Fcrn antagonists and methods of use

Abstract

Provided are novel FcRn antagonist compositions comprising a variant Fc region that binds specifically to FcRn with increased affinity and reduced pH dependence relative to the native Fc region. Also provided are FcRn antagonists with enhanced CD16 binding affinity. Also provided are methods of treating antibody-mediated disorders (e.g. autoimmune diseases) using the these FcRn antagonist compositions, nucleic acids encoding the FcRn antagonist compositions, recombinant expression vectors and host cells for making the FcRn antagonist compositions, and pharmaceutical compositions comprising the FcRn antagonist compositions.

1 - 44 . (canceled) 
     
     
         45 . A method of treating immune thrombocytopenia purpura (ITP) in a subject, the method comprising administering to the subject an effective amount of an isolated FcRn antagonist consisting of a variant Fc region, wherein said variant Fc region consists of two Fc domains which form a homodimer, wherein the amino acid sequence of each of the Fc domains consists of SEQ ID NO: 2. 
     
     
         46 . The method of  claim 45 , wherein the Fc domains of the variant Fc region comprise an N-linked glycan having a bisecting GlcNac at EU position 297 of the Fc domains. 
     
     
         47 . The method of  claim 45 , wherein the FcRn antagonist is administered to the subject simultaneously or sequentially with an additional therapeutic agent. 
     
     
         48 . The method of  claim 47 , wherein the additional therapeutic agent is an anti-inflammatory agent. 
     
     
         49 . The method of  claim 47 , wherein the additional therapeutic agent is a leukocyte depleting agent. 
     
     
         50 . The method of  claim 49 , wherein the leukocyte depleting agent is a B-cell depleting agent. 
     
     
         51 . The method of  claim 50 , wherein the B-cell depleting agent is an antibody. 
     
     
         52 . The method of  claim 51 , wherein the antibody specifically binds to a cell surface marker selected from the group consisting of CD10, CD19, CD20, CD21, CD22, CD23, CD24, CD37, CD53, CD70, CD72, CD74, CD75, CD77, CD79a, CD79b, CD80, CD81, CD82, CD83, CD84, CD85, and CD86. 
     
     
         53 . The method of  claim 47 , wherein the additional therapeutic agent is an antibody selected from the group consisting of rituximab, daclizumab, basiliximab, muronomab-CD3, infliximab, adalimumab, omalizumab, efalizumab, natalizumab, tocilizumab, eculizumab, golimumab, canakinumab, ustekinumab, belimumab, and any combination thereof. 
     
     
         54 . A method of treating immune thrombocytopenia purpura (ITP) in a subject, the method comprising administering to the subject an effective amount of an isolated FcRn antagonist consisting of a variant Fc region, wherein said variant Fc region consists of two Fc domains which form a homodimer, wherein the amino acid sequence of each of the Fc domains consists of SEQ ID NO: 3. 
     
     
         55 . The method of  claim 54 , wherein the Fc domains of the variant Fc region comprise an N-linked glycan having a bisecting GlcNac at EU position 297 of the Fc domains. 
     
     
         56 . The method of  claim 54 , wherein the FcRn antagonist is administered to the subject simultaneously or sequentially with an additional therapeutic agent. 
     
     
         57 . The method of  claim 56 , wherein the additional therapeutic agent is an anti-inflammatory agent. 
     
     
         58 . The method of  claim 56 , wherein the additional therapeutic agent is a leukocyte depleting agent. 
     
     
         59 . The method of  claim 58 , wherein the leukocyte depleting agent is a B-cell depleting agent. 
     
     
         60 . The method of  claim 59 , wherein the B-cell depleting agent is an antibody. 
     
     
         61 . The method of  claim 60 , wherein the antibody specifically binds to a cell surface marker selected from the group consisting of CD10, CD19, CD20, CD21, CD22, CD23, CD24, CD37, CD53, CD70, CD72, CD74, CD75, CD77, CD79a, CD79b, CD80, CD81, CD82, CD83, CD84, CD85, and CD86. 
     
     
         62 . The method of  claim 56 , wherein the additional therapeutic agent is an antibody selected from the group consisting of rituximab, daclizumab, basiliximab, muronomab-CD3, infliximab, adalimumab, omalizumab, efalizumab, natalizumab, tocilizumab, eculizumab, golimumab, canakinumab, ustekinumab, belimumab, and any combination thereof.