Treatment of Inflammatory Bowel Disease with IFN-Gamma Inhibitors

Abstract

The invention concerns a method for the prevention or treatment of inflammatory bowel disease by administering an interferon-γ inhibitor. The invention further concerns pharmaceutical compositions and bispecific molecules useful in such method.

1 - 29 . (canceled)  
   
   
       30 . An isolated bispecific molecule comprising a first binding domain connected to a second binding domain, wherein the first binding domain comprises an IFN-γ inhibitor comprising an anti-IFN-γ antibody, and the second binding domain comprising an IFN-γ inhibitor selected from the group consisting of an IFN-γ receptor, an extracellular domain of an IFN-γ receptor capable of binding IFN-γ, an IFN-γ receptor variant sequence capable of binding IFN-γ, an anti-IFN-γ receptor antibody, and anti-IFN-γ antibody sequence.  
   
   
       31 . The isolated bispecific molecule or  claim 30 , wherein the second binding domain comprises an IFN-γ receptor sequence.  
   
   
       32 . The isolated bispecific molecule of  claim 31 , wherein the second binding domain comprises an extracellular domain of an IFN-γ receptor sequence capable of binding IFN-γ.  
   
   
       33 . The isolated bispecific molecule of  claim 30 , wherein the second binding domain comprises an anti-IFN-γ antibody sequence.  
   
   
       34 . The isolated bispecific molecule of  claim 30 , wherein the second binding domain comprises an anti-IFN-γ receptor antibody sequence.  
   
   
       35 . The isolated bispecific molecule of  claim 30 , wherein the second binding domain comprises an IFN-γ receptor variant sequence.  
   
   
       36 . The isolated bispecific molecule of  claim 30 , wherein said first and second binding domains are connected with a linker.  
   
   
       37 . The isolated bispecific molecule of  claim 36 , wherein said linker comprises a polypeptide.  
   
   
       38 . The isolated bispecific molecule of  claim 37 , wherein said polypeptide comprises an immunoglobulin sequence.  
   
   
       39 . The isolated bispecific molecule of  claim 38 , wherein said bispecific molecule is a bispecific immunoadhesin.  
   
   
       40 . The isolated bispecific molecule of  claim 39 , wherein said first binding domain is fused to a first immunoglobulin constant domain sequence, and said second binding domain is fused to a second immunoglobulin constant domain sequence.  
   
   
       41 . The isolated bispecific molecule of  claim 40 , wherein said first binding domain is fused at its C-terminus to the N-terminus of a first immunoglobulin heavy chain constant domain sequence comprising at least a hinge region and the C H 2 and C H 3 domains of an IgG-1, IgG2 or IgG-3 immunoglobulin.  
   
   
       42 . The isolated bispecific molecule of  claim 41 , wherein said second binding domain is fused at its C-terminus to the N-terminus of a second immunoglobulin heavy chain constant domain sequence comprising at least a hinge region and the C H 2 and C H 3 domains of an IgG-1, IgG-2 or IgG-3 immunoglobulin.  
   
   
       43 . The isolated bispecific molecule of  claim 42 , wherein the fusion comprising said first binding domain and said first immunoglobulin heavy chain constant domain sequence is disulfide-linked to the fusion comprising said second binding domain and said second immunoglobulin heavy chain constant domain sequence.  
   
   
       44 . An isolated nucleic acid encoding a bispecific molecule according to  claim 30 .  
   
   
       45 . A replicable expression vector comprising the nucleic acid of  claim 44 .  
   
   
       46 . A host cell comprising a replicable expression vector of  claim 45 .  
   
   
       47 . A process comprising culturing a host cell of  claim 46 .  
   
   
       48 . A composition comprising a bispecific molecule according to  claim 30  in admixture with a carrier.  
   
   
       49 . A method for treatment of ulcerative colitis and Crohn's disease in a patient comprising administering to the patient an effective amount of a bispecific molecule of  claim 30 .  
   
   
       50 . An isolated bispecific molecule comprising a first binding domain connected to a second binding domain, wherein the first binding domain comprises an IFN-γ inhibitor and the second binding domain comprising an IL-1 inhibitor, a TNF-α inhibitor, a CD11a/18 inhibitor, a L-selectin inhibitor, or a VLA-4 inhibitor.  
   
   
       51 . An isolated bispecific molecule of  claim 50 , wherein the second binding domain is an IL-1 inhibitor selected from the group consisting of an IL-1 receptor, an extracellular domain of an IL-1 receptor capable of binding IL-1, an IL-1 receptor variant sequence capable of binding IL-1, an anti-IL-1 receptor antibody, and an anti-IL-1 antibody.  
   
   
       52 . An isolated bispecific molecule of  claim 50 , wherein the second binding domain is a TNF-α inhibitor selected from the group consisting of an anti-TNF-α antibody, an anti-TNF-α receptor antibody, a type 1 or a type 2 TNF-α receptor, and a TNF-α receptor immunoadhesin.  
   
