Antagonists of IL-6 to raise albumin and/or lower CRP

• US 9,994,635 B2
• Filed: 01/05/2016
• Issued: 06/12/2018
• Est. Priority Date: 11/25/2008
• Status: Active Grant

• Current Assignee: Vitaeris Inc. (CSL Limited)
• Original Assignee: AlderBio Holdings, LLC (Lundbeck Foundation)
• Inventors: Smith, Jeffrey T. L.
• Primary Examiner(s): Hama, Joanne
• Assistant Examiner(s): HAMUD, FOZIA M
• Application Number:
  US14/988,337
• Publication Number:
  US 20160355585A1
• Time in Patent Office: 889 Days
• Field of Search: None
• 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 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 38/16 Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof enzyme inhibitors A61K38/005
• CPC Class Codes: A61K 38/2013 IL-2
• CPC Class Codes: A61K 38/208 IL-12
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/00 Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
• 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 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• 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 2317/76 : 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

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, the anti-IL-6 antibodies will be humanized and/or will be aglycosylated. Also, 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 reducing serum C-reactive protein (“

CRP”

) level in a patient with an inflammatory condition wherein interleukin-6 (“

IL-6”

) is elevated by administering an effective amount of an anti-IL-6 antibody comprising the variable heavy and light chain polypeptides of SEQ ID NO;

657 and SEQ ID NO;

709 respectively and the constant regions of SEQ ID NO;

588 and 586 and monitoring the patient to assess the reduction in the patient'"'"'s serum CRP level.

2. The method of claim 1, wherein the anti-IL-6 antibody is aglycosylated.

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

4. The method of claim 3, wherein the patient'"'"'s serum CRP level remains decreased and/or serum albumin level remains raised for an entire period intervening two consecutive anti-IL-6 antibody administrations.

5. The method of claim 1, wherein the patient has been diagnosed with a condition selected from juvenile rheumatoid arthritis, psoriasis, psoriatic arthropathy, ankylosing spondylitis, systemic lupus erythematosus, Crohn'"'"'s disease, ulcerative colitis, pemphigus, dermatomyositis, polymyositis, polymyalgia rheumatica, giant cell arteritis, vasculitis, polyarteritis nodosa, Wegener'"'"'s granulomatosis, Kawasaki disease, isolated CNS vasculitis, Churg-Strauss arteritis, microscopic polyarteritis, microscopic polyangiitis, Henoch-Schö

nlein purpura, essential cryoglobulinemic vasculitis, rheumatoid vasculitis, cryoglobulinemia, relapsing polychondritis, Behcet'"'"'s disease, Takayasu'"'"'s arteritis, ischemic heart disease, stroke, multiple sclerosis, sepsis, vasculitis secondary to a viral infection, Buerger'"'"'s Disease, cancer, advanced cancer, Osteoarthritis, systemic sclerosis, CREST syndrome, Reiter'"'"'s disease, Paget'"'"'s disease of bone, Sjö

gren'"'"'s syndrome, diabetes type 1, diabetes type 2, familial Mediterranean fever, autoimmune thrombocytopenia, autoimmune hemolytic anemia, autoimmune thyroid diseases, pernicious anemia, vitiligo, alopecia greata, primary biliary cirrhosis, autoimmune chronic active hepatitis, alcoholic cirrhosis, viral hepatitis including hepatitis B and C, burn, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, allergic asthma, or any combination thereof.

6. The method of claim 1, further comprising:

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

7. The method of claim 1, further comprising administration of one or more statins to the patient.

8. The method of claim 7, wherein the one or more statins is selected from atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, or any combination thereof.

9. A method of increasing serum albumin level in a patient with an inflammatory condition wherein interleukin-6 (“

IL-6”

) is elevated by administering an effective amount of an anti-IL-6 antibody comprising the variable heavy and light chain polypeptides of SEQ ID NO;

657 and SEQ ID NO;

709 respectively and the constant regions of SEQ ID NO;

588 and 586, and monitoring the patient to assess the increase in the patient'"'"'s serum albumin level.

10. The method of claim 9, wherein the anti-IL-6 antibody is administered to the patient with a frequency at most once per period of approximately four weeks.

11. The method of claim 9, further comprising:

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

12. A method of reducing a patient'"'"'s serum CRP level and increasing the patient'"'"'s serum albumin level in a patient with an inflammatory condition wherein interleukin-6 (“

IL-6”

) is elevated by administering an effective amount of an anti-IL-6 antibody comprising the variable heavy and light chain polypeptides of SEQ ID NO;

657 and SEQ ID NO;

709 respectively and the constant regions of SEQ ID NO;

588 and 586, and monitoring the patient to assess the reduction in the patient'"'"'s serum CRP level and the increase in the patient'"'"'s serum albumin level.

13. The method of claim 12, wherein the anti-IL-6 antibody is administered to the patient with a frequency at most once per period of approximately four-weeks.

14. The method of claim 12, wherein the patient has been diagnosed with psoriasis, psoriatic arthropathy, ankylosing spondylitis, systemic lupus erythematosus, Crohn'"'"'s disease, ulcerative colitis, pemphigus, dermatomyositis, polymyositis, polymyalgia rheumatica, giant cell arteritis, vasculitis, polyarteritis nodosa, Wegener'"'"'s granulomatosis, Kawasaki disease, isolated CNS vasculitis, Churg-Strauss arteritis, microscopic polyarteritis, microscopic polyangiitis, Henoch-Schö

nlein purpura, essential cryoglobulinemic vasculitis, rheumatoid vasculitis, cryoglobulinemia, relapsing polychondritis, Behcet'"'"'s disease, Takayasu'"'"'s arteritis, ischemic heart disease, stroke, multiple sclerosis, sepsis, vasculitis secondary to viral infection, Buerger'"'"'s Disease, cancer, advanced cancer, Osteoarthritis, systemic sclerosis, CREST syndrome, Reiter'"'"'s disease, Paget'"'"'s disease of bone, Sjö

gren'"'"'s syndrome, diabetes type 1, diabetes type 2, familial Mediterranean fever, autoimmune thrombocytopenia, autoimmune hemolytic anemia, autoimmune thyroid diseases, pernicious anemia, vitiligo, alopecia areata, primary biliary cirrhosis, autoimmune chronic active hepatitis, alcoholic cirrhosis, viral hepatitis, burns, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, allergic asthma, or any combination thereof.