Anti-IL-6 antibodies or fragments thereof to treat or inhibit cachexia, associated with chemotherapy toxicity

• US 9,724,410 B2
• Filed: 11/24/2010
• Issued: 08/08/2017
• Est. Priority Date: 11/24/2009
• Status: Expired due to Fees

• Current Assignee: Vitaeris Inc. (CSL Limited)
• Original Assignee: AlderBio Holdings, LLC (Lundbeck Seattle Biopharmaceuticals, Inc.)
• Inventors: Smith, Jeffrey T. L., Latham, John A., Litton, Mark, Schatzman, Randall
• Primary Examiner(s): MERTZ, PREMA MARIA
• Application Number:
  US13/511,385
• Publication Number:
  US 20130028860A1
• Time in Patent Office: 2,449 Days
• Field of Search: 424 852, 4241331, 4241351, 4241411, 4241451
• 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 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 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 49/0004 Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
• CPC Class Codes: A61K 49/0058 Antibodies
• CPC Class Codes: A61K 51/1033 against receptors for cytokines, lymphokines or interferons
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• 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 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/06 Antiabortive agents; Labour repressants
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 : Antipsoriatics
• CPC Class Codes: A61P 17/14 : for baldness or alopecia
• CPC Class Codes: A61P 19/00 : Drugs for skeletal disorders
• 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 19/10 : for osteoporosis
• CPC Class Codes: A61P 21/00 : Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/24 : Antidepressants
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/16 : for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 33/06 : Antimalarials
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/02 : Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• 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: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07K 16/248 : IL-6
• CPC Class Codes: C07K 16/462 : Igs containing a variable region (Fv) from one specie and a constant region (Fc) from another
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/33 : Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• 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 2317/90 : characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
• 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 33/6863 : Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
• 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 and compositions, especially subcutaneous and intravenous composition using antibodies and fragments thereof having binding specificity for IL-6 to prevent or treat cachexia, fever, weakness and/or fatigue in 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. In another preferred embodiment, the patient'"'"'s survivability or quality of life will preferably be improved.

Claims

1. A method of treating or inhibiting cachexia in a patient exhibiting chemotherapy toxicity, comprising administering to the patient an anti-IL-6 antibody or an IL-6 binding antibody fragment comprising the variable light (V_L) chain CDR1 of SEQ ID NO:

4, CDR2 of SEQ ID NO;

5 and CDR3 of SEQ ID NO;

6, and the variable heavy (V_H) chain CDR1 of SEQ ID NO;

7, CDR2 of SEQ ID NO;

8 or 120, and CDR3 of SEQ ID NO;

9, wherein the patient'"'"'s cachexia associated with the chemotherapy toxicity is effectively treated or inhibited.

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

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

4. The method of claim 1, wherein the anti-IL-6 antibody or IL-6 binding antibody fragment is administered to the patient with a frequency of about once every four weeks or eight weeks.

5. The method of claim 1, wherein said anti-IL-6 antibody or IL-6 binding antibody fragment comprises a human Fc derived from IgG1, IgG2, IgG3, or IgG4.

6. The method of claim 1, wherein the anti-IL-6 antibody or IL-6 binding antibody fragment has an elimination half-life of at least about 22 days, at least about 25 days or at least about 30 days.

7. The method of claim 1, wherein the anti-IL-6 antibody or IL-6 binding antibody fragment is coadministered with a chemotherapy.

8. The method of claim 1, wherein the patient has been diagnosed with an autoimmune disorder, infectious disorder or cancer.

9. The method of claim 1, wherein the anti-IL-6 antibody or IL-6 binding antibody fragment comprises a V_H chain having at least 98% identity with the V_H chain of SEQ ID NO:

18 or 19, and a V_L chain having at least 98% identity with the V_L chain of SEQ ID NO;

20.

10. The method of claim 1, wherein the anti-IL-6 antibody or IL-6 binding antibody fragment is administered intravenously or subcutaneously to the patient at a dose of about (+/−

20%>

) 80, 160 or 320 mg.

11. The method of claim 10, wherein the patient is administered said dosage every 8 weeks or 2 months.

12. The method of claim 10, wherein said dosage is administered at least twice.

13. The method of claim 10, wherein the second dose is administered 8 weeks after the first dose.

14. The method of claim 1, wherein the anti-IL-6 antibody or IL-6 binding antibody fragment comprises a V_H chain having at least 95% identity with the V_H chain of SEQ ID NO:

18 or 19, and a V_L chain having at least 95% identity with the V_L chain of SEQ ID NO;

20.

15. The method of claim 1, wherein the anti-IL-6 antibody or IL-6 binding antibody fragment comprises the V_H chain of SEQ ID NO:

18 or 19, and the V_L chain of SEQ ID NO;

20.

16. The method of claim 1, wherein the patient is administered a composition comprising the anti-IL-6 antibody or IL-6 binding antibody fragment, and wherein the composition is formulated for subcutaneous or intravenous injection.

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

18. The method of claim 1, wherein the chemotherapy 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, Rituxan®

, ocrelizumab, ofatumumab, DXL625, Herceptin®

, or any combination thereof.

19. The method of claim 1, wherein the chemotherapy cytotoxicity is caused by a chemotherapeutic agent comprising an inhibitor of JAK1, JAK2, JAK3, or SYK.

20. The method of claim 1, further comprising:

measuring the patient'"'"'s body weight prior to administration of the anti-IL-6 antibody or IL-6 binding antibody fragment, and administering the anti-IL-6 antibody or antibody fragment to the patient if the patient'"'"'s weight has declined by greater than approximately 5% within approximately 30 days, or if the patient'"'"'s lean body mass index is less than about 17 kg/m² (male patient) or less than about 14 kg/m² (female patient).

21. The method of claim 1, further comprising:

measuring the patient'"'"'s muscular strength prior to administration of the anti-IL-6 antibody or IL-6 binding antibody fragment, and administering the anti-IL-6 antibody or antibody fragment to the patient if the patient'"'"'s muscular strength has declined by greater than approximately 20% within approximately 30 days.

22. The method of any one of claim 9, 14 or 15, wherein the anti-IL-6 antibody or IL-6 binding antibody fragment comprises the V_H chain of SEQ ID NO:

19.

23. The method of claim 1, wherein the V_H chain CDR2 is SEQ ID NO:

120.

24. The method of claim 1, wherein the anti-IL-6 antibody or IL-6 binding antibody fragment comprises the V_H chain of SEQ ID NO:

19 and the V_L chain of SEQ ID NO;

20 and human IgG1 constant domains.

25. The method of claim 1, wherein the anti-IL-6 antibody or IL-6 binding antibody fragment comprises the V_H chain of SEQ ID NO:

18 and the V_L chain of SEQ ID NO;

20 and human IgG1 constant domains.