IL-1 binding proteins

• US 9,447,184 B2
• Filed: 12/26/2013
• Issued: 09/20/2016
• Est. Priority Date: 05/14/2010
• Status: Active Grant

• Current Assignee: Abbvie Incorporated
• Original Assignee: Abbvie Incorporated
• Inventors: Wu, Chengbin, Ambrosi, Dominic J., Hsieh, Chung-ming, Ghayur, Tariq
• Primary Examiner(s): Wu, Julie
• Application Number:
  US14/141,317
• Publication Number:
  US 20140220020A1
• Time in Patent Office: 999 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• 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 47/6879 the immunoglobulin having two or more different antigen-binding sites, e.g. bispecific or multispecific immunoglobulin
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0031 Rectum, anus
• CPC Class Codes: A61K 9/0034 Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61K 9/007 Pulmonary tract; Aromatherapy
• CPC Class Codes: A61K 9/0085 Brain, e.g. brain implants; Spinal cord
• 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 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• 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 11/16 : Central respiratory analeptics
• CPC Class Codes: A61P 13/02 : of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/08 : of the prostate
• CPC Class Codes: A61P 13/12 : of the kidneys
• CPC Class Codes: A61P 15/02 : for disorders of the vagina
• 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 15/10 : for impotence
• 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 17/08 : Antiseborrheics
• 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 19/06 : Antigout agents, e.g. antihyperuricemic or uricosuric agents
• 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 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 : Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 : Antimigraine agents
• CPC Class Codes: A61P 25/14 : for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 : Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 : Anxiolytics
• 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 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 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 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/08 : for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 3/14 : for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/06 : for tuberculosis
• 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 31/14 : for RNA viruses
• CPC Class Codes: A61P 31/16 : for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 31/20 : for DNA viruses
• CPC Class Codes: A61P 33/00 : Antiparasitic agents
• CPC Class Codes: A61P 33/02 : Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 33/06 : Antimalarials
• CPC Class Codes: A61P 33/08 : for Pneumocystis carinii
• 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 37/04 : 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 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 5/16 : for decreasing, blocking or antagonising the activity of the thyroid hormones
• CPC Class Codes: A61P 5/18 : of the parathyroid hormones
• CPC Class Codes: A61P 5/48 : of the pancreatic hormones
• CPC Class Codes: A61P 5/50 : for increasing or potentiating the activity of insulin
• 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 7/10 : Antioedematous agents; Diuretics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/06 : Antiarrhythmics
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• 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: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07K 14/545 : IL-1
• CPC Class Codes: C07K 16/245 : IL-1
• CPC Class Codes: C07K 16/468 : Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/31 : multispecific
• CPC Class Codes: C07K 2317/33 : Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• 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 2317/64 : comprising a combination of variable region and constant region components
• 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: G01N 2333/545 : IL-1
• CPC Class Codes: G01N 2800/00 : Detection or diagnosis of diseases
• CPC Class Codes: G01N 33/6869 : Interleukin
• 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

Proteins that bind IL-1α and IL-1β are described along with their use in compositions and methods for treating, preventing, and diagnosing IL-1-related disorders and for detecting IL-1α and IL-1β in cells, tissues, samples, and compositions.

Claims

1. A method for treating a subject for a disorder in which IL-1 activity is detrimental comprising administering to the subject a binding protein, wherein the binding protein comprises first and second polypeptide chains, wherein said first polypeptide chain comprises a first VD1-(X1)n-VD2-C-(X2)n, wherein:

VD1 is a first heavy chain variable domain;

VD2 is a second heavy chain variable domain;

C is a heavy chain constant domain;

X1 is a linker with the proviso that it is not CH1;

X2 is an Fc region; and

n is independently 0 or 1; and

wherein said second polypeptide chain comprises a second VD1-(X1)n-VD2-C-(X2)n, wherein;

VD1 is a first light chain variable domain;

VD2 is a second light chain variable domain;

C is a light chain constant domain;

X1 is a linker with the proviso that it is not CH1;

X2 does not comprise an Fc region; and

n is independently 0 or 1;

wherein, in said first polypeptide chain, VD1 comprises an amino acid sequence of SEQ ID NO;

204; and

VD2 comprises an amino acid of SEQ ID NO;

213;

wherein, in said second polypeptide chain, VD1 comprises an amino acid sequence of SEQ ID NO;

238; and

VD2 comprises an amino acid sequence of SEQ ID NO;

216; and

wherein the binding protein binds human IL-1β and

human IL-1α

, such that treatment for the disorder is achieved.

