Methods of reducing CRP and/or increasing serum albumin in patients in need using IL-6 antibodies of defined epitopic specificity

• US 8,535,671 B2
• Filed: 09/22/2011
• Issued: 09/17/2013
• Est. Priority Date: 05/21/2007
• Status: Active Grant

• Current Assignee: Vitaeris Inc. (CSL Limited)
• Original Assignee: AlderBio Holdings, LLC (Lundbeck Seattle Biopharmaceuticals, Inc.)
• Inventors: Smith, Jeffrey T. L.
• Primary Examiner(s): Bunner, Bridget E
• Assistant Examiner(s): HAMUD, FOZIA M
• Application Number:
  US13/240,181
• Publication Number:
  US 20120014955A1
• Time in Patent Office: 726 Days
• Field of Search: None
• US Class Current: 424/139.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 2317/41 Glycosylation, sialylation, or fucosylation
• 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 2333/4737 C-reactive protein
• CPC Class Codes: G01N 2333/765 Serum albumin, e.g. HSA
• CPC Class Codes: G01N 2800/52 Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Abstract

The present invention is directed to therapeutic methods using IL-6 antagonists such as antibodies and fragments thereof having binding specificity for IL-6 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 or a reduced serum albumin level prior to treatment. In another preferred embodiment, the patient'"'"'s Glasgow Prognostic Score will be increased and survivability will preferably be improved.

Claims

1. A method of improving survivability or quality of life of a patient in need thereof having elevated C-reactive protein levels, comprising administering to the patient an anti-interleukin-6 (“

IL-6”

), antibody or anti-IL-6 antibody fragment, wherein the antibody or antibody fragment specifically binds to an epitope on an intact human IL-6 polypeptide, wherein said epitope, when ascertained by epitopic mapping using overlapping linear peptide fragments which span the full length of the native human IL-6 polypeptide, includes one or more residues comprised in each of the human IL-6 fragments selected from those respectively consisting of (a) amino acid residues 37-51, (b) amino acid residues 70-84, (c) amino acid residues 169-183, (d) amino acid residues 31-45 and (e) amino acid residues 58-72 of the human IL-6 polypeptide having the sequence in SEQ ID NO;

1, and whereby the patient'"'"'s serum C-reactive protein (“

CRP”

) is reduced, and further whereby the administration of the anti-IL-6 antibody or antibody fragment results in improved survivability and/or quality of life of said patient.

4. The method of any one of claims 1-3, wherein before or after the administration of said anti-IL-6 antibody or fragment either or both serum albumin and C-reactive protein levels are determined.

5. The method of any one of claims 1-3, wherein after the administration of said anti-IL-6 antibody or fragment either or both serum albumin and C-reactive protein levels are monitored.

6. The method of any one of claims 1-3, wherein said patient has an elevated serum C-reactive protein (“

CRP”

) level or reduced serum albumin level prior to treatment.

7. The method of any one of claims 1-3, wherein the anti-IL-6 antibody is an anti-IL-6 antibody fragment.

8. The method of any one of claims 1-3, wherein the anti-IL-6 antibody is an intact anti-IL-6 antibody.

9. The method of any one of claims 1-3, wherein the anti-IL-6 antibody or antibody fragment is administered to the patient with a frequency at most once per period of approximately four weeks.

10. The method of any one of claims 1-3, wherein the patient'"'"'s serum C-reactive protein (“

CRP”

) level remains decreased and/or serum albumin level remains raised for an entire period intervening two consecutive anti-IL-6 antibody or antibody fragment administrations.

11. The method of any one of claims 1-3, wherein the anti-IL-6 antibody or antibody fragment has an elimination half-life of at least about 22 days.

12. The method of claim 1 or 3, further comprising:

measuring the patient'"'"'s serum C-reactive protein (“

CRP”

) level prior to administration of the anti-IL-6 antibody or antibody fragment, and administering the anti-IL-6 antibody or antibody fragment if the patient'"'"'s serum CRP level is at least approximately 5 mg/L.

13. The method of claim 12, wherein the patient'"'"'s serum C-reactive protein (“

CRP”

) level is reduced to less than approximately 5 mg/L within 1 week of administration of the anti-IL-6 antibody or antibody fragment.

