Humanized anti-IL-6 antibodies

• US 8,062,866 B2
• Filed: 11/13/2009
• Issued: 11/22/2011
• Est. Priority Date: 11/13/2008
• Status: Expired due to Fees

• Current Assignee: Femta Pharmaceuticals, Inc.
• Original Assignee: Femta Pharmaceuticals, Inc.
• Inventors: Chang, Hwai Wen, Frey, Gerhard, Short, Jay
• Primary Examiner(s): Shafer; Shulamith H
• Application Number:
  US12/617,915
• Publication Number:
  US 20100138945A1
• Time in Patent Office: 739 Days
• Field of Search: None
• US Class Current: 435/70.21
• 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 1/12 Antidiarrhoeals
• 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 11/06 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 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• 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 17/14 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 21/00 : Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 : Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 21/04 : for myasthenia gravis
• CPC Class Codes: A61P 23/00 : Anaesthetics
• CPC Class Codes: A61P 23/02 : Local anaesthetics
• CPC Class Codes: A61P 25/04 : Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/18 : Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 : Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 : Anxiolytics
• CPC Class Codes: A61P 25/24 : Antidepressants
• CPC Class Codes: A61P 25/32 : Alcohol-abuse
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 27/14 : Decongestants or antiallergics
• 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 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/02 : Nutrients, e.g. vitamins, minerals
• 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 31/10 : Antimycotics
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• 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 39/00 : General protective or antinoxious agents
• CPC Class Codes: A61P 39/02 : Antidotes
• 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 5/24 : of the sex hormones
• CPC Class Codes: A61P 5/50 : for increasing or potentiating the activity of insulin
• 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 9/08 : Vasodilators for multiple indications
• 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 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• 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 novel chimeric, humanized or CDR-grafted anti-IL-6 antibodies, 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:

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

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

3. The antibody or fragment according to claim 1, wherein said antibody or fragment competitively inhibits in vivo the binding to human IL-6 of an anti IL-6 murine antibody.

4. The anti-IL-6 antibody or antibody fragment that binds to human IL-6 according to claim 1, wherein said antibody or specified portion or variant binds IL-6 with an affinity (K_d) of at least 10⁻

9 M.

5. The IL-6 antibody or antibody fragment that binds to human IL-6 according to claim 1, wherein said antibody or specified portion or variant binds IL-6 with an affinity (K_d) of at least 10⁻

11 M.

6. The IL-6 antibody or antibody fragment that binds to human IL-6 according to claim 1, wherein said antibody or specified portion or variant binds with an affinity (K_d) of at least 10⁻

12 M.

7. The IL-6 antibody or antibody fragment that binds to human IL-6 according to claim 1, wherein said antibody or specified portion or variant substantially neutralizes at least one activity of at least one IL-6.

8. The IL-6 antibody or antibody fragment that binds to human IL-6 according to claim 7, wherein said activity is at least one selected from the group consisting of 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.

9. A pharmaceutical composition comprising an isolated IL-6 antibody or antibody fragment that binds to human IL-6 according to claim 1, and a carrier or diluent.

10. The composition according to claim 9, further comprising at least one compound or protein selected from at least one of TNF antagonist, an antirheumatic, a muscle relaxant, a narcotic, a non-steroid anti-inflamatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anesthetic, 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 immunization, 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, and an anti-TNFα

or IL-12/IL-23 monoclonal antibody.

11. An isolated fully human antibody or antibody fragment that binds to human IL-6 thereof, wherein said antibody or antibody fragment that binds to human IL-6 binds the same epitope or antigenic region as an anti-IL-6 antibody or fragment according to claim 1.

12. A pharmaceutical composition comprising at least one anti-IL-6 antibody or fragment according to claim 1, and at least one carrier 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, or mixtures thereof, in an aqueous diluent.

13. The composition of claim 12, wherein the concentration of anti-IL-6 antibody or antibody fragment that binds to human IL-6 is about 0.1 mg/ml to about 100 mg/ml.

14. The composition of claim 12, further comprising an isotonicity agent.

15. The composition of claim 12, further comprising a physiologically acceptable buffer.

16. A kit comprising at least one anti-IL-6 antibody or fragment according to claim 1 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.

17. The kit of claim 16, wherein the concentration of anti-IL-6 antibody or antibody fragment that binds to human IL-6 is reconstituted to a concentration of about 0.1 mg/ml to about 500 mg/ml.

18. The kit of claim 16, further comprising an isotonicity agent.

19. The kit of claim 16, further comprising a physiologically acceptable buffer.

20. An article of manufacture for human pharmaceutical use, comprising packaging material and a container comprising a solution or a lyophilized form of at least one IL-6 antibody or antibody fragment that binds to human IL-6 according to claim 1.

21. The article of manufacture of claim 20, wherein said container is a glass or plastic container having a stopper for multi-use administration.

22. A method for producing an anti-IL-6 antibody or fragment according to claim 1, comprising expressing said antibody or fragment in an isolated host cell transformed with a nucleotide sequence encoding said antibody or fragment and recovering such antibody or fragment therefrom.

23. The method according to claim 22, wherein said isolated host cell is a mammalian cell, a plant cell or a yeast cell.

24. At least one anti-IL-6 antibody or antibody fragment that binds to human IL-6 produced by a method according to claim 22.

2. An isolated antibody or antibody fragment that binds to human IL-6, comprising a heavy chain and light chain complementarity determining regions (CDRs) derived by affinity maturation from the variable regions of BA399, and a constant region derived from one or more human antibodies.