Antibodies to IL-6 and use thereof

• US 8,323,649 B2
• Filed: 07/14/2009
• Issued: 12/04/2012
• 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, Ojala, Ethan, Kovacevich, Brian, Latham, John, Smith, Jeffrey T. L.
• Primary Examiner(s): Kemmerer, Elizabeth C
• Assistant Examiner(s): HAMUD, FOZIA M
• Application Number:
  US12/502,581
• Publication Number:
  US 20100129357A1
• Time in Patent Office: 1,239 Days
• Field of Search: None
• US Class Current: 424/141.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/54 characterised by the route of administration
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 39/39533 against materials from animals
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/248 IL-6
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• 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 2317/41 Glycosylation, sialylation, or fucosylation
• CPC Class Codes: C07K 2317/54 F(ab')2
• CPC Class Codes: C07K 2317/55 Fab or Fab'
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/569 Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
• CPC Class Codes: C07K 2317/622 Single chain antibody (scFv)
• 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: C07K 2317/94 Stability, e.g. half-life, pH, temperature or enzyme-resistance
• 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 present invention is directed to therapeutic methods using IL-6 antagonists such as an Ab1 antibody or antibody fragment having binding specificity for IL-6 to prevent or treat disease or to improve survivability or quality of life of a patient in need thereof. In preferred embodiments these patients will comprise those exhibiting (or at risk of developing) an elevated serum C-reactive protein level, reduced serum albumin level, elevated D-dimer or other coagulation cascade related protein(s), cachexia, fever, weakness and/or fatigue prior to treatment. The subject therapies also may include the administration of other actives such as chemotherapeutics, anti-coagulants, statins, and others.

Claims

1. A method of treating one or more symptoms of a disease or condition associated with elevated interleukin 6 (IL-6), comprising administration of an anti-human IL-6 antibody or antibody fragment to a subject in need thereof, wherein the anti-human IL-6 antibody or antibody fragment comprises:

a variable light (VL) region comprising the VL complementarity regions CDR1, CDR2 and CDR3, respectively having the sequences of SEQ ID NO;

4, 5 and 6, and a variable heavy (VH) region comprising the VH complementarity regions CDR1, CDR2 and CDR3, respectively having the sequences of SEQ ID NO;

7, 8 or 120 and 9; and

wherein said anti-human IL-6 antibody or antibody fragment specifically binds to human IL-6 and antagonizes one or more activities associated with IL-6 in vivo, thereby treating one or more symptoms of said disease or condition associated with elevated interleukin 6 (IL-6).

2. The method of claim 1, wherein the light chain polypeptide is at least 90% identical to the light chain framework region having the sequence of SEQ ID NO:

699 and further wherein the VL complementarity regions CDR1, CDR2 and CDR3, in SEQ ID NO;

699 respectively comprise the sequences of SEQ ID NO;

4, 5 and 6.

3. The method of claim 1, wherein the heavy chain polypeptide is at least 90% identical to the heavy chain framework region having the sequence of SEQ ID NO:

657 and further wherein the VH complementarity regions CDR1, CDR2 and CDR3, respectively comprise the sequences of SEQ ID NO;

7, 8 or 120 and 9.

4. The method of claim 1, wherein said anti-human IL-6 antibody or antibody fragment is selected from the group consisting of Fab, Fab′

, F(ab′

)₂, Fv, scFv, IgNAR, SMIP, camelbodies, and nanobodies.

5. The method of claim 1, wherein the anti-human IL-6 antibody or antibody fragment has an in vivo half-life of at least about 22 days in a healthy human subject.

6. The method of claim 1, wherein the anti-human IL-6 antibody or antibody fragment has an in vivo half-life of at least about 25 days in a healthy human subject.

7. The method of claim 1, wherein the anti-human IL-6 antibody or antibody fragment has an in vivo half-life of at least about 30 days in a healthy human subject.

8. The method of claim 1, wherein the anti-human 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<sup>−

1</sup>.

9. The method of claim 1, wherein the anti-human IL-6 antibody or antibody fragment specifically binds to the same epitope on an intact human IL-6 polypeptide or fragment thereof as an anti-IL-6 antibody consisting essentially of the polypeptides of SEQ ID NO:

702 and SEQ ID NO;

704 or an antibody comprising the VL and VH polypeptides of SEQ ID NO;

2 and SEQ ID NO;

3.

10. The method of claim 9, wherein said binding to the same epitope) on an intact human IL-6 polypeptide or fragment thereof is ascertained by epitopic mapping using overlapping linear peptide fragments which span the full length of the native human IL-6 polypeptide and includes one or more residues comprised in IL-6 fragments selected from those respectively encompassing 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.

11. The method of claim 1, wherein the anti-human IL-6 antibody or antibody fragment is aglycosylated.

12. The method of claim 1, wherein the anti-human IL-6 antibody or antibody fragment contains an Fc region that has been modified to alter effector function, half-life, proteolysis, and/or glycosylation.

13. The method of claim 1, wherein the anti-human IL-6 antibody or antibody fragment is a human, humanized, single chain, or chimeric antibody.

14. The method of claim 1, wherein the anti-human IL-6 antibody or antibody fragment is selected from the group consisting of Fab, Fab′

, F(ab′

)₂, Fv, and scFv.

15. The method of claim 1, wherein said anti-human IL-6 antibody or antibody fragment further comprises a human F_c.

16. The method of claim 15, wherein said human F_c is derived from IgG1, IgG2, IgG3, IgG4, IgG5, IgG6, IgG7, IgG8, IgG9, IgG10, IgG11, IgG12, IgG13, IgG14, IgG15, IgG16, IgG17, IgG18 or IgG19.

17. The method of claim 1, wherein the anti-human IL-6 antibody or antibody fragment is expressed from a recombinant cell.

18. The method of claim 17, wherein the cell is selected from a mammalian, yeast, bacterial, and insect cell.

19. The method of claim 18, wherein the cell is a yeast cell.

20. The method of claim 19, wherein the cell is a diploidal yeast cell.

21. The method of claim 19, wherein the yeast cell is a Pichia yeast.

22. The method of claim 1, wherein the anti-human IL-6 antibody or fragment is an IgG1.

23. The method of claim 22, wherein said anti-human IL-6 antibody comprises the variable light region having the sequence in SEQ ID NO:

20 and the variable heavy region having the sequence in SEQ ID NO;

19.

24. The method of claim 22, wherein said anti-human IL-6 antibody comprises the variable light region having the sequence in SEQ ID NO:

20 and the variable heavy region having the sequence in SEQ ID NO;

18.

25. The method of claim 1, wherein the anti-human IL-6 antibody or fragment competes with the binding of human IL-6 to gp130.

26. The method of claim 1, wherein the anti-human IL-6 antibody or fragment competes with the binding of human IL-6 to IL-6R1 (interleukin-6 receptor R1).

27. The method of claim 1, wherein the anti-human IL-6 antibody or fragment competes with the binding of human IL-6 to gp130 and IL-6R1 (interleukin-6 receptor R1).

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