Interferon alpha receptor I antibodies and their use
View Patent ↗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. A method of treating systemic lupus erythematosus in a subject in need of treatment, comprising administering to the subject an isolated human monoclonal antibody, or an antigen-binding portion thereof, that specifically binds to human interferon alpha receptor 1 (IFNAR-1), wherein the antibody inhibits the biological activity of IFN-β and does not bind the same epitope as mouse monoclonal antibody 64G12 (ECACC Deposit No. 92022605), such that the systemic lupus erythematosus in the subject is treated.
2. A method of treating systemic lupus erythematosus in a subject in need of treatment comprising administering to the subject an effective amount of an isolated human monoclonal antibody, or an antigen-binding portion thereof, that inhibits the biological activity of IFN-β and cross-competes for binding to human interferon alpha receptor 1 (IFNAR-1) with a reference antibody, wherein the reference antibody is selected from the group consisting of:
a) an antibody comprising 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;
b) an antibody comprising 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; and
c) an antibody comprising 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.
3. A method of treating a type-1 interferon mediated disease or disorder selected from the group consisting of: insulin dependent diabetes mellitus, multiple sclerosis, psoriasis, autoimmune thyroiditis, rheumatoid arthritis, glomerulonephritis, HIV infection, AIDS, transplant rejection, and graft versus host disease, in a subject in need of treatment, comprising administering to the subject an isolated human monoclonal antibody, or an antigen-binding portion thereof, that specifically binds to human interferon alpha receptor 1 (IFNAR-1), wherein the antibody inhibits the biological activity of IFN-β and does not bind the same epitope as mouse monoclonal antibody 64G12 (ECACC Deposit No. 92022605), such that the type-1 interferon mediated disease or disorder in the subject is treated.
4. A method of treating a type-1 interferon mediated disease or disorder selected from the group consisting of: insulin dependent diabetes mellitus, multiple sclerosis, psoriasis, autoimmune thyroiditis, rheumatoid arthritis, glomerulonephritis, HIV infection, AIDS, transplant rejection, and graft versus host disease, in a subject in need of treatment, comprising administering to the subject an effective amount of an isolated human monoclonal antibody, or an antigen-binding portion thereof, that inhibits the biological activity of IFN-β and cross-competes for binding to human interferon alpha receptor 1 (IFNAR-1) with a reference antibody, wherein the reference antibody is selected from the group consisting of:
a) an antibody comprising 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;
b) an antibody comprising 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; and
c) an antibody comprising 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.
5. The method of claim 1 , 2 , 3 , or 4 , wherein the anti-type 1 interferon receptor antibody is administered intravenously.
6. The method of claim 1 , 2 , 3 , or 4 , wherein the anti-type 1 interferon receptor antibody is administered in a dosage range of between about 1 mg/kg body weight and 10 mg/kg body weight.
7. The method of claim 6 , wherein the anti-type 1 interferon receptor antibody is administered in a dosage selected from the group consisting of: about 0.3 mg/kg body weight, about 1 mg/kg body weight, about 3 mg/kg body weight, about 5 mg/kg body weight and about 10 mg/kg body weight.
8. The method of claim 1 , 2 , 3 , or 4 , wherein the anti-type 1 interferon receptor antibody is administered at a frequency selected from the group consisting of once per week, once every two weeks, once every three weeks, once every four weeks, once a month, once every 3 months and once every three to 6 months.
9. The method of claim 1 , 2 , 3 , or 4 , wherein the anti-type 1 interferon receptor antibody is administered every four weeks for six dosages, followed by once every three months.
10. The method of claim 1 , 2 , 3 , or 4 , wherein the anti-type 1 interferon receptor antibody is administered once at about 3 mg/kg body weight followed by about 1 mg/kg body weight every three weeks.
11. The method of claim 1 or 3 , wherein the isolated human monoclonal antibody, or antigen-binding portion thereof, comprises:
(a) a human heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 1;
(b) a human heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:5;
(c) a human heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:9;
(d) a human light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 13;
(e) a human light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 17; and
(f) a human light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:21.
12. The method of claim 1 or 3 , wherein the isolated human monoclonal antibody, or antigen-binding portion thereof, comprises:
(a) a human heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:2;
(b) a human heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:6;
(c) a human heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 10;
(d) a human light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 14;
(e) a human light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 18; and
(f) a human light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:22.
13. The method of claim 1 or 3 , wherein the isolated human monoclonal antibody, or antigen-binding portion thereof, comprises:
(a) a human heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:4;
(b) a human heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:8;
(c) a human heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 12;
(d) a human light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 16;
(e) a human light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:20; and
(f) a human light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:24.
14. The method of claim 1 or 3 , wherein the isolated human monoclonal antibody, or antigen-binding portion thereof, comprises:
(a) a human heavy chain variable region comprising the amino acid sequence of SEQ ID NO:25; and
(b) a human light chain variable region comprising the amino acid sequence of SEQ ID NO:29.
15. The method of claim 1 or 3 , wherein the isolated human monoclonal antibody, or antigen-binding portion thereof, comprises:
(a) a human heavy chain variable region comprising the amino acid sequence of SEQ ID NO:26; and
(b) a human light chain variable region comprising the amino acid sequence of SEQ ID NO:30.
16. The method of claim 1 or 3 , wherein the isolated human monoclonal antibody, or antigen-binding portion thereof, comprises:
(a) a human heavy chain variable region comprising the amino acid sequence of SEQ NO:28; and
(b) a human light chain variable region comprising the amino acid sequence of SEQ ID NO:32.
17. The method of claim 2 , or 4 , wherein the reference antibody is an antibody comprising 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.
18. The method of claim 1 , 2 , 3 , or 4 , wherein the anti-type 1 interferon receptor antibody is administered by a route selected from the group consisting of subcutaneously, intramuscularly, intradermally, intraperitoneally, and intravenously.