ANTIBODIES THAT BIND IL-4 AND/OR IL-13 AND THEIR USES
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 - 49 . (canceled)
50 . A method of treating an IL-4 and/or IL-13 mediated disease 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 a first pair of polypeptides and a second pair of polypeptides;
wherein the first pair of polypeptides comprise 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 the second pair of polypeptides comprise 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);
wherein:
(a) the outer (N-terminal) variable light chain domain and outer (N-terminal) variable heavy chain domain form an outer (N-terminal) antigen-binding site that specifically binds IL-13, and the inner (C-terminal) variable light chain domain and the inner (C-terminal) variable heavy chain domain form an inner (C-terminal) antigen-binding site that specifically binds IL-4; or
(b) the outer (N-terminal) variable light chain domain and outer (N-terminal) variable heavy chain domain form an outer (N-terminal) antigen-binding site that specifically binds IL-4, and the inner (C-terminal) variable light chain domain and the inner (C-terminal) variable heavy chain domain form an inner (C-terminal) antigen-binding site that specifically binds IL-13; and
wherein the bispecific antibody or bispecific antibody fragment thereof competitively inhibits:
(i) the binding of an anti-IL-13 antibody or antibody fragment thereof to IL-13, wherein the anti-IL-13 antibody or antibody fragment thereof comprises a variable light chain domain comprising the amino acid sequence of SEQ ID NO: 1, and a variable heavy chain domain comprising the amino acid sequence of SEQ ID NO: 2;
(ii) the binding of an anti-IL-13 antibody or antibody fragment thereof to IL-13, wherein the anti-IL-13 antibody or antibody fragment thereof comprises the amino acid sequences of RASESVDSYGQSYMH (SEQ ID NO: 8), LASNLES (SEQ ID NO: 9), QQNAEDSRT (SEQ ID NO: 10), GFSLTDSSIN (SEQ ID NO: 11), DGRID (SEQ ID NO: 12), and DGYFPYAMDF (SEQ ID NO: 13);
(iii) the binding of an anti-IL-4 antibody or antibody fragment thereof to IL-4, wherein the anti-IL-4 antibody or antibody fragment thereof comprises a variable light chain domain comprising the amino acid sequence of SEQ ID NO: 3, and a variable heavy chain domain comprising the amino acid sequence of SEQ ID NO: 4;
(iv) the binding of an anti-IL-4 antibody or antibody fragment thereof to IL-4, wherein the anti-IL-4 antibody or antibody fragment thereof comprises a variable light chain domain comprising the amino acid sequence of SEQ ID NO: 3, and a variable heavy chain domain comprising the amino acid sequence of SEQ ID NO: 5;
(v) the binding of an anti-IL-4 antibody or antibody fragment thereof to IL-4, wherein the anti-IL-4 antibody or antibody fragment thereof comprises the amino acid sequences of HASQNIDVWLS (SEQ ID NO: 14), KASNLHTG (SEQ ID NO: 15), QQAHSYPFT (SEQ ID NO: 16), GYSFTSYWIH (SEQ ID NO: 17), IDPSDGETR (SEQ ID NO: 18) and LKEYGNYDSFYFDV (SEQ ID NO: 19);
(vi) the binding of an anti-IL-4 antibody or antibody fragment thereof to IL-4, wherein the anti-IL-4 antibody or antibody fragment thereof comprises the amino acid sequences of HASQNIDVWLS (SEQ ID NO: 14), KASNLHTG (SEQ ID NO: 15), QQAHSYPFT (SEQ ID NO: 16), GYSFTSYWIH (SEQ ID NO: 20), IDASDGETR (SEQ ID NO: 21), and LKEYGNYDSFYFDV (SEQ ID NO: 22);
(vii) the binding of an anti-IL-13 antibody or antibody fragment thereof to IL-13, wherein the anti-IL-13 antibody or antibody fragment thereof comprises a variable light chain domain comprising the amino acid sequence of SEQ ID NO: 1 and a variable light chain domain comprising the amino acid sequence of SEQ ID NO: 2, and the binding of an anti-IL-4 antibody or antibody fragment thereof to IL-4, wherein the anti-IL-4 antibody or antibody fragment thereof comprises a variable light chain domain comprising the amino acid sequence of SEQ ID NO: 3 and a variable heavy chain domain comprising the amino acid sequence of SEQ ID NO: 4;
