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 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); or
(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).
51 . (canceled)
52 . The bispecific antibody or bispecific antibody fragment thereof of claim 50 , 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.
53 . (canceled)
54 . The bispecific antibody or bispecific antibody fragment thereof of claim 52 , wherein the peptide linker consists of the amino acid sequence of SEQ ID NO: 6.
55 . 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.
56 . The bispecific antibody or bispecific antibody fragment thereof of claim 50 that is further conjugated to an effector molecule.
57 . The bispecific antibody or bispecific antibody fragment thereof of claim 56 , wherein the effector molecule is a heterologous polypeptide, drug, radionucleotide, or toxin.
58 . 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.
59 . A nucleic acid molecule encoding the bispecific antibody or bispecific antibody fragment thereof of claim 50 .
60 . A vector comprising the nucleic acid molecule of claim 59 .
61 . A host cell comprising the vector of claim 60 .
62 . A pharmaceutical composition comprising the bispecific antibody or bispecific antibody fragment thereof of claim 50 and a pharmaceutically acceptable carrier.
63 . 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 .
64 . The method of claim 63 , 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.
65 . 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 .
66 . 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.
67 . A kit comprising the bispecific antibody or bispecific antibody fragment thereof of claim 50 and instructions for use.