Anti-IL-6 antibodies for the treatment of oral mucositis

• US 8,992,908 B2
• Filed: 11/23/2011
• Issued: 03/31/2015
• Est. Priority Date: 11/23/2010
• Status: Active Grant

• Current Assignee: Vitaeris Inc. (CSL Limited)
• Original Assignee: AlderBio Holdings, LLC (Lundbeck Seattle Biopharmaceuticals, Inc.)
• Inventors: Smith, Jeffrey T.L., Garcia-Martinez, Leon F., Feldhaus, Andrew L.
• Primary Examiner(s): Bunner, Bridget E
• Assistant Examiner(s): HAMUD, FOZIA M
• Application Number:
  US13/304,173
• Publication Number:
  US 20120189629A1
• Time in Patent Office: 1,224 Days
• Field of Search: None
• US Class Current: 424/130.1
• 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 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/7105 Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 38/204 IL-6
• 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 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 Antianaemics
• 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 2317/565 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: C07K 2317/94 : Stability, e.g. half-life, pH, temperature or enzyme-resistance
• 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
• CPC Class Codes: G01N 33/57407 : Specifically defined cancers
• CPC Class Codes: G01N 33/57484 : involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites

Abstract

The present invention is directed to therapeutic methods using IL-6 antagonists such as anti-IL-6 antibodies and fragments thereof having binding specificity for IL-6 to prevent or treat mucositis (e.g., oral mucositis) including persons on a treatment regimen with a drug or chemotherapy and/or radiation for cancer (e.g., head and neck cancer) that is associated with increased risk of mucositis, including oral mucositis.

Claims

1. A method of treating or reducing the occurrence of mucositis in a subject in need thereof, comprising administering a composition comprising an effective amount of an anti-interleukin 1 (IL-6) antibody or antibody fragment thereof that binds IL-6, wherein said antibody or antibody fragment thereof comprises the variable light (V_L) complementarity determining regions (CDRs) in SEQ ID NO:

4, 5 and 6, and the variable heavy (V_H) CDRs in SEQ ID NO;

7, 8 or 120, and 9, respectively.

2. The method of claim 1, wherein said mucositis is oral mucositis.

3. The method of claim 1, wherein said mucositis is alimentary track mucositis.

4. The method of claim 1, wherein said mucositis is gastrointestinal tract mucositis.

5. The method of claim 1, wherein said mucositis is mucositis associated with chemotherapy.

6. The method of claim 5, wherein said chemotherapy comprises administration of a chemotherapy agent selected from the group consisting of Alemtuzumab (Campath™

), Asparaginase (Elspar™

), Bleomycin (Blenoxane™

), Busulfan (Myleran™

, Busulfex™

), Capecitabine (Xeloda™

), Carboplatin (Paraplatin™

), Cisplatin (PLATINOL™

), Cyclophosphamide (Cytoxan™

), Cytarabine (Cytosar-U™

), Daunorubicin (Cerubidine™

), Docetaxel (Taxotere™

), Doxorubicin (Adriamycin™

), Epirubicin (Ellence™

), Etoposide (VePesid™

), Fluorouracil (5-FU™

), Gemcitabine (Gemzar™

), Gemtuzumab ozogamicin (Mylotarg™

), Hydroxyurea (Hydrea™

), Idarubicin (Idamycin™

), Interleukin 2 (Proleukin™

) Irinotecan (Camptosar™

), Lomustine (CeeNU™

), Mechlorethamine (Mustargen™

), Melphalan (Alkeran™

), Methotrexate (Rheumatrex™

), Mitomycin (Mutamycin™

), Mitoxantrone (Novantrone™

), Oxaliplatin (Eloxatin™

), Paclitaxel (Taxol™

), Pemetrexed (Alimta™

) Pentostatin (Nipent™

), Procarbazine (Matulane™

), Thiotepa (Thioplex™

), Topotecan (Hycamtin™

), Trastuzumab (Herceptin™

), Tretinoin (Vesanoid™

), Vinblastine (Velban™

), and Vincristine (Oncovin™

).

