Methods of treating anemia using anti-IL- 6 antibodies

• US 8,337,847 B2
• Filed: 11/24/2009
• Issued: 12/25/2012
• Est. Priority Date: 11/25/2008
• Status: Active Grant

• Current Assignee: Vitaeris Inc. (CSL Limited)
• Original Assignee: AlderBio Holdings, LLC (Lundbeck Seattle Biopharmaceuticals, Inc.)
• Inventors: Smith, Jeffrey T. L., Latham, John, Litton, Mark, Schatzman, Randall
• Primary Examiner(s): Kemmerer, Elizabeth C
• Assistant Examiner(s): HAMUD, FOZIA M
• Application Number:
  US12/624,816
• Publication Number:
  US 20100158859A1
• Time in Patent Office: 1,127 Days
• Field of Search: None
• US Class Current: 424/141.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• 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 2317/34 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 2317/76 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: 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 provides methods of treating anemia in patients in need thereof, particularly in patients having anemia associated with chronic and/or inflammatory conditions such as cancers and arthritic conditions by administering antibodies or antibody fragments that bind IL-6. The treatment methods result in increased hemoglobin.

Claims

1. A method of treating anemia in a patient having a disorder involving elevated interleukin-6 (IL-6), comprising administering to the patient an anti-IL-6 antibody or antibody fragment, said antibody or antibody fragment comprising the variable light complementarity regions (CDR'"'"'s) of SEQ ID NO:

4, 5 and 6 and the variable heavy complementarity regions (CDR'"'"'s) of SEQ ID NO;

7, 8 or 120 and 9.

2. The method of claim 1 wherein the anti-IL-6 antibody comprising said CDRs contains a variable heavy chain possessing at least 90% sequence identity to the variable heavy chain polypeptide of SEQ ID NO:

657 and a variable light chain possessing at least 90% sequence identity to the variable light chain polypeptide of SEQ ID NO;

709.

3. The method of claim 2, wherein the anti-IL-6 antibody comprises a variable heavy chain possessing at least 95% sequence identity to the polypeptide of SEQ ID NO:

657 and a variable light chain possessing at least 95% sequence identity to the polypeptide of SEQ ID NO;

709.

4. The method of claim 2, wherein the anti-IL-6 antibody further comprises the heavy chain and light chain constant regions of SEQ ID NO:

588 and SEQ ID NO;

586.

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

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

7. The method of claim 1, wherein the anti-IL-6 antibody or antibody fragment is administered to the patient with a frequency selected from the following:

(i) at most once per period of approximately four weeks, (ii) at most once per period of approximately eight weeks (iii) at most once per period of approximately twelve weeks or (iv) at most once per period of approximately sixteen weeks.

8. The method of claim 3 wherein said antibody further comprises the heavy constant and light constant sequences in SEQ ID NO:

588 and SEQ ID NO;

586.

9. The method of claim 1, wherein the patient'"'"'s serum hemoglobin levels increase after said anti-IL-6 antibody or antibody fragment administration.

10. The method of claim 1, wherein the patient has been diagnosed with cancer.

11. The method of claim 1, wherein said antibody comprises a human F_c derived from IgG1, IgG2, IgG3, or IgG4.

12. The method of claim 1, wherein the anti-IL-6 antibody or antibody fragment has an elimination half-life selected from (i) at least about 22 days, (ii) at least about 25 days and (iii) at least about 30 days.

13. The method of claim 1, wherein the anti-IL-6 antibody or antibody fragment is co-administered with another therapeutic agent.

14. The method of claim 13, wherein the other therapeutic agent is selected from VEGF antagonists, EGFR antagonists, platins, taxols, irinotecan, 5-fluorouracil, gemcytabine, leucovorine, steroids, cyclophosphamide, melphalan, vinca alkaloids, vinblastine, mustines, tyrosine kinase inhibitors, radiotherapy, sex hormone antagonists, selective androgen receptor modulators, selective estrogen receptor modulators, PDGF antagonists, TNF antagonists, IL-1 antagonists, interleukins, IL-12R antagonists, Toxin conjugated monoclonal antibodies, tumor antigen specific monoclonal antibodies, Erbitux™

, Avastin™

, Pertuzumab, anti-CD20 antibodies, ocrelizumab, ofatumumab, DXL625, Herceptin®

, or any combination thereof;

or comprises an inhibitor of JAK1, JAK2, JAK3, or SYK.

15. The method of claim 1 wherein the disease or condition associated with anemia is a cancer;

or rheumatoid arthritis.

16. The method of claim 1, further comprising administration of an antagonist of a cachexia-associated factor, weakness-associated factor, fatigue-associated factor, and/or fever-associated factor.