2. The method according to claim 1, wherein said administering to the subject is by at least one mode selected from parenteral, subcutaneous, intramuscular, intravenous, intra-articular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, and transdermal.

7. The method of claim 1, wherein the disorder is an inflammatory disorder.

11. The method of claim 7, wherein said disorder is selected from the group consisting of:

rheumatoid arthritis;

osteoarthritis;

juvenile chronic arthritis;

septic arthritis;

Lyme arthritis;

psoriatic arthritis; and

reactive arthritis.

15. The method according to claim 1, wherein said first polypeptide chain comprises an amino acid sequence of SEQ ID NO:

212.

16. The method according to claim 1, wherein said second polypeptide chain comprises an amino acid sequence of SEQ ID NO:

215.

19. The method according to claim 1, wherein said first polypeptide chain comprises the amino acid sequence of SEQ ID NO:

212, and said second polypeptide chain comprises the amino acid sequence of SEQ ID NO;

215.

21. The method according to claim 11, wherein said first polypeptide chain comprises the amino acid sequence of SEQ ID NO:

212, and said second polypeptide chain comprises the amino acid sequence of SEQ ID NO;

215.

23. The binding protein according to claim 21, wherein said heavy chain constant domain of the first polypeptide comprises SEQ ID NO:

214, and said light chain constant domain of the second polypeptide comprises SEQ ID NO;

5.

3. A method of treating a patient suffering from a disorder in which IL-1 is detrimental comprising the step of administering a binding protein before, concurrently with, or after the administration of a second agent, wherein the binding protein comprises first and second polypeptide chains, wherein said first polypeptide chain comprises a first VD1-(X1)n-VD2-C-(X2)n, wherein:

VD1 is a first heavy chain variable domain;

VD2 is a second heavy chain variable domain;

C is a heavy chain constant domain;

X1 is a linker with the proviso that it is not CH1;

X2 is an Fc region; and

n is independently 0 or 1; and

wherein said second polypeptide chain comprises a second VD1-(X1)n-VD2-C-(X2)n, wherein;

VD1 is a first light chain variable domain;

VD2 is a second light chain variable domain;

C is a light chain constant domain;

X1 is a linker with the proviso that it is not CH1;

X2 does not comprise an Fc region; and

n is independently 0 or 1;

wherein, in said first polypeptide chain, VD1 comprises an amino acid sequence of SEQ ID NO;

204; and

VD2 comprises an amino acid sequence of SEQ ID NO;

213;

wherein, in said second polypeptide chain, VD1 comprises an amino acid sequence of SEQ ID NO;

238; and

VD2 comprises an amino acid sequence of SEQ ID NO;

216; and

wherein the binding protein binds human IL-1β and

human IL-1α

;

wherein the second agent is selected from the group consisting of;

an antibody, or fragment thereof, capable of binding human IL-1β

;

an antibody, or fragment thereof, capable of binding human IL-1α

;

methotrexate;

a corticosteroid;

a beta-agonist;

an antagonist of a leukotriene;

an antagonist of a leukotriene receptor;

ADVAIR;

an IgE inhibitor;

an anti-IgE antibody;

XOLAIR;

a phosphodiesterase inhibitor;

a PDE4 inhibitor;

a xanthine;

an anticholinergic drug;

a mast cell-stabilizing agent;

Cromolyn;

an IL-4 inhibitor;

an IL-5 inhibitor;

an eotaxin/CCR3 inhibitor;

an antagonist of histamine;

an antagonist of a histamine receptor, an antagonist of prostaglandin D;

an inhibitor of receptor DP1;

an inhibitor of CRTH2;

a TNF antagonist;

a soluble fragment of a TNF receptor;

ENBREL;

a TNF enzyme antagonist;

a TNF converting enzyme (TACE) inhibitor;

a muscarinic receptor antagonist;

a TGF-beta antagonist;

interferon gamma;

perfenidone;

a chemotherapeutic agent, leflunomide;

sirolimus (rapamycin) or an analog thereof, CCI-779;

a COX2 or cPLA2 inhibitor;

a non-steroidal anti-inflammatory drug (NSAID);

an immunomodulator;

a p38 inhibitor;

a TPL-2 inhibitor;

an MK-2 inhibitor;

an NFκ

B inhibitor;

budenoside;

epidermal growth factor;

cyclosporine;

sulfasalazine;

an amino salicylate;

