Anti-blood dendritic cell antigen 2 antibodies and uses thereof

Abstract

Antibodies and antibody fragments that bind to BDCA2 are disclosed. Also disclosed are methods of using the antibodies and antibody fragments to induce death of a plasmacytoid dendritic cell, inhibit production or secretion of inflammatory cytokines and chemokines, and treat or prevent immunological disorders such as inflammatory and autoimmune conditions.

1 .- 38 . (canceled) 
     
     
         39 . A composition comprising an anti-BDCA2 antibody or BDCA2-binding fragment thereof and a second agent selected from the group consisting of an anti-malarial drug, a kinase inhibitor, a disease-modifying antirheumatic drug, a TLR7 signaling inhibitor, a TLR9 signaling inhibitor a glucocorticoid, a phosphodiesterase inhibitor, an endothelin antagonist, a statin, an ACE inhibitor, a calcium channel blocker, and combinations thereof, wherein the anti-BDCA2 antibody or BDCA2-binding fragment comprises a variable heavy (VH) domain comprising VH complementarity determining region (CDR)1, VH CDR2, and VH CDR3, wherein:
 the VH CDR1 comprises the amino acid sequence GFTFSTYTMS (SEQ ID NO:9);   the VH CDR2 comprises the amino acid sequence TISPGDSFGYYYPDSVQG (SEQ ID NO:10); and   the VH CDR3 comprises the amino acid sequence DIYYNYGAWFAY (SEQ ID NO:11); and   wherein the antibody comprises a variable light (VL) domain comprising VL CDR1, VL CDR2, and VL CDR3, wherein:   the VL CDR1 comprises the amino acid sequence KASQSVDYDGDSYMN (SEQ ID NO:5);   the VL CDR2 comprises the amino acid sequence AASTLES (SEQ ID NO:6); and   the VL CDR3 comprises the amino acid sequence QQANEDPRT (SEQ ID NO:7).   
     
     
         40 . The composition of  claim 39 , wherein the VH domain comprises the amino acid sequence set forth in SEQ ID NO:24. 
     
     
         41 . The composition of  claim 39 , wherein the antibody comprises a heavy chain and wherein the heavy chain comprises the amino acid sequence set forth in SEQ ID NO:4. 
     
     
         42 . The composition of  claim 39 , wherein the VL domain comprises the amino acid sequence set forth in SEQ ID NO:23. 
     
     
         43 . The composition of  claim 39 , wherein the antibody comprises a light chain and wherein the light chain comprises the amino acid sequence set forth in SEQ ID NO:3. 
     
     
         44 . The composition of  claim 39 , wherein the VH domain comprises the amino acid sequence set forth in SEQ ID NO:24 and the VL domain comprises the amino acid sequence set forth in SEQ ID NO:23. 
     
     
         45 . The composition of  claim 39 , wherein the antibody comprises a heavy chain and a light chain, and wherein the heavy chain comprises the amino acid sequence set forth in SEQ ID NO:4 and the light chain comprises the amino acid sequence set forth in SEQ ID NO:3. 
     
     
         46 . The composition of  claim 39 , wherein the antibody is a humanized antibody. 
     
     
         47 . The composition of  claim 39 , wherein the antibody is a chimeric antibody. 
     
     
         48 . The composition of  claim 39 , wherein the antibody comprises an IgG1 heavy chain constant region. 
     
     
         49 . The composition of  claim 39 , wherein the second agent is an anti-malarial drug that is selected from the group consisting of hydroxychloroquine, amodiaquine, pyrimethamine, proguanil, sulfonamides, mefloquine, atovaquone, primaquine, artemisinin, halofantrine, doxycycline, clindamycin 
     
     
         50 . The composition of  claim 39 , wherein the second agent is a kinase inhibitor that is selected from the group consisting of a BTK inhibitor, a JAK1 inhibitor, a JAK2 inhibitor, a JAK3 inhibitor, and a Tyk2 inhibitor. 
     
