variable light chain domain comprises the amino acid sequence of SEQ ID NO: 3, the inner (C-terminal) variable light chain domain comprises the amino acid sequence of SEQ ID NO: 1, the outer (N-terminal) variable heavy chain domain comprises the amino acid sequence of SEQ ID NO: 4, and the inner (C-terminal) variable heavy chain domain comprises the amino acid sequence of SEQ ID NO: 2.
20. The method of claim 14 , wherein the outer (N-terminal) variable light chain domain comprises the amino acid sequence of SEQ ID NO: 3, the inner (C-terminal) variable light chain domain comprises the amino acid sequence of SEQ ID NO: 1, the outer (N-terminal) variable heavy chain domain comprises the amino acid sequence of SEQ ID NO: 5, and the inner (C-terminal) variable heavy chain domain comprises the amino acid sequence of SEQ ID NO: 2.
21. The method of any one of claims 14 - 20 , wherein the outer variable light chain and the inner variable light chain are linked by a peptide linker and the outer variable heavy chain and the inner variable heavy chain are linked by a peptide linker.
22. The method of claim 21 , wherein the linker comprises the amino acid sequence of SEQ ID NO:6.
23. The method of claim 14 , wherein the second pair of polypeptides further comprises CH2 and CH3 domains.
24. The method of claim 14 , wherein the method is for treating asthma.
25. The method of claim 14 , wherein the method is for treating idiopathic pulmonary fibrosis.
26. The method of claim 14 , wherein the mammal is a human.