Methods of treating or diagnosing conditions associated with elevated IL-6 using anti-IL-6 antibodies or fragments

• US 9,452,227 B2
• Filed: 11/24/2009
• Issued: 09/27/2016
• Est. Priority Date: 11/25/2008
• Status: Active Grant

• Current Assignee: Vitaeris Inc. (CSL Limited)
• Original Assignee: AlderBio Holdings, LLC (Lundbeck Foundation)
• Inventors: Garcia-Martinez, Leon, Jensen, Anne Elisabeth Carvalho, Olson, Katie, Dutzar, Ben, Latham, John, Kovacevich, Brian, Smith, Jeffrey T. L., Litton, Mark, Schatzman, Randall
• Primary Examiner(s): Bunner, Bridget E
• Assistant Examiner(s): HAMUD, FOZIA M
• Application Number:
  US12/624,778
• Publication Number:
  US 20100150829A1
• Time in Patent Office: 2,499 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 49/0058 Antibodies
• CPC Class Codes: A61K 51/1033 against receptors for cytokines, lymphokines or interferons
• CPC Class Codes: C07K 16/248 IL-6
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/51 Complete heavy chain or Fd fragment, i.e. VH + CH1
• CPC Class Codes: C07K 2317/515 Complete light chain, i.e. VL + CL
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: G01N 2333/5412 IL-6
• CPC Class Codes: G01N 2800/7095 Inflammation
• CPC Class Codes: G01N 33/6869 Interleukin
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

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.

Claims

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 in 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 both gp130 and IL-6R1.

11. The method of claim 1, wherein said anti-IL-6 antibody or fragment neutralizes IL-6 in vivo.

12. The method of claim 1, wherein the anti-IL-6 antibody or antibody fragment comprises a human constant region.

13. The method of claim 12, wherein said human constant region comprises an IgG1, IgG2, IgG3 or IgG4 constant region.

14. The method of claim 12, wherein said human constant region comprises an IgG1 constant region.

15. 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 the variable light chain and variable heavy chain polypeptides of SEQ ID NOs:

709 and 657, respectively.

16. The method of claim 15, 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.

17. The method of claim 15, 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.

18. The method of claim 15, wherein the anti-IL-6 antibody or antibody fragment -comprises a human constant region.

19. The method of claim 18, wherein said human constant region comprises an IgG1, IgG2, IgG3 or IgG4 constant region.

20. The method of claim 18, wherein said human constant region comprises an IgG1 constant region.

21. 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 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.