(viii) the binding of an anti-IL-13 antibody or antibody fragment thereof to IL-13, wherein the anti-IL-13 antibody or antibody fragment thereof comprises a variable light chain domain comprising the amino acid sequence of SEQ ID NO: 1 and a variable heavy chain domain comprising the amino acid sequence of SEQ ID NO: 2, and the binding of an anti-IL-4 antibody or antibody fragment thereof to IL-4, wherein the anti-IL-4 antibody or antibody fragment thereof comprises a variable light chain domain comprising the amino acid sequence of SEQ ID NO: 3 and a variable heavy chain domain comprising the amino acid sequence of SEQ ID NO: 5;
(ix) the binding of an anti-IL-13 antibody or antibody fragment thereof to IL-13, wherein the anti-IL-13 antibody or antibody fragment thereof comprises the amino acid sequences of RASESVDSYGQSYMH (SEQ ID NO: 8), LASNLES (SEQ ID NO: 9), QQNAEDSRT (SEQ ID NO: 10), GFSLTDSSIN (SEQ ID NO: 11), DGRID (SEQ ID NO: 12), and DGYFPYAMDF (SEQ ID NO: 13), and the binding of an anti-IL-4 antibody or antibody fragment thereof to IL-4, wherein the anti-IL-4 antibody or antibody fragment thereof comprises the amino acid sequences of HASQNIDVWLS (SEQ ID NO: 14), KASNLHTG (SEQ ID NO: 15), QQAHSYPFT (SEQ ID NO: 16 GYSFTSYWIH (SEQ ID NO: 17), IDPSDGETR (SEQ ID NO: 18) and LKEYGNYDSFYFDV (SEQ ID NO: 19); or
(x) the binding of an anti-IL-13 antibody or antibody fragment thereof to IL-13, wherein the anti-IL-13 antibody or antibody fragment thereof comprises the amino acid sequences of RASESVDSYGQSYMH (SEQ ID NO: 8), LASNLES (SEQ ID NO: 9), QQNAEDSRT (SEQ ID NO: 10), GFSLTDSSIN (SEQ ID NO: 11), DGRID (SEQ ID NO: 12), and DGYFPYAMDF (SEQ ID NO: 13), and the binding of an anti-IL-4 antibody or antibody fragment thereof to IL-4, wherein the anti-IL-4 antibody or antibody fragment thereof comprises the amino acid sequences of HASQNIDVWLS (SEQ ID NO: 14), KASNLHTG (SEQ ID NO: 15), QQAHSYPFT (SEQ ID NO: 16 GYSFTSYWIH (SEQ ID NO: 20), IDASDGETR (SEQ ID NO: 21), and LKEYGNYDSFYFDV SE ID NO: 22).
51 . (canceled)
52 . The method of claim 50 , wherein the IL-4 and/or IL-13 mediated disease is an allergic disease, cancer, asthma, a disease associated with abnormal production of IL-4 and/or IL-13, an autoimmune disease, scleroderma, or idiopathic pulmonary fibrosis.
53 . A method of suppressing a TH-2 mediated response 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 a first pair of polypeptides and a second pair of polypeptides;
wherein the first pair of polypeptides comprise 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 the second pair of polypeptides comprise 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);
wherein:
(a) the outer (N-terminal) variable light chain domain and outer (N-terminal) variable heavy chain domain form an outer (N-terminal) antigen-binding site that specifically binds IL-13, and the inner (C-terminal) variable light chain domain and the inner (C-terminal) variable heavy chain domain form an inner (C-terminal) antigen-binding site that specifically binds IL-4; or
(b) the outer (N-terminal) variable light chain domain and outer (N-terminal) variable heavy chain domain form an outer (N-terminal) antigen-binding site that specifically binds IL-4, and the inner (C-terminal) variable light chain domain and the inner (C-terminal) variable heavy chain domain form an inner (C-terminal) antigen-binding site that specifically binds IL-13; and wherein the bispecific antibody or bispecific antibody fragment thereof competitively inhibits:
(i) the binding of an anti-IL-13 antibody or antibody fragment thereof to IL-13, wherein the anti-IL-13 antibody or antibody fragment thereof comprises a variable light chain domain comprising the amino acid sequence of SEQ ID NO: 1, and a variable heavy chain domain comprising the amino acid sequence of SEQ ID NO: 2;
(ii) the binding of an anti-IL-13 antibody or antibody fragment thereof to IL-13, wherein the anti-IL-13 antibody or antibody fragment thereof comprises the amino acid sequences of RASESVDSYGQSYMH (SEQ ID NO: 8), LASNLES (SEQ ID NO: 9), QQNAEDSRT (SEQ ID NO: 10), GFSLTDSSIN (SEQ ID NO: 11), DGRID (SEQ ID NO: 12), and DGYFPYAMDF (SEQ ID NO: 13);
