NOVEL COMPOSITIONS AND METHODS FOR TREATING IgE-MEDIATED DISORDERS

Abstract

The present invention relates to immunoglobulins that bind IgE and FcγRIIb with high affinity, said compositions being capable of inhibiting cells that express membrane-anchored IgE. Such compositions are useful for treating IgE-mediated disorders, including allergies and asthma.

We claim: 
     
         1 . A method of inhibiting an IgE+ FcγRIIb+ cell comprising contacting the cell with an coengagement molecule, wherein said coengagement molecule binds FcγRIIb with a Kd of less than about 100 nM, and wherein said coengagement molecule coengages IgE and FcγRIIb on the cell's surface. 
     
     
         2 . The method of  claim 1 , wherein said coengagement molecule is an antibody with specificity for IgE. 
     
     
         3 . The method of  claim 1 , wherein the coengagement molecule is a bispecific antibody comprising a first Fv region and a second Fv region, wherein said first Fv region binds IgE and said second Fv region binds FcγRIIb with a Kd of less than about 100 nM. 
     
     
         4 . The method of  claim 1 , wherein said coengagement molecule is an Fc fusion comprising an Fc region, wherein said Fc region binds FcγRIIb with a Kd of less than about 100 nM. 
     
     
         5 . The method of  claim 1 , wherein the cell is a B cell. 
     
     
         6 . A coengagement molecule having specificity for IgE, wherein said coengagement molecule comprises an Fc variant of a parent Fc polypeptide, wherein said Fc variant has an enhanced binding affinity to FcγRIIb relative to the parent Fc polypeptide. 
     
     
         7 . The coengagement molecule of  claim 6 , wherein said Fc variant comprises at least one amino acid modification in the Fc region compared to the parent Fc polypeptide, wherein said modification is selected from the group consisting of 234, 235, 236, 237, 239, 265, 266, 267, 268, 298, 325, 326, 327, 328, 329, 330, 331, and 332, wherein numbering is according to the EU index. 
     
     
         8 . The coengagement molecule of  claim 6 , wherein said modification is a substitution selected from the group consisting of L235Y, G236D, S239D, V266M, S267E, H268D, H268E, L328F, L328W, and L328Y 267D and 267E. 
     
     
         9 . The coengagement molecule of  claim 8 , wherein said modification is a substitution selected from the group consisting of 267D and 267E. 
     
     
         10 . The coengagement molecule of  claim 9 , further comprising a substitution selected from the group consisting of 328F, 325D, 325Y, 239D, 332E, 268D, 268E, 236D, 236N, 328W, 328Y, 234D, 234E, 234W, 237D, 237N, 327D, 327E, 235F, 235R, 239E, and 266M, wherein numbering is according to the EU index. 
     
     
         11 . An antibody comprising a variable region and an Fc region, wherein said variable region binds membrane anchored IgE, and wherein said Fc region binds FcγRIIb with a Kd of less than about 100 nM. 
     
     
         12 . The antibody of  claim 11 , wherein the variable region VH domain comprises a CDR1 of SEQ ID NO:2, a CDR2 of SEQ ID NO:3 and a CDR3 of SEQ ID NO:4 or a CDR1 of SEQ ID NO:18, a CDR2 of SEQ ID NO:19 and a CDR3 of SEQ ID NO:20. 
     
     
         13 . The antibody of  claim 11 , wherein the variable region VL domain comprises a CDR1 of SEQ ID NO:6, a CDR2 of SEQ ID NO:7 and a CDR3 of SEQ ID NO:8 or a CDR1 of SEQ ID NO:22, a CDR2 of SEQ ID NO:23 and a CDR3 of SEQ ID NO:24.