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 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 four polypeptide chains that form four antigen binding sites;
wherein two polypeptide chains have a structure represented by the formula:
V L1 -L 1 -V L2 -C L [I]
and two polypeptide chains have a structure represented by the formula:
V H1 -L 2 -V H2 -C H1 [II]
wherein:
V L1 is a first immunoglobulin light chain variable domain;
V L2 is a second immunoglobulin light chain variable domain;
V H1 is a first immunoglobulin heavy chain variable domain;
V H2 is a second immunoglobulin heavy chain variable domain;
C L is an immunoglobulin light chain constant domain;
C H1 is the immunoglobulin C H1 heavy chain constant domain;
L 1 and L 2 are amino acid linkers; and
wherein:
(a) V L1 comprises the amino acid sequence of SEQ ID NO: 1, V L2 comprises the amino acid sequence of SEQ ID NO: 3, V H1 comprises the amino acid sequence of SEQ ID NO: 2, and V H2 comprises the amino acid sequence of SEQ ID NO: 4;
(b) V L1 comprises the amino acid sequence of SEQ ID NO: 1, V L2 comprises the amino acid sequence of SEQ ID NO: 3, V H1 comprises the amino acid sequence of SEQ ID NO: 2, and V H2 comprises the amino acid sequence of SEQ ID NO: 5;
(c) V L1 comprises the amino acid sequence of SEQ ID NO: 3, V L2 comprises the amino acid sequence of SEQ ID NO: 1, V H1 comprises the amino acid sequence of SEQ ID NO: 4, and V H2 comprises the amino acid sequence of SEQ ID NO: 2;
(d) V L1 comprises the amino acid sequence of SEQ ID NO: 3, V L2 comprises the amino acid sequence of SEQ ID NO: 1, V H1 comprises the amino acid sequence of SEQ ID NO: 5, and V H2 comprises the amino acid sequence of SEQ ID NO: 2;
(e) V L1 comprises the amino acid sequences RASESVDSYGQSYMH (SEQ ID NO: 8), LASNLES (SEQ ID NO: 9), and QQNAEDSRT (SEQ ID NO: 10), V L2 comprises the amino acid sequences HASQNIDVWLS (SEQ ID NO: 14), KASNLHTG (SEQ ID NO: 15), and QQAHSYPFT (SEQ ID NO: 16), V H1 comprises the amino acid sequences GFSLTDSSIN (SEQ ID NO: 11), DGRID (SEQ ID NO: 12), and DGYFPYAMDF (SEQ ID NO: 13), and V H2 comprises the amino acid sequences GYSFTSYWIH (SEQ ID NO: 17), IDPSDGETR (SEQ ID NO: 18), and LKEYGNYDSFYFDV (SEQ ID NO: 19);
(f) V L1 comprises the amino acid sequences RASESVDSYGQSYMH (SEQ ID NO: 8), LASNLES (SEQ ID NO: 9), and QQNAEDSRT (SEQ ID NO: 10), V L2 comprises the amino acid sequences HASQNIDVWLS (SEQ ID NO: 14), KASNLHTG (SEQ ID NO: 15), and QQAHSYPFT (SEQ ID NO: 16), V H1 comprises the amino acid sequences GFSLTDSSIN (SEQ ID NO: 11), DGRID (SEQ ID NO: 12), and DGYFPYAMDF (SEQ ID NO: 13), and V H2 comprises the amino acid sequences GYSFTSYWIH (SEQ ID NO: 20), IDASDGETR (SEQ ID NO: 21), and LKEYGNYDSFYFDV (SEQ ID NO: 22); or
(g) V L1 comprises the amino acid sequences HASQNIDVWLS (SEQ ID NO: 14), KASNLHTG (SEQ ID NO: 15), and QQAHSYPFT (SEQ ID NO: 16), V L2 comprises the amino acid sequences RASESVDSYGQSYMH (SEQ ID NO: 8), LASNLES (SEQ ID NO: 9), and QQNAEDSRT (SEQ ID NO: 10), V H1 comprises the amino acid sequences GYSFTSYWIH (SEQ ID NO: 17), IDPSDGETR (SEQ ID NO: 18), and LKEYGNYDSFYFDV (SEQ ID NO: 19), and V H2 comprises the amino acid sequences GFSLTDSSIN (SEQ ID NO: 11), DGRID (SEQ ID NO: 12), and DGYFPYAMDF (SEQ ID NO: 13); or
(h) V L1 comprises the amino acid sequences HASQNIDVWLS (SEQ ID NO: 14), KASNLHTG (SEQ ID NO: 15), and QQAHSYPFT (SEQ ID NO: 16), V L2 comprises the amino acid sequences RASESVDSYGQSYMH (SEQ ID NO: 8), LASNLES (SEQ ID NO: 9), and QQNAEDSRT (SEQ ID NO: 10), V H1 comprises the amino acid sequences GYSFTSYWIH (SEQ ID NO: 20), IDASDGETR (SEQ ID NO: 21), and LKEYGNYDSFYFDV (SEQ ID NO: 22), and V H2 comprises the amino acid sequences GFSLTDSSIN (SEQ ID NO: 11), DGRID (SEQ ID NO: 12), and DGYFPYAMDF (SEQ ID NO: 13).
51 . (canceled)
52 . The bispecific antibody or bispecific antibody fragment thereof of claim 50 that further comprises additional constant region domains.
53 . The bispecific antibody or bispecific antibody fragment thereof of claim 52 , wherein the additional constant region domains consist of C H2 and C H3 .
54 . The bispecific antibody or bispecific antibody fragment thereof of claim 50 , wherein L 1 and L 2 consist of the amino acid sequence of SEQ ID NO: 6.
55 . The bispecific antibody or bispecific antibody fragment thereof of claim 50 , wherein either L 1 and/or L 2 are absent.
56 . The bispecific antibody or bispecific antibody fragment thereof of claim 50 that further comprises a label, wherein the label is a radiolabel, fluorophore, chromophore, imaging agent, or metal ion.
57 . The bispecific antibody or bispecific antibody fragment thereof of claim 50 that is further conjugated to an effector molecule.
58 . The bispecific antibody or bispecific antibody fragment thereof of claim 57 , wherein the effector molecule is a heterologous polypeptide, drug, radionucleotide, or toxin.
59 . The bispecific antibody or bispecific antibody fragment thereof of claim 50 , wherein the bispecific antibody or bispecific antibody fragment thereof neutralizes IL-4 and/or IL-13 activity and preferably neutralizes IL-4 or IL-13 mediated cell proliferation in TF-1 cells.
60 . A nucleic acid molecule encoding the bispecific antibody or bispecific antibody fragment thereof of claim 50 .
61 . A vector comprising the nucleic acid molecule of claim 60 .
62 . A host cell comprising the vector of claim 61 .
63 . A pharmaceutical composition comprising the bispecific antibody or bispecific antibody fragment thereof of claim 50 and a pharmaceutically acceptable carrier.
64 . 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 the bispecific antibody or bispecific antibody fragment thereof of claim 50 .
65 . The method of claim 64 , 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.
66 . 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 the bispecific antibody or bispecific antibody fragment thereof of claim 50 .
67 . A method of manufacturing the bispecific antibody or bispecific antibody fragment thereof of claim 50 comprising expressing a nucleic acid molecule encoding the bispecific antibody or bispecific antibody fragment thereof in a suitable host cell.
68 . A kit comprising the bispecific antibody or bispecific antibody fragment thereof of claim 50 and instructions for use.