Methods of treating or diagnosing conditions associated with elevated IL-6 using anti-IL-6 antibodies or fragments
View Patent ↗The invention relates to the use of anti-IL-6 antibodies or antibody fragments containing a specific epitopic specificity to treat conditions involving elevated Il-6. In some embodiments the anti-IL-6 antibodies contain specific CDRs.
1. A method of treating a disease or condition associated with elevated human interleukin-6 (IL-6), comprising administering a therapeutically effective amount of an anti-IL-6 antibody or antibody fragment to a subject in need thereof, wherein the antibody or antibody fragment comprises:
a variable light chain polypeptide comprising the CDRs of SEQ ID NOs:4, 5 and 6 and possessing at least 90% identity to the variable light chain polypeptide of SEQ ID NO:709, and
a variable heavy chain polypeptide comprising the CDRs of SEQ ID NOs:7, 8 or 120, and 9 and possessing at least 90% identity to the variable heavy chain polypeptide of SEQ ID NO:657, and;
wherein the antibody or antibody fragment specifically binds to IL-6 and antagonizes one or more activities associated with IL-6 and specifically binds to the same epitope(s) on IL-6 as an anti-IL-6 antibody comprising the variable light chain polypeptide of SEQ ID NO:709 and the variable heavy chain polypeptide of SEQ ID NO:657.
2. The method of claim 1 , wherein the variable light chain polypeptide and the variable heavy chain polypeptide each possess at least 95% sequence identity to the variable light chain and variable heavy chain polypeptides of SEQ ID NOs: 709 and 657, respectively.
3. The method of claim 1 , wherein the variable light chain polypeptide and the variable heavy chain polypeptide each possess at least 97% sequence identity to the variable light chain and variable heavy chain polypeptides of SEQ ID NOs: 709 and 657, respectively.
4. The method of claim 1 , wherein the antibody or antibody fragment has an in vivo half-life of at least about 22 days in a healthy human subject.
5. The method of claim 1 , wherein the antibody or antibody fragment has a binding affinity (Kd) for IL-6 of less than about 50 picomolar, or a rate of dissociation (K off ) from IL-6 of less than or equal to 10 -4 S -1 .
6. The method of claim 1 , wherein the antibody or antibody fragment contains an Fc region that has been modified to alter effector function, half-life, proteolysis, and/or glycosylation.
7. The method of claim 1 , wherein the antibody is selected from a humanized, single chain, or chimeric antibody and the antibody fragment is selected from a Fab, Fab′, F(ab′) 2 , Fv, or scFv.
8. The method of claim 1 , wherein the therapeutically effective amount is between about 0.1 and 20 mg/kg of body weight of recipient subject.
9. The method of claim 1 , wherein said anti-IL-6 antibody or fragment inhibits the binding of IL-6 to gp130.
10. The method of claim 1 , wherein said anti-IL-6 antibody or fragment inhibits the binding of IL-6 to IL-6R1.
11. The method of claim 1 , wherein said anti-IL-6 antibody or fragment inhibits the binding of IL-6 to both gp 130 and IL-6R1.
12. The method of claim 1 , wherein said anti-IL-6 antibody or fragment neutralizes IL-6 in vivo.
13. The method of claim 1 , wherein the anti-IL-6 antibody or antibody fragment comprises a human constant region.
14. The method of claim 13 , wherein said human constant region comprises an IgG1, IgG2, IgG3 or IgG4 constant region.
15. The method of claim 13 , wherein said human constant region comprises an IgG1 constant region.
16. A method of treating a disease or condition associated with elevated human interleukin-6 (IL-6), comprising administering a therapeutically effective amount of an anti-IL-6 antibody or antibody fragment to a subject in need thereof, wherein the antibody or antibody fragment specifically binds to the same epitope(s) on an intact human IL-6 polypeptide or fragment thereof as an anti-IL-6 antibody comprising the variable light chain and variable heavy chain polypeptides of SEQ ID NOs:709 and 657, respectively, wherein said epitopic specificity is ascertained by epitopic mapping using overlapping linear peptide fragments which span the full length of the native human IL-6 polypeptide and said epitope(s) comprise one or more residues in an IL-6 fragment selected from amino acid residues 37-51, amino acid residues 70-84, amino acid residues 169-183, amino acid residues 31-45 and/or amino acid residues 58-72 of SEQ ID NO:1.
17. The method of claim 16 , wherein said anti-IL-6 antibody or fragment inhibits the binding of IL-6 to gp 130.
18. The method of claim 16 , wherein said anti-IL-6 antibody or fragment inhibits the binding of IL-6 to IL-6R1.
19. The method of claim 16 , wherein said anti-IL-6 antibody or fragment inhibits the binding of IL-6 to both gp 130 and IL-6R1.
20. The method of claim 16 , wherein said anti-IL-6 antibody or fragment neutralizes IL-6 in vivo.
21. The method of claim 16 , wherein said anti-IL-6 antibody or antibody fragment has a binding affinity (Kd) for IL-6 of less than about 50 picomolar, or a rate of dissociation (K off ) from IL-6 of less than or equal to 10 -4 S -1 .
22. The method of claim 16 , wherein the anti-IL-6 antibody or antibody fragment contains an Fc region that has been modified to alter effector function, half-life, proteolysis, and/or glycosylation.
23. The method of claim 16 , wherein the anti-IL-6—antibody or fragment is selected from a human, humanized, single chain, or chimeric antibody and the antibody fragment is selected from a Fab, Fab′, F(ab′) 2 , Fv, or scFv.
24. The method of claim 16 , wherein the anti-IL-6 antibody or antibody fragment comprises a human constant region.
25. The method of claim 24 , wherein said human constant region comprises an IgG1, IgG2, IgG3 or IgG4 constant region.
26. The method of claim 24 , wherein said human constant region comprises an IgG1 constant region.
27. A method of treating a disease or condition associated with elevated human interleukin-6 (IL-6), comprising administering a therapeutically effective amount of an anti-IL-6 antibody or antibody fragment to a subject in need thereof, wherein the antibody or antibody fragment comprises:
(a) variable light and variable heavy chain polypeptides comprising: SEQ ID NO:709 and SEQ ID NO:657; SEQ ID NO:702 and SEQ ID NO:704; SEQ ID NO:706 and SEQ ID NO:708; SEQ ID NO:20 and SEQ ID NO:19; or SEQ ID NO:2 and SEQ ID NO:3; or
(b) a polypeptide having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to any of the polypeptides and comprising the same CDRs of the corresponding polypeptide of (a);
wherein the antibody or antibody fragment specifically binds to IL-6 and antagonizes one or more activities associated with IL-6 and specifically binds to the same epitope(s) on a-human IL-6 as an anti-IL-6 antibody comprising the variable light chain polypeptide in of SEQ ID NO:709 and the variable heavy chain polypeptide of SEQ ID NO:657.