Interferon receptor 1 antibodies and their uses

Abstract

The present invention provides isolated human monoclonal antibodies that bind to IFNAR-1 and that are capable of inhibiting the biological activity of Type I interferons. Immunoconjugates, bispecific molecules and pharmaceutical compositions comprising the antibodies of the invention are also provided. The invention also provides methods for inhibiting Type I interferon-mediated disorders using the antibodies of the invention, including methods for treating autoimmune disorders, transplant rejection or Graft Versus Host Disease using the antibodies of the invention.

1 - 40 . (canceled) 
     
     
         41 . A method of treating autoimmune disease comprising administering to a subject in need thereof an effective amount of an antibody, or antigen-binding portion thereof, that specifically binds to human interferon alpha receptor 1 (IFNAR-1), wherein the antibody, or antigen-binding portion thereof, comprises:
 (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 4; a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 8; a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 12; a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 16; a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 20; and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 24;   (b) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 1; a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 5; a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 9; a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 13; a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 17; and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 21; or   (c) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 2; a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 6; a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 10; a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 14; a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 18; and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 22.   
     
     
         42 . The method of  claim 41 , wherein the autoimmune disease is selected from the group consisting of insulin-dependent diabetes mellitus, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, psoriasis, autoimmune thyroiditis, and glomerulonephritis. 
     
     
         43 . The method of  claim 41 , wherein the antibody is a human antibody. 
     
     
         44 . The method of  claim 41 , wherein the antibody, or antigen-binding portion thereof, is conjugated to a therapeutic agent. 
     
     
         45 . The method of  claim 44 , wherein the therapeutic agent is a cytotoxin or a radioactive isotope. 
     
     
         46 . The method of  claim 41 , wherein the antibody, or antigen-binding portion thereof, is administered intravenously. 
     
     
         47 . The method of  claim 41 , wherein the antibody, or antigen binding portion thereof, comprises a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 4; a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 8; a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 12; a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 16; a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 20; and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 24. 
     
     
         48 . The method of  claim 41 , wherein the antibody, or antigen binding portion thereof, comprises a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 1; a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 5; a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 9; a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 13; a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 17; and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 21. 
     
     
         49 . The method of  claim 41 , wherein the antibody, or antigen binding portion thereof, comprises a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 2; a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 6; a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 10; a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 14; a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 18; and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 22. 
     
     
         50 . A method of treating autoimmune disease comprising administering to a subject in need thereof an effective amount of an antibody, or antigen-binding portion thereof, that specifically binds to human interferon alpha receptor 1 (IFNAR-1), wherein the antibody, or antigen-binding portion thereof, comprises:
 (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 28 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 32;   (b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 25 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 29; or   (c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 26 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 30.   
     
     
         51 . The method of  claim 50 , wherein the autoimmune disease is selected from the group consisting of insulin-dependent diabetes mellitus, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, psoriasis, autoimmune thyroiditis, and glomerulonephritis. 
     
     
         52 . The method of  claim 50 , wherein the antibody is a human antibody. 
     
     
         53 . The method of  claim 50 , wherein the antibody, or antigen-binding portion thereof, is conjugated to a therapeutic agent. 
     
     
         54 . The method of  claim 53 , wherein the therapeutic agent is a cytotoxin or a radioactive isotope. 
     
     
         55 . The method of  claim 50 , wherein the antibody, or antigen-binding portion thereof, is administered intravenously. 
     
     
         56 . The method of  claim 50 , wherein the antibody, or antigen binding portion thereof, comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 28 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 32. 
     
     
         57 . The method of  claim 50 , wherein the antibody, or antigen binding portion thereof, comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 25 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 29. 
     
     
         58 . The method of  claim 50 , wherein the antibody, or antigen binding portion thereof, comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 26 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 30. 
     
     
         59 . A method of detecting human interferon alpha receptor 1 (IFNAR-1) in a sample comprising:
 (a) contacting the sample with an antibody, or antigen-binding portion thereof, which specifically binds to IFNAR-1 under conditions that allow for formation of a complex between the antibody, or antigen-binding portion thereof, and IFNAR-1, wherein the antibody, or antigen-binding portion thereof, comprises:
 (i) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 4; a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 8; a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 12; a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 16; a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 20; and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 24; 
 (ii) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 1; a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 5; a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 9; a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 13; a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 17; and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 21; or 
 (iii) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 2; a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 6; a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 10; a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 14; a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 18; and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 22, and 
   (b) detecting the complex between the antibody, or antigen-binding portion thereof, and IFNAR-1.