Compositions and methods for targeting type 1 interferon producing cells

Abstract

The present disclosure provides a method for treating lupus, Sjörgen's syndrome or scleroderma, the method comprising administering to the mammal an immunoglobulin which binds an interleukin 3 receptor α (IL-3Rα) chain and which depletes or at least partly eliminates plasmacytoid dendritic cells (p DCs) and basophils to which it binds.

1 .- 30 . (canceled) 
     
     
         31 . A method of treating lupus in a mammal, the method comprising administering to the mammal an immunoglobulin which binds an interleukin 3 receptor α (IL-3Rα) chain and competitively inhibits the binding of monoclonal antibody 7G3 to IL-3Rα and which depletes or at least partly eliminates plasmacytoid dendritic cells (pDCs) and basophils to which it binds to thereby treat lupus in the mammal, wherein the immunoglobulin is not conjugated to a toxic compound that kills a cell to which the immunoglobulin binds, and wherein the immunoglobulin is capable of inducing an enhanced level of effector function. 
     
     
         32 . The method of  claim 31 , wherein the lupus is systemic lupus erythematosus (SLE) 
     
     
         33 . The method of  claim 31 , wherein the IL-3Rα chain is expressed by a pDC that produces one or more type I interferons and/or wherein the IL-3Rα chain is expressed by a basophil that produces one or more cytokines. 
     
     
         34 . The method of  claim 31 , wherein the immunoglobulin binds to the same epitope as monoclonal antibody 7G3 or an overlapping epitope. 
     
     
         35 . The method of  claim 31 , wherein the immunoglobulin neutralizes IL-3 signaling. 
     
     
         36 . The method of  claim 31 , wherein the immunoglobulin is an antibody or an antigen binding fragment thereof. 
     
     
         37 . The method of  claim 36 , wherein the antibody is a chimeric antibody. 
     
     
         38 . The method of  claim 37 , wherein the chimeric antibody is a chimeric antibody comprising the variable regions of monoclonal antibody 7G3. 
     
     
         39 . The method of  claim 36 , wherein the antibody is a humanized antibody. 
     
     
         40 . The method of  claim 39 , wherein the humanized antibody is a humanized antibody comprising complementarity determining regions derived from monoclonal antibody 7G3. 
     
     
         41 . The method of  claim 40 , wherein the humanized antibody comprises a light chain variable region (V L ) comprising a sequence set forth in SEQ ID NO: 3 and a heavy chain variable region (V H ) comprising a sequence set forth in SEQ ID NO: 2. 
     
     
         42 . The method of  claim 36 , wherein the antibody is a human antibody. 
     
     
         43 . The method of  claim 31 , wherein the effector function is antibody-dependent cell cytotoxicity (ADCC), antibody-dependent cell mediated phagocytosis (ADCP) and/or complement dependent cytotoxicity (CDC). 
     
     
         44 . The method of  claim 31  wherein the level of effector function induced by the immunoglobulin is enhanced relative to that of the immunoglobulin when it comprises a wild-type IgG1 Fc region or chimeric 7G3 or hz7G3 (comprising light chain comprising a sequence set forth in SEQ ID NO: 5 and a heavy chain comprising a sequence set forth in SEQ ID NO: 4). 
     
     
         45 . The method of  claim 31 , wherein the immunoglobulin comprises a Fc region that is afucosylated. 
     
     
         46 . The method of  claim 31 , wherein the immunoglobulin comprises an Fc portion comprising one or more amino acid sequence substitutions that enhance the effector function induced by the immunoglobulin. 
     
     
         47 . The method of  claim 46 , wherein the one or more amino acid sequence substitutions are:
 (i) S239D, A330L and I332E according to the EU numbering system of Kabat; or   (ii) S239D and I332E according to the EU numbering system of Kabat.   
     
     
         48 . The method of  claim 47 , wherein the immunoglobulin is and antibody comprising a light chain comprising a sequence set forth in SEQ ID NO: 5 and a heavy chain comprising a sequence set forth in SEQ ID NO: 7 (hz7G3V2). 
     
     
         49 . The method of  claim 31 , wherein following administration of the immunoglobulin the number of plasmacytoid dendritic cells (pDCs) and basophils in circulation in the mammal is reduced by at least about 50% compared to the number of the pDCs and/or basophils in circulation in the mammal prior to administering the immunoglobulin. 
     
     
         50 . The method of  claim 49 , wherein at least about six hours following administration of the immunoglobulin, the number of pDCs and basophils in circulation in the mammal is reduced by at least about 50% compared to the number of the pDCs and/or basophils in circulation in the mammal prior to administering the immunoglobulin. 
     
     
         51 . The method of  claim 49 , wherein the number of pDCs and basophils in circulation in the mammal is reduced by at least about 50% compared to the number of pDCs and/or basophils in circulation in the mammal prior to administering the immunoglobulin for at least 7 days post administration without further administrations of the immunoglobulin. 
     
     
         52 . The method of  claim 31  comprising administering between about 0.001 mg/kg and 50 mg/kg of immunoglobulin to the mammal. 
     
     
         53 . The method of  claim 52 , wherein the immunoglobulin is administered to the mammal a plurality of times and wherein the period between administrations is at least about 11 days. 
     
     
         54 . A method of treating lupus in a mammal, the method comprising administering to the mammal an immunoglobulin which binds an interleukin 3 receptor α (IL-3Rα) chain and which depletes or at least partly eliminates plasmacytoid dendritic cells (pDCs) and basophils to which it binds to thereby treat lupus in the mammal, wherein the immunoglobulin is not conjugated to a toxic compound that kills a cell to which the immunoglobulin binds, and wherein the immunoglobulin is capable of inducing an enhanced level of effector function. 
     
     
         55 . The method of  claim 54 , wherein the immunoglobulin neutralizes IL-3 signaling. 
     
     
         56 . The method of  claim 55 , wherein the immunoglobulin and competitively inhibits the binding of monoclonal antibody 7G3 to IL-3Rα.