초록 ▼

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 dise

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.

대표청구항 ▼

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

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 VLhB-B13, a light chain variable domain VLhBD4-8, a heavy chain variable domain VHhB-B13 and a heavy chain variable domain VHhBD4-8; wherein: said VLhB-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 VLhBD4-8 comprises CDRs comprising the amino acid sequences HASQNIDVWLS (SEQ ID NO: 14), KASNLHTG (SEQ ID NO: 15), and QQAHSYPFT (SEQ ID NO: 16),said VHhB-B13 comprises CDRs comprising the amino acid sequences GFSLTDSSIN (SEQ ID NO: 11), DGRID (SEQ ID NO: 12), and DGYFPYAMDF (SEQ ID NO: 13), andsaid VHhBD4-8 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 VLhB-B13 comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:1,said VLhBD4-8 comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:3,said VHhB-B13 comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:2, andsaid VHhBD4-8 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)-VLhB-B13-linker-VLhBD4-8-CL-carboxy terminus (C) and the heavy chains comprise the structure N-VHhB-B13-linker-VHhBD4-8-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 VLhB-B13 comprises the amino acid sequence of SEQ ID NO:1,said VLhBD4-8 comprises the amino acid sequence of SEQ ID NO:3,said VHhB-B13 comprises the amino acid sequence of SEQ ID NO:2, andsaid VHhBD4-8 comprises the amino acid sequence of SEQ ID NO:4. 5. The bispecific antibody or bispecific antibody fragment thereof of claim 2, wherein said VLhB-B13 comprises the amino acid sequence of SEQ ID NO:1,said VLhBD4-8 comprises the amino acid sequence of SEQ ID NO:3,said VHhB-B13 comprises the amino acid sequence of SEQ ID NO:2, andsaid VHhBD4-8 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-VLhBD4-8-linker-VLhB-B13-CL-C and the heavy chains comprise the structure N-VHhBD4-8-linker-VHhB-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 VLhBD4-8 comprises the amino acid sequence of SEQ ID NO:3,said VLhB-B13 comprises the amino acid sequence of SEQ ID NO:1,said VHhBD4-8 comprises the amino acid sequence of SEQ ID NO:4, andsaid VHhB-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 VLhBD4-8 comprises the amino acid sequence of SEQ ID NO:3,said VLhB-B13 comprises the amino acid sequence of SEQ ID NO:1,said VHhBD4-8 comprises the amino acid sequence of SEQ ID NO:5, andsaid VHhB-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-VLhB-B13-L1-VLhBD4-8-CL-C and the heavy chains comprise the structure N—VHhB-B13-L2-VHhBD4-8-CH1-C; wherein L1 and L2 are amino acid linkers. 17. The bispecific antibody or bispecific antibody fragment thereof of claim 16, wherein said VLhB-B13 comprises the amino acid sequence of SEQ ID NO:1,said VLhBD4-8 comprises the amino acid sequence of SEQ ID NO:3,said VHhB-B13 comprises the amino acid sequence of SEQ ID NO:2, andsaid VHhBD4-8 comprises the amino acid sequence of SEQ ID NO:4. 18. The bispecific antibody or bispecific antibody fragment thereof of claim 16, wherein said VLhB-B13 comprises the amino acid sequence of SEQ ID NO:1,said VLhBD4-8 comprises the amino acid sequence of SEQ ID NO:3,said VHhB-B13 comprises the amino acid sequence of SEQ ID NO:2, andsaid VHhBD4-8 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-VLhBD4-8-L1-VLhB-B13-CL-C and the heavy chains comprise the structure N-VHhBD4-8-L2-VHhB-B13-CH1-C. 24. The bispecific antibody or bispecific antibody fragment thereof of claim 23, wherein said VLhBD4-8 comprises the amino acid sequence of SEQ ID NO:3,said VLhB-B13 comprises the amino acid sequence of SEQ ID NO:1,said VHhBD4-8 comprises the amino acid sequence of SEQ ID NO:4, andsaid VHhB-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 VLhBD4-8 comprises the amino acid sequence of SEQ ID NO:3,said VLhB-B13 comprises the amino acid sequence of SEQ ID NO:1,said VHhBD4-8 comprises the amino acid sequence of SEQ ID NO:5, andsaid VHhB-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; andwherein:(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); andwherein:(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.