Chimeric and humanised monoclonal antibodies against interleukin-13

Abstract

The present invention concerns immunoglobulins, particularly antibodies which specifically bind human Interleukin 13 (hIL-13). Antibodies of the invention may be used in the treatment of a variety of diseases or disorders responsive to modulation of the interaction between hIL-13 and the human IL-13 receptor. Such diseases include severe asthma, atopic dermatitis, COPD and various fibrotic diseases. Pharmaceutical compositions comprising said antibodies and methods of manufacture are also disclosed.

1 - 73 . (canceled) 
     
     
         74 . A therapeutic antibody or antigen binding fragment thereof which specifically binds the epitope between residues 103 to 107 inclusively of SEQ ID NO:9 and inhibits the interaction between hIL-13 and hIL-13R. 
     
     
         75 . A therapeutic antibody or antigen binding fragment of  claim 74  wherein the binding of the antibody with human IL-13 depends upon the presence of an arginine residue at position 107 of SEQ ID NO:9. 
     
     
         76 . A therapeutic antibody or antigen binding fragment of  claim 75  wherein substitution of the arginine residue at position 107 of SEQ ID NO:9 with an alanine residue leads to a loss of binding between said antibody and human IL-13 compared to the binding between said antibody and antigen binding fragment thereof and SEQ ID NO:9 without said substitution at position 107 of SEQ ID NO:9. 
     
     
         77 . A therapeutic antibody or antigen binding fragment of  claim 74  wherein the antibody is an intact antibody. 
     
     
         78 . A therapeutic antibody  claim 74  wherein the antibody is a humanised or chimaeric antibody. 
     
     
         79 . The antibody of  claim 74  wherein the antibody comprises a human constant region. 
     
     
         80 . The antibody of  claim 79  wherein the antibody comprises a constant region of IgG isotype. 
     
     
         81 . The antibody of  claim 80  wherein the antibody is IgG1 or IgG4. 
     
     
         82 . An antigen binding fragment of  claim 74  wherein the fragment is a Fab, Fab′, F(ab′) 2 , Fv, diabody, triabody, tetrabody, miniantibody, minibody, isolated VH, isolated VL. 
     
     
         83 . An antibody according to  claim 77  comprising a mutated Fc region such that said antibody has reduced ADCC and/or complement activation. 
     
     
         84 . A therapeutic antibody that competitively inhibits the binding of an antibody of  claim 74  to human IL-13. 
     
     
         85 . A therapeutic antibody or antigen binding fragment of  claim 74  that specifically binds human IL-13 and inhibits the interaction between human IL-13 and human IL-13R and has a dissociation constant k off  in the range 1.4×10 −4  to 8.22×10 −5  s −1  as measured by Biacore™. 
     
     
         86 . A recombinant transformed or transfected host cell comprising a first and second vector, said first vector comprising a polynucleotide encoding a heavy chain of an antibody according to  claim 74  and said second vector comprising a polynucleotide encoding a light chain of  claim 74 . 
     
     
         87 . The host cell of  claim 86  wherein the cell is eukaryotic. 
     
     
         88 . The host cell of  claim 87  wherein the cell is mammalian. 
     
     
         89 . The host cell of  claim 88  wherein the cell is CHO or NS0. 
     
     
         90 . A method for the production of a therapeutic antibody of  claim 74  which method comprises the step of culturing a host cell of any one of  claim 86  in a serum-free culture media. 
     
     
         91 . The method of  claim 90  wherein said antibody is secreted by said host cell into said culture media. 
     
     
         92 . The method of  claim 91  wherein said antibody is further purified to at least 95% or greater with respect to said antibody containing culture media. 
     
     
         93 . A pharmaceutical composition comprising a therapeutic antibody or antigen fragment binding thereof of any one of  claim 74  and a pharmaceutically acceptable carrier. 
     
     
         94 . A kit-of-parts comprising the composition of  claim 93  together with instructions for use. 
     
     
         95 . A method of treating a human patient afflicted with asthma which method comprises the step of administering a therapeutically effective amount of therapeutic antibody of  claim 74 . 
     
     
         96 . The method of  claim 95  wherein said patient is afflicted with allergic asthma. 
     
     
         97 . The method of  claim 95  wherein the patient is afflicted with severe asthma. 
     
     
         98 . The method of  claim 95  wherein the patient is afflicted with difficult asthma. 
     
     
         99 . The method of  claim 95  wherein the patient is afflicted with brittle asthma. 
     
     
         100 . The method of  claim 95  wherein the patient is afflicted with nocturnal asthma, premenstrual asthma, steroid resistant asthma, steroid dependent asthma, aspirin induced asthma, adult-onset asthma, paediatric asthma. 
     
     
         101 . A method of treating a human patient afflicted with an asthmatic condition which is refractory to treatment with corticosteroids which method comprises the step of administering to said patient a therapeutically effective amount of the antibody or antigen binding fragment of  claim 74 . 
     
     
         102 . A method of preventing acute asthmatic attacks in a human patient which method comprises the step of administering to said patient a therapeutically effective amount of an antibody of  claim 74 . 
     
     
         103 . A method of reducing the frequency of and/or mitigating the effects of acute asthmatic attacks in a human patient which method comprises the step of administering to said patient a therapeutically effective amount of an antibody of any one of  claim 74 . 
     
     
         104 . A method of treating a human patient afflicted with a disease or disorder selected from the group consisting of atopic dermatitis, allergic rhinitis, Crohn's disease, COPD, fibrotic diseases or disorders such as idiopathic pulmonary fibrosis, progressive systemic sclerosis, hepatic fibrosis, hepatic granulomas, schistosomiasis, leishmaniasis, diseases of cell cycle regulation such as Hodgkins disease, B cell chronic lymphocytic leukaemia; which method comprises administering a therapeutically effective amount of an antibody of  claim 74 . 
     
     
         105 . A method of treating a human patient afflicted with a disease or disorder selected from the group consisting of; Allergic asthma, severe asthma, difficult asthma, brittle asthma, nocturnal asthma, premenstrual asthma, steroid resistant asthma, steroid dependent asthma, aspirin induced asthma, adult-onset asthma, paediatric asthma, atopic dermatitis, allergic rhinitis, Crohn's disease, COPD, fibrotic diseases or disorders such as idiopathic pulmonary fibrosis, progressive systemic sclerosis, hepatic fibrosis, hepatic granulomas, schistosomiasis, leishmaniasis, diseases of cell cycle regulation such as Hodgkins disease, B cell chronic lymphocytic leukaemia; which method comprises administering a therapeutically effective amount of an antibody of  claim 74  and a therapeutically effective amount of an anti-IL-4 monoclonal antibody. 
     
     
         106 . The method of  claim 105  wherein the anti-IL-4 monoclonal antibody is administered simultaneously, sequentially or separately with the antibody of  claim 74 . 
     
     
         107 . The method of  claim 105  wherein the anti-IL-4 antibody is pascolizumab. 
     
     
         108 . A kit-of-parts comprising a first pharmaceutical composition comprising an antibody of  claim 74  and a pharmaceutically acceptable carrier and a second pharmaceutical composition comprising an anti-IL-4 monoclonal antibody such as pascolizumab and a pharmaceutically acceptable carrier optionally together with instructions for use. 
     
     
         109 . A pharmaceutical composition comprising a first antibody of  claim 74  and a second antibody wherein said second antibody is an anti-IL-4 antibody and a pharmaceutically acceptable carrier. 
     
     
         110 . The kit-of-parts of  claim 109  wherein the anti-IL-4 antibody is pascolizumab.