6-mercaptopurine;

azathioprine;

metronidazole;

a lipoxygenase inhibitor;

mesalamine;

olsalazine;

balsalazide;

an antioxidant;

a thromboxane inhibitor;

an IL-1 receptor antagonist;

a growth factor;

an elastase inhibitor;

a pyridinyl-imidazole compound;

an antibody or agonists of TNF, LT, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31, IL-32, IL-33, EMAP-II, GM-CSF, FGF, or PDGF;

an antibody to CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90;

FK506;

mycophenolate mofetil;

ibuprofen;

prednisolone;

an adensosine agonist;

an antithrombotic agent;

a complement inhibitor;

an adrenergic agent;

a kinase inhibitor;

an IL-1β

converting enzyme inhibitors;

a T-cell signaling inhibitor;

a metalloproteinase inhibitor;

an angiotensin converting enzyme inhibitor;

soluble cytokine receptor;

soluble p55 TNF receptor;

soluble p75 TNF receptor;

soluble IL-1RI;

soluble IL-1RII;

soluble IL-6R;

an anti-inflammatory cytokine;

IL-4;

IL-10;

IL-11; and

TGF-β

.

8. The method of claim 3, wherein the disorder is an inflammatory disorder.

12. The method of claim 8, wherein said disorder is selected from the group consisting of:

rheumatoid arthritis;

osteoarthritis;

juvenile chronic arthritis;

septic arthritis;

Lyme arthritis;

psoriatic arthritis; and

reactive arthritis.

17. The method according to claim 3, wherein said first polypeptide chain comprises an amino acid sequence of SEQ ID NO:

212.

18. The method according to claim 3, wherein said second polypeptide chain comprises an amino acid sequence of SEQ ID NO:

215.

20. The method according to claim 3, wherein said first polypeptide chain comprises the amino acid sequence of SEQ ID NO:

212, and said second polypeptide chain comprises the amino acid sequence of SEQ ID NO;

215.

22. The method according to claim 12, wherein said first polypeptide chain comprises the amino acid sequence of SEQ ID NO:

212, and said second polypeptide chain comprises the amino acid sequence of SEQ ID NO;

215.

24. The binding protein according to claim 22, wherein said heavy chain constant domain of the first polypeptide comprises SEQ ID NO:

214, and said light chain constant domain of the second polypeptide comprises SEQ ID NO;

5.

4. A method for treating a subject for a disorder in which IL-1 activity is detrimental comprising administering to the subject a binding protein, wherein the binding protein comprises first and second polypeptide chains, wherein said first polypeptide chain comprises a first VD1-(X1)n-VD2-C-(X2)n, wherein:

VD1 is a first heavy chain variable domain;

VD2 is a second heavy chain variable domain;

C is a heavy chain constant domain;

X1 is a linker with the proviso that it is not CH1;

X2 is an Fc region; and

n is independently 0 or 1; and

wherein said second polypeptide chain comprises a second VD1-(X1)n-VD2-C-(X2)n, wherein;

VD1 is a first light chain variable domain;

VD2 is a second light chain variable domain;

C is a light chain constant domain;

X1 is a linker with the proviso that it is not CH1;

X2 does not comprise an Fc region; and

n is independently 0 or 1;

wherein said first polypeptide chain comprises an amino acid sequence of SEQ ID NO;

212;

wherein said second polypeptide chain comprises an amino acid sequence of SEQ ID NO;

215; and

wherein the binding protein binds human IL-1β and

human IL-1α

, such that treatment of the disorder is achieved.

5. The method according to claim 4, wherein said administering to the subject is by at least one mode selected from parenteral, subcutaneous, intramuscular, intravenous, intra-articular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, and transdermal.

9. The method of claim 4, wherein the disorder is an inflammatory disorder.

13. The method of claim 9, wherein said disorder is selected from the group consisting of:

rheumatoid arthritis;

osteoarthritis;

juvenile chronic arthritis;

septic arthritis;

Lyme arthritis;

psoriatic arthritis; and

reactive arthritis.

25. The binding protein according to claim 13, wherein said heavy chain constant domain of the first polypeptide comprises SEQ ID NO:

214, and said light chain constant domain of the second polypeptide comprises SEQ ID NO;

5.

