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 . Use of an interferon-gamma (IFN-γ) inhibitor in the preparation of a medicament for treatment of inflammatory bowel disease.  
   
   
       2 . Use according to  claim 1  wherein the inflammatory bowel disease is ulcerative colitis.  
   
   
       3 . Use according to  claim 1  wherein the inflammatory bowel disease is Crohn's disease.  
   
   
       4 . Use according to  claim 1  wherein the IFN-γ inhibitor comprises an amino acid sequence from an anti-IFN-γ antibody, an anti-IFN-γ receptor antibody, an IFN-γ receptor or an IFN-γ variant.  
   
   
       5 . Use according to  claim 1  wherein the IFN-γ inhibitor comprises an IFN-γ receptor amino acid sequence capable of binding IFN-γ.  
   
   
       6 . Use according to  claim 5  wherein said IFN-γ receptor amino acid sequence is the extracellular portion of an IFN-γ receptor.  
   
   
       7 . Use according to  claim 6  wherein said IFN-γ receptor amino acid sequence is fused to a stable plasma protein.  
   
   
       8 . Use according to  claim 7  wherein said stable plasma protein is an immunoglobulin.  
   
   
       9 . Use according to  claim 8  wherein said immunoglobulin is of the IgA, IgG, IgE, or IgM class.  
   
   
       10 . Use according to  claim 9  wherein said IFN-γ receptor amino acid sequence is fused to an immunoglobulin constant domain sequence.  
   
   
       11 . Use according to  claim 10  wherein the extracellular portion of the IFN-γ receptor is fused, at its C-terminus, to the N-terminus of an immunoglobulin sequence comprising a heavy chain constant domain.  
   
   
       12 . Use according to  claim 11  wherein said immunoglobutin sequence is composed of the hinge and Fc portion of an IgG heavy chain.  
   
   
       13 . Use according to  claim 12  wherein said IgG is of the IgG-1 or IgG-3 isotype.  
   
   
       14 . Use according to  claim 7  wherein said stable plasma protein is an albumin, a lipoprotein, an apolipoprotein or transferrin.  
   
   
       15 . A bispecific molecule comprising an IFN-γ inhibitor amino acid sequence and a further amino acid sequence capable of binding a target involved in the initiation or development of inflammatory bowel disease.  
   
   
       16 . The bispecific molecule of  claim 15  wherein said IFN-γ inhibitor is 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.  
   
   
       17 . The bispecific molecule of  claim 16  wherein said IFN-γ inhibitor comprises the extracellular portion of an IFN-γ receptor.  
   
   
       18 . The bispecific molecule of  claim 17  wherein said further amino acid sequence is from a polypeptide selected from the group consisting of an IFN-γ inhibitor other than an IFN-γ receptor, an IL-1 inhibitor, a TNF-α inhibitor, a CD11a/18 inhibitor, a CD11b/18 (VLA-4) inhibitor, and an L-selectin inhibitor.  
   
   
       19 . The bispecific molecule of  claim 18  further comprising an immunoglobulin sequence.  
   
   
       20 . The bispecific molecule of  claim 19  comprising a fusion of an IFN-γ inhibitor amino acid sequence to a first immunoglobutin constant domain sequence, and a fusion of a further amino acid sequence capable of binding a target involved in the initiation or development of IBD to a second immunoglobulin constant domain sequence.  
   
   
       21 . The bispecific molecule of  claim 20  wherein each of said IFN-γ inhibitor amino acid sequence and said further amino acid sequence is fused at its C-terminus to the N-terminus of an 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.  
   
   
       22 . The bispecific molecule of  claim 21  wherein said fusions are disulfide-linked.  
   
   
       23 . The bispecific molecule of  claim 22  wherein at least one of said fusions is associated with an immunoglobulin light chain.  
   
   
       24 . A nucleotide sequence encoding the bispecific molecule of  claim 15 .  
   
   
       25 . A replicable expression vector containing and capable of expressing, in a suitable host cell, the nucleotide sequence of  claim 24 .  
   
   
       26 . A host cell transformed with the vector of  claim 25 .  
   
   
       27 . A process comprising culturing the host cell of  claim 26  so as to express the encoded bispecific molecule.  
   
   
       28 . The process of  claim 27  further comprising recovering the bispecific molecule from the host cell culture.  
   
   
       29 . A pharmaceutical composition comprising a bispecific molecule of  claim 15  in an amount capable of inhibiting IFN-γ biological activity, in admixture with a pharmaceutically acceptable carrier.