     
         51 . The composition of  claim 39 , wherein the second agent is a that is a disease-modifying antirheumatic drug that is selected from the group consisting of methotrexate, mycophenolate mofetil, azathioprine, cyclophosphamide, sulfasalazine, and leflunomide. 
     
     
         52 . A pharmaceutical comprising an anti-BDCA2 antibody or BDCA2-binding fragment thereof, wherein the anti-BDCA2 antibody or BDCA2-binding fragment comprises a variable heavy (VH) domain comprising VH complementarity determining region (CDR)1, VH CDR2, and VH CDR3, wherein:
 the VH CDR1 comprises the amino acid sequence GFTFSTYTMS (SEQ ID NO:9);   the VH CDR2 comprises the amino acid sequence TISPGDSFGYYYPDSVQG (SEQ ID NO:10); and   the VH CDR3 comprises the amino acid sequence DIYYNYGAWFAY (SEQ ID NO:11); and   wherein the antibody comprises a variable light (VL) domain comprising VL CDR1, VL CDR2, and VL CDR3, wherein:   the VL CDR1 comprises the amino acid sequence KASQSVDYDGDSYMN (SEQ ID NO:5);   the VL CDR2 comprises the amino acid sequence AASTLES (SEQ ID NO:6); and   the VL CDR3 comprises the amino acid sequence QQANEDPRT (SEQ ID NO:7); and   10 to 25 mM citrate, 100 to 200 mM sodium chloride, 0.01 to 0.3% Tween-80, and a pH of 5.5 to 6.5.   
     
     
         53 . A method of reducing production of a type I interferon, IL-6, TNF-α, CCL3, CCL4, IP10, and RANTES by a plasmacytoid dendritic cell expressing BDAC2 in a human subject, the method comprising contacting a plasmacytoid dendritic cell that expresses BDCA2 with an effective amount of the composition of  claim 39 . 
     
     
         54 . A method of treating an inflammatory disorder associated with the presence of plasmacytoid dendritic cells expressing BDCA2 in a human subject having said inflammatory disorder, comprising administering to the human subject an effective amount of the composition of  claim 39 . 
     
     
         55 . A method of treating an autoimmune disease associated with the presence of plasmacytoid dendritic cells expressing BDCA2 in a human subject having said autoimmune disease, comprising administering to the human subject an effective amount of the composition of  claim 39 . 
     
     
         56 . A method for making an anti-BDCA2 antibody or BDCA2-binding fragment thereof, the method comprising:
 (a) providing a cell comprising a nucleic encoding an anti-BDCA2 antibody or BDCA2-binding fragment thereof, wherein the anti-BDCA2 antibody or BDCA2-binding fragment comprises a variable heavy (VH) domain comprising VH complementarity determining region (CDR)1, VH CDR2, and VH CDR3, wherein:   the VH CDR1 comprises the amino acid sequence GFTFSTYTMS (SEQ ID NO:9);   the VH CDR2 comprises the amino acid sequence TISPGDSFGYYYPDSVQG (SEQ ID NO:10); and   the VH CDR3 comprises the amino acid sequence DIYYNYGAWFAY (SEQ ID NO:11); and   wherein the antibody comprises a variable light (VL) domain comprising VL CDR1, VL CDR2, and VL CDR3, wherein:   the VL CDR1 comprises the amino acid sequence KASQSVDYDGDSYMN (SEQ ID NO:5);   the VL CDR2 comprises the amino acid sequence AASTLES (SEQ ID NO:6); and   the VL CDR3 comprises the amino acid sequence QQANEDPRT (SEQ ID NO:7);   (b) the cell under conditions that permit the expression of the anti-BDCA2 antibody or BDCA2-binding fragment; and   (c) isolating the anti-BDCA2 antibody or BDCA2-binding fragment.   
     
     
         57 . The method of  claim 56 , wherein the cell is a CHO cell or a 293 cell. 
     
     
         58 . The method of  claim 56 , wherein the VH domain comprises the amino acid sequence set forth in SEQ ID NO:24 and the VL domain comprises the amino acid sequence set forth in SEQ ID NO:23.