Anti-IL-6 antibodies, compositions, methods and uses

• US 7,612,182 B2
• Filed: 08/01/2007
• Issued: 11/03/2009
• Est. Priority Date: 11/14/2001
• Status: Expired due to Term

• Current Assignee: Eusa Pharma (USA) Incorporated (Jazz Pharmaceuticals Plc)
• Original Assignee: Centocor Incorporated (Johnson & Johnson)
• Inventors: Knight, David, Giles-Komar, Jill, Peritt, David, Trikha, Mohit
• Primary Examiner(s): Yu; Misook
• Assistant Examiner(s): Halvorson; Mark
• Application Number:
  US11/832,323
• Publication Number:
  US 20070292420A1
• Time in Patent Office: 825 Days
• Field of Search: None
• US Class Current: 530/388.1
• CPC Class Codes: A01K 2267/0331 Animal model for proliferative diseases
• CPC Class Codes: A01K 67/0271 Chimeric vertebrates, e.g. comprising exogenous cells
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• 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 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 1/10 Laxatives
• 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 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/04 for throat disorders
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/14 Antitussive agents
• CPC Class Codes: A61P 11/16 Central respiratory analeptics
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• 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 17/04 : Antipruritics
• CPC Class Codes: A61P 17/06 : Antipsoriatics
• CPC Class Codes: A61P 17/12 : Keratolytics, e.g. wart or anti-corn preparations
• CPC Class Codes: A61P 17/14 : for baldness or alopecia
• CPC Class Codes: A61P 19/02 : for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 : for osteoporosis
• CPC Class Codes: A61P 21/04 : for myasthenia gravis
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/30 : for treating abuse or dependence
• CPC Class Codes: A61P 25/32 : Alcohol-abuse
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• 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 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/08 : for leprosy
• CPC Class Codes: A61P 31/10 : Antimycotics
• 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 35/04 : specific for metastasis
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/04 : Immunostimulants
• 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 5/00 : Drugs for disorders of the endocrine system
• 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 7/08 : Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock artificial tears A61P27/04
• 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 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07K 16/248 : IL-6
• CPC Class Codes: C07K 16/4241 : against anti-human or anti-animal Ig
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/73 : Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• 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 relates to at least one novel chimeric, humanized or CDR-grafted anti-IL-6 antibodies derived from the murine CLB-8 antibody, including isolated nucleic acids that encode at least one such anti-IL-6 antibody, vectors, host cells, transgenic animals or plants, and methods of making and using thereof, including therapeutic compositions, methods and devices.

Claims

1. An isolated antibody or antibody fragment that binds to human IL-6, comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO:

7, a light chain variable region having the amino acid sequence of SEQ ID NO;

8, and a constant region derived from one or more human antibodies.

3. An IL-6 antibody or antibody fragment according to claim 1, wherein said antibody or antibody fragment binds IL-6 with an affinity (Kd) of at least 10⁻

9M.

4. An IL-6 antibody or antibody fragment according to claim 1 or 2, wherein said antibody or specified portion or variant substantially neutralizes at least one activity of at least one IL-6.

5. An IL-6 antibody or antibody fragment according to claim 4, wherein said activity is at least one selected from the group consisting of inhibition of IgM mu secretion from SKW6.4 cells, inhibition of IL-6 mediated MCP-1 production, inhibition of IL-6 signaling in THP-1 human monocytic leukemia cells, inhibition of IL-6 induced serum amyloid A production from HepG2 cells, and inhibition of rhIL-6 induced cell proliferation.

6. An IL-6 antibody composition or antibody fragment composition, comprising an isolated IL-6 antibody or antibody fragment according to claim 1 or 2, and a carrier or diluent.

7. A composition according to claim 6, further comprising at least one compound or protein selected from at least one of a TNF antagonist, an antirheumatic, a muscle relaxant, a narcotic, a non-steroid anti-inflamatory drug (SNAID), an analgesic, an anesthetic, a sedative, a local anethetic, a neuromuscular blocker, an antimicrobial, an antipsoriatic, a corticosteriod, an anabolic steroid, a diabetes related agent, a mineral, a nutritional, a thyroid agent, a vitamin, a calcium related hormone, an antidiarrheal, an antitussive, an antiemetic, an antiulcer, a laxative, an anticoagulant, an erythropieitin, a filgrastim, a sargramostim, an immunication, an immunoglobulin, an immunosuppressive, a growth hormone, a hormone replacement drug, an estrogen receptor modulator, a mydriatic, a cycloplegic, an alkylating agent, an antimetabolite, a mitotic inhibitor, a radiopharmaceutical, an antidepressant, antimanic agent, an antipsychotic, an anxiolytic, a hypnotic, a sympathomimetic, a stimulant, donepezil, tacrine, an asthma medication, a beta agonist, an inhaled steroid, a leukotriene inhibitor, a methylxanthine, a cromolyn, an epinephrine or analog, dornase alpha, a cytokine, a cytokine antagonist.

8. A formulation comprising at least one IL-6 antibody or antibody fragment according to claim 1 or 2, and at least one selected from sterile water, sterile buffered water, or at least one preservative selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride, alkylparaben, benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal, ormixtures thereof, in an aqueous diluent.

9. A formulation of claim 8, wherein the concentration of IL-6 antibody or antibody fragment is about 0.1 mg/ml to about 100 mg/ml.

10. A formulation of claim 8, further comprising an isotonicity agent.

11. A formulation of claim 8, further comprising a physiologically acceptable buffer.

12. A formulation comprising at least one IL-6 antibody or antibody fragment according to claim 1 or 2 in lyophilized form in a first container, and an optional second container comprising sterile water, sterile buffered water, or at least one preservative selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride, alkylparaben, benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal, or mixtures thereof in an aqueous diluent.

13. A formulation of claim 12, wherein the concentration of IL-6 antibody or antibody fragment is reconsituted to a concentration of about 0.1 mg/ml to about 500 mg/ml.

14. A formulation of claim 12, further comprising an isotonicity agent.

15. A formulation of claim 12, further comprising a physiologically acceptable buffer.

2. An isolated antibody or antibody fragment that binds to human IL-6, comprising the heavy chain and light chain complementarity determining regions (CDRs) having the amino acid sequences of SEQ ID NOS:

1-6, and a constant region derived from one or more human antibodies.