(iii) the binding of an anti-IL-4 antibody or antibody fragment thereof to IL-4, wherein the anti-IL-4 antibody or antibody fragment thereof comprises a variable light chain domain comprising the amino acid sequence of SEQ ID NO: 3, and a variable heavy chain domain comprising the amino acid sequence of SEQ ID NO: 4;
(iv) the binding of an anti-IL-4 antibody or antibody fragment thereof to IL-4, wherein the anti-IL-4 antibody or antibody fragment thereof comprises a variable light chain domain comprising the amino acid sequence of SEQ ID NO: 3, and a variable heavy chain domain comprising the amino acid sequence of SEQ ID NO: 5;
(v) the binding of an anti-IL-4 antibody or antibody fragment thereof to IL-4, wherein the anti-IL-4 antibody or antibody fragment thereof comprises the amino acid sequences of HASQNIDVWLS (SEQ ID NO: 14), KASNLHTG (SEQ ID NO: 15), QQAHSYPFT (SEQ ID NO: 16), GYSFTSYWIH (SEQ ID NO: 17), IDPSDGETR (SEQ ID NO: 18) and LKEYGNYDSFYFDV (SEQ ID NO: 19);
(vi) the binding of an anti-IL-4 antibody or antibody fragment thereof to IL-4, wherein the anti-IL-4 antibody or antibody fragment thereof comprises the amino acid sequences of HASQNIDVWLS (SEQ ID NO: 14), KASNLHTG (SEQ ID NO: 15), QQAHSYPFT (SEQ ID NO: 16), GYSFTSYWIH (SEQ ID NO: 20), IDASDGETR (SEQ ID NO: 21), and LKEYGNYDSFYFDV (SEQ ID NO: 22);
(vii) the binding of an anti-IL-13 antibody or antibody fragment thereof to IL-13, wherein the anti-IL-13 antibody or antibody fragment thereof comprises a variable light chain domain comprising the amino acid sequence of SEQ ID NO: 1 and a variable heavy chain domain comprising the amino acid sequence of SEQ ID NO: 2, and the binding of an anti-IL-4 antibody or antibody fragment thereof to IL-4, wherein the anti-IL-4 antibody or antibody fragment thereof comprises a variable light chain domain comprising the amino acid sequence of SEQ ID NO: 3 and a variable heavy chain domain comprising the amino acid sequence of SEQ ID NO: 4;
(viii) the binding of an anti-IL-13 antibody or antibody fragment thereof to IL-13, wherein the anti-IL-13 antibody or antibody fragment thereof comprises a variable light chain domain comprising the amino acid sequence of SEQ ID NO: 1 and a variable heavy chain domain comprising the amino acid sequence of SEQ ID NO: 2, and the binding of an anti-IL-4 antibody or antibody fragment thereof to IL-4, wherein the anti-IL-4 antibody or antibody fragment thereof comprises a variable light chain domain comprising the amino acid sequence of SEQ ID NO: 3 and a variable heavy chain domain comprising the amino acid sequence of SEQ ID NO: 5;
(ix) the binding of an anti-IL-13 antibody or antibody fragment thereof to IL-13, wherein the anti-IL-13 antibody or antibody fragment thereof comprises the amino acid sequences of RASESVDSYGQSYMH (SEQ ID NO: 8), LASNLES (SEQ ID NO: 9), QQNAEDSRT (SEQ ID NO: 10), GFSLTDSSIN (SEQ ID NO: 11), DGRID (SEQ ID NO: 12), and DGYFPYAMDF (SEQ ID NO: 13), and the binding of an anti-IL-4 antibody or antibody fragment thereof to IL-4, wherein the anti-IL-4 antibody or antibody fragment thereof comprises the amino acid sequences of HASQNIDVWLS (SEQ ID NO: 14), KASNLHTG (SEQ ID NO: 15), QQAHSYPFT (SEQ ID NO: 16 GYSFTSYWIH (SEQ ID NO: 17), IDPSDGETR (SEQ ID NO: 18) and LKEYGNYDSFYFDV (SEQ ID NO: 19); or
(x) the binding of an anti-IL-13 antibody or antibody fragment thereof to IL-13, wherein the anti-IL-13 antibody or antibody fragment thereof comprises the amino acid sequences of RASESVDSYGQSYMH (SEQ ID NO: 8), LASNLES (SEQ ID NO: 9), QQNAEDSRT (SEQ ID NO: 10), GFSLTDSSIN (SEQ ID NO: 11), DGRID (SEQ ID NO: 12), and DGYFPYAMDF (SEQ ID NO: 13), and the binding of an anti-IL-4 antibody or antibody fragment thereof to IL-4, wherein the anti-IL-4 antibody or antibody fragment thereof comprises the amino acid sequences of HASQNIDVWLS (SEQ ID NO: 14), KASNLHTG (SEQ ID NO: 15), QQAHSYPFT (SEQ ID NO: 16 GYSFTSYWIH (SEQ ID NO: 20), IDASDGETR (SEQ ID NO: 21), and LKEYGNYDSFYFDV SE ID NO: 22).
54 . (canceled)