   
       53 . An isolated bispecific molecule of  claim 50 , wherein the second binding domain is a CD11a/18 inhibitor selected from the group consisting of a CD11a/18 receptor, an extracellular domain of a CD11a/18 receptor capable of binding CD11a/18, a CDl la/18 receptor variant sequence capable of binding CD11a/18, an anti-CD11 a/18 receptor antibody, and anti-CD11a/18 antibody.  
   
   
       54 . An isolated bispecific molecule of  claim 50 , wherein the second binding domain is a L-selectin inhibitor selected from the group consisting of a L-selectin receptor, an extracellular domain of a L-selectin receptor capable of binding L-selectin, a L-selectin receptor variant sequence capable of binding L-selectin, an anti-L-selectin receptor antibody, and anti-L-selectin antibody.  
   
   
       55 . An isolated bispecific molecule of  claim 50 , wherein the second binding domain is a VLA-4 inhibitor selected from the group consisting of a VLA-4 receptor, an extracellular domain of a VLA-4 receptor capable of binding VLA-4, a VLA-4 receptor variant sequence capable of binding VLA-4, an anti-VLA-4 receptor antibody, and anti-VLA-4 antibody.  
   
   
       56 . The isolated bispecific molecule of  claim 50 , wherein said first and second binding domains are connected with a linker.  
   
   
       57 . The isolated bispecific molecule of  claim 56 , wherein said linker comprises a polypeptide.  
   
   
       58 . The isolated bispecific molecule of  claim 50 , wherein said polypeptide comprises an immunoglobulin sequence.  
   
   
       59 . The isolated bispecific molecule of  claim 58 , wherein said bispecific molecule is a bispecific immunoadhesin.  
   
   
       60 . An isolated nucleic acid encoding a bispecific molecule according to  claim 50 .  
   
   
       61 . A replicable expression vector comprising the nucleic acid of  claim 60 .  
   
   
       62 . A host cell comprising a replicable expression vector of  claim 61 .  
   
   
       63 . A process comprising culturing a host cell of  claim 62 .  
   
   
       64 . A composition comprising a bispecific molecule according to  claim 50  in admixture with a carrier.  
   
   
       65 . A method for treatment of ulcerative colitis and Crohn's disease in a patient comprising administering to the patient an effective amount of a bispecific molecule of  claim 50 .  
   
   
       66 . A method for treatment of ulcerative colitis and Crohn's disease in a patient comprising administering to the patient an effective amount of an interferon-gamma (IFN-γ) inhibitor selected from the group consisting of an IFN-γ receptor, an anti-IFN-γ antibody, an anti-IFN-γ receptor antibody, and an IFN-γ variant, wherein said IFN-γ variant is a variant of human IFN-γ that retains the receptor binding domain and which-inhibits the binding of native IFN-γ to its native receptor.  
   
   
       67 . A method for treating ulcerative colitis and Crohn's disease in a patient comprising administering to the patient an effective amount of (a) interferon-gamma (IFN-γ), an anti-IFN-γ receptor antibody, or an IFN-γ variant, wherein said IFN-γ variant is a variant of human IFN-γ that retains the receptor binding domain and inhibits the binding of native IFN-γ to its native receptor, and (b) IL-1 inhibitor, a TNF-α inhibitor, a CD11a/18 inhibitor, a L-selectin inhibitor, or a VLA-4 inhibitor.  
   
   
       68 . The method of  claim 67 , wherein (b) is a TNF-α inhibitor selected from the group consisting of an anti-TNF-α antibody, an anti-TNF-α receptor antibody, a type 1 or a type 2 TNF-α receptor, and a TNF-α receptor immunoadhesin.  
   
   
       69 . The method of  claim 67 , wherein (b) is an IL-1 inhibitor selected from the group consisting of an IL-1 receptor, an extracellular domain of an IL-1 receptor capable of binding IL-1, an IL-1 receptor variant sequence capable of binding IL-1, an anti-IL-1 receptor antibody, and an anti-IL-1 antibody.  
   
   
       70 . The method of  claim 67 , wherein (b) is a CD11a/18 inhibitor selected from the group consisting of a CD11a/18 receptor, an extracellular domain of a CD11a/18 receptor capable of binding CD11a/18, a CD11a/18 receptor variant sequence capable of binding CD11a/18, an anti-CD11a/18 receptor antibody, and anti-CD11a/18 antibody.  
   
   
       71 . The method of  claim 67 , wherein (b) is a L-selectin inhibitor selected from the group consisting of a L-selectin receptor, an extracellular domain of a L-selectin receptor capable of binding L-selectin, a L-selectin receptor variant sequence capable of binding L-selectin, an anti-L-selectin receptor antibody, and anti-L-selectin antibody.  
   
   
       72 . A The method of  claim 67 , wherein (b) is a VLA-4 inhibitor selected from the group consisting of a VLA-4 receptor, an extracellular domain of a VLA-4 receptor capable of binding VLA-4, a VLA-4 receptor variant sequence capable of binding VLA-4, an anti-VLA-4 receptor antibody, and anti-VLA-4 antibody.  
   
   
       73 . The method of  claim 66 , wherein the anti-IFN-γ antibody is a humanized antibody.  
   
   
       74 . The method of  claim 67 , wherein the anti-IFN-γ antibody is a humanized antibody.