14. The method of claim 1 or 3, wherein the patient'"'"'s serum C-reactive protein (“

CRP”

) level is reduced to below 10 mg/L within about 1 week of the anti-IL-6 antibody or antibody fragment administration.

15. The method of claim 1 or 3, further comprising:

measuring the patient'"'"'s serum albumin level prior to administration of the anti-IL-6 antibody or antibody fragment, and administering the anti-IL-6 antibody or antibody fragment , and administering the IL-6 antibody if the patient'"'"'s serum albumin level is less than approximately 35 g/L.

16. The method of claim 15, wherein the patient'"'"'s serum albumin level is increased to more than approximately 35 g/L within about 5 weeks of administration of the anti-IL-6 antibody or antibody fragment.

17. The method of any one of claims 1-3, further comprising administration of one or more statins to the patient.

18. The method of any one of claims 1-3, wherein the anti-IL-6 antibody or fragment is aglycosylated.

19. The method of any one of claims 1-3, wherein the anti-IL-6 antibody or fragment comprises a human constant domain.

20. The method of any one of claims 1-3, wherein the anti-IL-6 antibody or fragment comprises a human gamma 1 constant domain.

21. The method of any one of claims 1-3, wherein said antibody is administered in a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.

22. The method of any one of claims 1-3, wherein the anti-IL-6 antibody or fragment is administered intravenously, intraperitoneally, intramuscularly, or subcutaneously.

23. The method of any one of claims 1-3, 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.

24. The method of any one of claims 1-3, wherein the anti-IL-6 antibody or antibody fragment is a human, humanized, single chain or chimeric antibody.

25. The method of any one of claims 1-3, wherein the anti-IL-6 antibody or antibody fragment is aglycosylated.

26. The method of any one of claims 1-3, wherein the anti-IL-6 antibody or antibody fragment substantially neutralizes IL-6 in vivo and inhibits the interaction of human IL-6 with both gp 130 and IL-6R.

27. The method of any one of claims 1-3, wherein the serum albumin levels in the patient remain elevated and/or the CRP levels remain decreased after antibody administration has been discontinued for at least 14 days.

28. The method of any one of claims 1-3, wherein the serum albumin level in the patient remains elevated and/or the CRP level remains decreased after antibody administration has been discontinued for at least 21 days.

2. A method of improving survivability or quality of life of a patient in need thereof having reduced serum albumin levels, comprising administering to the patient an anti-interleukin-6 (“

IL-6”

) antibody or antibody fragment, wherein the antibody or antibody fragment specifically binds to an epitope on an intact human IL-6 polypeptide, wherein said epitope, when ascertained by epitopic mapping using overlapping linear peptide fragments which span the full length of the native human IL-6 polypeptide, includes one or more residues comprised in each of the human IL-6 fragments selected from those respectively consisting of (a) amino acid residues 37-51, (b) amino acid residues 70-84, (c) amino acid residues 169-183, (d) amino acid residues 31-45 and (e) amino acid residues 58-72 of the human IL-6 polypeptide having the sequence in SEQ ID NO;

1, whereby the patient'"'"'s serum albumin level is increased, and further whereby the administration of the anti-IL-6 antibody or antibody fragment results in improved survivability and/or quality of life of said patient.

3. A method of improving survivability or quality of life of a patient in need thereof having increased C reactive protein and reduced serum albumin levels, comprising administering to the patient an anti-interleukin-6 (“

IL-6”

) antibody or antibody fragment, wherein the antibody or antibody fragment specifically binds to an epitope on an intact human IL-6 polypeptide, wherein said epitope, when ascertained by epitopic mapping using overlapping linear peptide fragments which span the full length of the native human IL-6 polypeptide, includes one or more residues comprised in each of the human IL-6 fragments selected from those respectively consisting of (a) amino acid residues 37-51, (b) amino acid residues 70-84, (c) amino acid residues 169-183, (d) amino acid residues 31-45 and (e) amino acid residues 58-72 of the human IL-6 polypeptide having the sequence in SEQ ID NO;

1, and whereby this administration results in the reduction of the patient'"'"'s serum C-reactive protein (“

CRP”

) level and the increase in the patient'"'"'s serum albumin level, and further whereby the administration of the anti-IL-6 antibody or antibody fragment results in improved survivability and/or quality of life of said patient.