6. A method of treating a patient suffering from a disorder in which IL-1 is detrimental comprising the step of administering a binding protein before, concurrently with, or after the administration of a second agent, wherein the binding protein comprises first and second polypeptide chains, wherein said first polypeptide chain comprises a first VD1-(X1)n-VD2-C-(X2)n, wherein:

VD1 is a first heavy chain variable domain;

VD2 is a second heavy chain variable domain;

C is a heavy chain constant domain;

X1 is a linker with the proviso that it is not CH1;

X2 is an Fc region; and

n is independently 0 or 1; and

wherein said second polypeptide chain comprises a second VD1-(X1)n-VD2-C-(X2)n, wherein;

VD1 is a first light chain variable domain;

VD2 is a second light chain variable domain;

C is a light chain constant domain;

X1 is a linker with the proviso that it is not CH1;

X2 does not comprise an Fc region; and

n is independently 0 or 1;

wherein said first polypeptide chain comprises an amino acid sequence of SEQ ID NO;

212;

wherein said second polypeptide chain comprises an amino acid sequence of SEQ ID NO;

215; and

wherein the binding protein binds human IL-1β and

human IL-1α

,

wherein the second agent is selected from the group consisting of;

an antibody, or fragment thereof, capable of binding human IL-1β

;

an antibody, or fragment thereof, capable of binding human IL-1α

;

methotrexate;

a corticosteroid;

a beta-agonist;

an antagonist of a leukotriene;

an antagonist of a leukotriene receptor;

ADVAIR;

an IgE inhibitor;

an anti-IgE antibody;

XOLAIR;

a phosphodiesterase inhibitor;

a PDE4 inhibitor;

a xanthine;

an anticholinergic drug;

a mast cell-stabilizing agent;

Cromolyn;

an IL-4 inhibitor;

an IL-5 inhibitor;

an eotaxin/CCR3 inhibitor;

an antagonist of histamine;

an antagonist of a histamine receptor, an antagonist of prostaglandin D;

an inhibitor of receptor DP1;

an inhibitor of CRTH2;

a TNF antagonist;

a soluble fragment of a TNF receptor;

ENBREL;

a TNF enzyme antagonist;

a TNF converting enzyme (TACE) inhibitor;

a muscarinic receptor antagonist;

a TGF-beta antagonist;

interferon gamma;

perfenidone;

a chemotherapeutic agent, leflunomide;

sirolimus (rapamycin) or an analog thereof, CCI-779;

a COX2 or cPLA2 inhibitor;

a non-steroidal anti-inflammatory drug (NSAID);

an immunomodulator;

a p38 inhibitor;

a TPL-2 inhibitor;

an MK-2 inhibitor;

an NFκ

B inhibitor;

budenoside;

epidermal growth factor;

cyclosporine;

sulfasalazine;

an amino salicylate;

6-mercaptopurine;

azathioprine;

metronidazole;

a lipoxygenase inhibitor;

mesalamine;

olsalazine;

balsalazide;

an antioxidant;

a thromboxane inhibitor;

an IL-1 receptor antagonist;

a growth factor;

an elastase inhibitor;

a pyridinyl-imidazole compound;

an antibody or agonists of TNF, LT, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31, IL-32, IL-33, EMAP-II, GM-CSF, FGF, or PDGF;

an antibody to CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90;

FK506;

mycophenolate mofetil;

ibuprofen;

prednisolone;

an adensosine agonist;

an antithrombotic agent;

a complement inhibitor;

an adrenergic agent;

a kinase inhibitor;

an IL-1β

converting enzyme inhibitors;

a T-cell signaling inhibitor;

a metalloproteinase inhibitor;

an angiotensin converting enzyme inhibitor;

soluble cytokine receptor;

soluble p55 TNF receptor;

soluble p75 TNF receptor;

soluble IL-1RI;

soluble IL-1RII;

soluble IL-6R;

an anti-inflammatory cytokine;

IL-4;

IL-10;

IL-11; and

TGF-β

.

10. The method of claim 6, wherein the disorder is an inflammatory disorder.

14. The method of claim 10, wherein said disorder is selected from the group consisting of:

rheumatoid arthritis;

osteoarthritis;

juvenile chronic arthritis;

septic arthritis;

Lyme arthritis;

psoriatic arthritis; and

reactive arthritis.

26. The binding protein according to claim 14, wherein said heavy chain constant domain of the first polypeptide comprises SEQ ID NO:

214, and said light chain constant domain of the second polypeptide comprises SEQ ID NO;

5.