17. The method of claim 16, wherein the cachexia-associated factor, weakness-associated factor, fatigue-associated factor, and/or fever-associated factor is selected from tumor necrosis factor-alpha, Interferon gamma, Interleukin 1 alpha, Interleukin 1 beta, Interleukin 6, proteolysis inducing factor, leukemia-inhibitory factor, or any combination thereof or is selected from cannabis, dronabinol (Marinol™

), nabilone (Cesamet), cannabidiol, cannabichromene, tetrahydrocannabinol, Sativex, megestrol acetate, or any combination thereof.

18. The method of claim 1, further comprising administration of an anti-nausea or antiemetic agent selected from 5-HT3 receptor antagonists, ajwain, alizapride, anticholinergics, antihistamines, aprepitant, benzodiazepines, cannabichromene, cannabidiol, cannabinoids, cannabis, casopitant, chlorpromazine, cyclizine, dexamethasone, dexamethasone, dimenhydrinate (Gravol™

), diphenhydramine, dolasetron, domperidone, dopamine antagonists, doxylamine, dronabinol (Marinol™

), droperidol, emetrol, ginger, granisetron, haloperidol, hydroxyzine, hyoscine, lorazepam, meclizine, metoclopramide, midazolam, muscimol, nabilone (Cesamet), nk1 receptor antagonists, ondansetron, palonosetron, peppermint, Phenergan, prochlorperazine, Promacot, promethazine, Pentazine, propofol, sativex, tetrahydrocannabinol, trimethobenzamide, tropisetron, nandrolone, stilbestrol, thalidomide, lenalidomide, ghrelin agonists, myostatin antagonists, anti-myostatin antibodies, selective androgen receptor modulators, selective estrogen receptor modulators, angiotensin All antagonists, beta two adenergic receptor agonists, beta three adenergic receptor agonists, or any combination thereof.

28. The method of claim 1, wherein the antibody or antibody fragment is administered intravenously or subcutaneously.

31. The method of claim 1 wherein the anti-IL-6 antibody or antibody fragment comprising said CDRs contains a variable heavy chain polypeptide identical to the polypeptide in SEQ ID NO:

657 and a variable light chain identical to the polypeptide in SEQ ID NO;

709.

32. The method of claim 31 wherein said antibody or antibody fragment further comprises the heavy constant and light constant sequences in SEQ ID NO:

588 and SEQ ID NO;

586.

33. The method of claim 1, wherein the treated anemia treated comprises or is associated with a condition selected from a chronic disease involving inflammation, cancer, autoimmune hemolytic anemia, and pernicious anemia.

34. The method of claim 33, wherein the anti-IL-6 antibody or antibody fragment comprising said CDRs contains a variable heavy chain polypeptide identical to the polypeptide in SEQ ID NO:

657 and a variable light chain identical to the polypeptide in SEQ ID NO;

709.

35. The method of claim 34 wherein said antibody or antibody fragment further comprises the heavy constant and light constant sequences in SEQ ID NO:

588 and SEQ ID NO;

586 respectively.

19. A dosage regimen for treating anemia in a patient having a disease associated with elevated IL-6, comprising administering one or more dosages of an anti-IL-6 antibody or antibody fragment containing the VL CDRs of SEQ ID NO:

4, 5 and 6-respectively amid the VH CDRs of SEQ ID NO;

7, 8 or 120 and 9 respectively, wherein said one or more antibody dosages comprise about 80, 160 or 320 mg of said antibody or antibody fragment.

20. The method of claim 19, wherein the disease is cancer.

21. The method of claim 19, wherein the antibody or antibody fragment dosage is contained in phosphate buffered saline.

22. The method of claim 19, wherein the antibody or antibody fragment is administered about every 8 weeks.

23. The method of claim 19 wherein one dosage of said antibody or antibody fragment is administered.

24. The method of claim 19 wherein three dosages of said antibody or antibody fragment are administered.

25. The method of claim 20 wherein the patient has non-small cell lung cancer.

26. The method of claim 20, wherein the patient has colon cancer.

27. The method of claim 19 wherein the antibody or antibody fragment is administered intravenously or subcutaneously.

29. The method of claim 19, wherein the anti-IL-6 antibody or antibody fragment comprising said CDRs contains a variable heavy chain polypeptide identical to the polypeptide in SEQ ID NO:

657 and a variable light chain identical to the polypeptide in SEQ ID NO;

709.

30. The method of claim 29, wherein said antibody or antibody fragment further comprises the heavy constant and light constant sequences in SEQ ID NO:

588 and SEQ ID NO;

586.