7. The method of claim 1, wherein said mucositis is mucositis associated with radiotherapy.

8. The method of claim 1, wherein said mucositis is mucositis associated with cancer.

9. The method of claim 1, wherein said mucositis is mucositis associated with hematopoietic stem cell transplant (HSCT).

10. The method of claim 1, wherein said anti-IL-6 antibody or antibody fragment thereof comprises at least one light chain selected from the group consisting of an amino acid sequence with at least about 90% sequence identity to an amino acid sequence of SEQ ID NO:

2, 20, 647, 648, 649, 650, 651, 655, 660, 666, 667, 671, 675, 679, 683, 687, 693, 699, 702, 706, or 709.

11. The method of claim 1, wherein said anti-IL-6 antibody or antibody fragment thereof comprises at least one heavy chain selected from the group consisting of an amino acid sequence with at least about 90% sequence identity to an amino acid sequence of SEQ ID NO:

3, 18, 19, 652, 653, 654, 655, 656, 657, 658, 661, 664, 665, 668, 672, 676, 680, 684, 688, 691, 692, 704, or 708.

12. The method of claim 1, wherein said antibody or antibody fragment thereof comprises a light chain comprising the amino acid sequence of SEQ ID NO:

2, 20, 647, 648, 649, 650, 651, 660, 666, 699, 702, 706, or 709.

13. The method of claim 1, wherein said antibody or antibody fragment thereof comprises a humanized light chain comprising the amino acid sequence of SEQ ID NO:

648, 649, or 650.

14. The method of claim 1, wherein said antibody or antibody fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:

3, 18, 19, 652, 653, 654, 655, 656, 657, 658, 661, 664, 665, 704, or 708.

15. The method of claim 1, wherein said antibody or antibody fragment thereof comprises a humanized heavy chain comprising the amino acid sequence of SEQ ID NO:

653, 654, or 655.

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

17. The method of claim 16, wherein the cell is mammalian, yeast, bacterial, or insect cell.

18. The method of claim 17, wherein the cell is a yeast cell.

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

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

21. The method of claim 1, wherein said antibody or antibody fragment thereof is asialated.

22. The method of claim 1, wherein said antibody fragment is a Fab, Fab′

, F(ab′

)₂, Fv, scFv, IgNAR, SMIP, camelbody, or nanobody.

23. The method of claim 1, wherein said antibody or antibody fragment thereof has an in vivo half-life of at least about 30 days.

24. The method of claim 1, wherein the antibody or antibody fragment thereof is aglycosylated.

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

26. The method of claim 1, wherein the antibody or antibody fragment thereof is a human, humanized, single chain, or chimeric antibody.

27. The method of claim 1, wherein the antibody or antibody fragment thereof further comprises a human F_c.

28. The method of claim 1, wherein said anti-IL-6 antibody or antibody fragment thereof is administered prior to, concurrent with or after chemotherapy or radiotherapy.

29. The method of claim 1, wherein said subject is receiving concomitant chemotherapy.

30. The method claim 1, wherein said treated mucositis comprises oral or oropharyngeal mucositis induced by chemoradiation (CRT) regimens or hematopoietic stem cell transplant (HSCT) used for the treatment of cancers of the head and neck.

31. A method of treating or reducing the occurrence of emesis in a subject in need thereof, comprising administering a composition comprising an effective amount of an anti-interleukin 1 (IL-6) antibody or antibody fragment thereof that binds IL-6, wherein said antibody or antibody fragment thereof comprises the variable light (V_L) complementarity determining regions (CDRs) in SEQ ID NO:

4, 5 and 6, and the variable heavy (V_H) CDRs in SEQ ID NO;

7, 8 or 120, and 9, respectively.

32. The method of claim 31, wherein said emesis is emesis associated with chemotherapy.

33. The method of claim 31, wherein said emesis is emesis associated with radiotherapy.

34. The method of claim 31, wherein said emesis is emesis associated with hematopoietic stem cell transplant (HSCT).

35. A method for treating oral mucositis in a subject with head and neck cancer receiving concomitant chemotherapy, comprising administering an effective amount of a humanized monoclonal antibody that specifically binds interleukin-6 (IL-6), wherein said antibody or antibody fragment thereof comprises the variable light (V_L) CDRs in SEQ ID NO:

4, 5 and 6, and the variable heavy (V_H) CDRs in SEQ ID NO;

7, 8 or 120, and 9, respectively.