Anti-ifnar1 antibodies with reduced fc ligand affinity

Abstract

The invention provides anti-IFNAR1 antibodies with reduced affinity for Fc receptors and/or ligands and methods of making and using such antibodies.

1 . A pharmaceutical composition comprising a modified IgG class monoclonal antibody specific for IFNAR1 and a pharmaceutical acceptable excipient, wherein said antibody comprises in the Fc region at least one amino acid substitution selected from the group consisting of L234F, L235E, and P331 S, as numbered by the EU index as set forth in Kabat and wherein said antibody exhibits reduced affinity for at least one Fc ligand compared to an unmodified antibody. 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein, said antibody is an IgG1 or IgG4 subclass. 
     
     
         3 . The pharmaceutical composition of  claim 2 , wherein said antibody is an IgG1 class molecule. 
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein said antibody comprises an amino acid substitution of P331S. 
     
     
         5 . The pharmaceutical composition of  claim 3 , wherein said antibody comprises the amino acid substitutions: L234F and L235E. 
     
     
         6 . The pharmaceutical composition of  claim 3 , wherein said antibody comprises the amino acid substitutions: L234F, L235E and P331S. 
     
     
         7 . The pharmaceutical composition of  claim 3  wherein, said antibody is an IgG4 class molecule. 
     
     
         8 - 18 . (canceled) 
     
     
         19 . The pharmaceutical composition of  claim 1 , wherein, said antibody comprises the light chain constant region sequence of Seq ID No: 41. 
     
     
         20 . The pharmaceutical composition of  claim 1 , wherein, said antibody comprises the heavy chain constant region of Seq ID No: 42. 
     
     
         21 . The pharmaceutical composition of  claim 1 , wherein, said antibody comprises the light chain constant region having the amino acid sequence of SEQ ID No:41 and the heavy chain constant region having the amino acid sequence of Seq ID No: 42. 
     
     
         22 . The pharmaceutical composition of  claim 1 , wherein, said antibody comprises a heavy chain amino acid sequence comprising allelic variation, wherein said allelic variation is at least one or more positions selected from the group consisting of 214, 221, 356 and 358 as defined by the EU index numbering system. 
     
     
         23 . The pharmaceutical composition of  claim 1 , wherein, said antibody is selected from the group consisting of: human antibody, humanized antibody, chimeric antibody, intrabody, and a synthetic antibody. 
     
     
         24 - 27 . (canceled) 
     
     
         28 . A transgenic mouse comprising human immunoglobulin heavy and light chain transgenes, wherein the mouse expresses a modified IgG class monoclonal antibody specific for IFNAR1 and a pharmaceutical acceptable excipient, wherein said antibody comprises in the Fc region at least one amino acid substitution selected from the group consisting of L234F, L235E, and P331 S, as numbered by the EU index as set forth in Kabat and wherein said antibody exhibits reduced affinity for at least one Fc ligand compared to an unmodified antibody. 
     
     
         29 . A hybridoma prepared from the mouse of  claim 28  wherein the hybridoma produces said antibody. 
     
     
         30 - 67 . (canceled) 
     
     
         68 . The transgenic mouse of  claim 28 , wherein said antibody comprises: a. a human heavy chain variable region comprising the amino acid sequence of Seq ID No: 38; and b. a human light chain variable region comprising the amino acid sequence of Seq ID No: 40. 
     
     
         69 . The transgenic mouse of  claim 28 , wherein said antibody comprises the light chain constant region sequence of Seq ID No: 41. 
     
     
         70 . The transgenic mouse of  claim 28  wherein said antibody comprises the heavy chain constant region of Seq ID No: 42. 
     
     
         71 . The transgenic mouse of  claim 28  wherein said antibody comprises the light chain constant region having the amino acid sequence of SEQ ID No:41 and the heavy chain constant region having the amino acid sequence of Seq ID No: 42. 
     
     
         72 . The transgenic mouse of any of  claims 68  to  71 , wherein, said antibody comprises a heavy chain amino acid sequence comprising allelic variation, wherein said allelic variation is at least one or more positions selected from the group consisting of 214, 221, 356 and 358 as defined by the EU index numbering system. 
     
     
         73 . The transgenic mouse of  claim 28 , wherein said antibody is selected from the group consisting of: human antibody, humanized antibody, chimeric antibody, intrabody, and a synthetic antibody.