Il-1 binding proteins

Abstract

The present invention encompasses IL-1α binding proteins. Specifically, the invention relates to antibodies that are chimeric, CDR grafted and humanized antibodies. Antibodies of the invention have high affinity for IL-1α and neutralize IL-1α activity. An antibody of the invention can be a full-length antibody or an antigen-binding portion thereof. Method of making and method of using the antibodies of the invention are also provided. The antibodies, or antibody portions, of the invention are useful for detecting IL-1α and for inhibiting IL-1α activity, e.g., in a human subject suffering from a disorder in which IL-1α activity is detrimental.

1 - 47 . (canceled) 
     
     
         48 . A method for reducing human IL-1α activity in a human subject suffering from a disorder in which IL-1α activity is detrimental comprising administering to the human subject an antibody comprising a variable heavy chain domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 48, SEQ ID NO: 50, SEQ ID NO: 52, and SEQ ID NO: 54; and a variable light chain domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 41 SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 51, SEQ ID NO: 53, and SEQ ID NO: 55; wherein the antibody is capable of specifically binding human IL-1α such that human IL-1α activity in the human subject is reduced. 
     
     
         49 . A method for treating a subject for a disease or a disorder in which IL-1α activity is detrimental comprising administering to the subject an antibody comprising a variable heavy chain domain comprising an amino acid sequence selected from the group consisting ID NO: 40, SEQ ID NO: 48, SEQ ID NO: 50, SEQ ID NO: 52, and SEQ ID NO: 54; and a variable light chain domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 41 SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 51, SEQ ID NO: 53, and SEQ ID NO: 55; wherein the antibody is capable of specifically binding human IL-1α, such that treatment is achieved. 
     
     
         50 . (canceled) 
     
     
         51 . A method of for treating a patient suffering from a disease or a disorder in which IL-1α is detrimental comprising the step of administering the binding protein of  claim 48  or  49  either before, concurrent, or after the administration of a second agent, wherein the second agent is selected from the group consisting of TNF antagonists; a soluble fragment of a TNF receptor; ENBREL; TNF enzyme antagonists; TNF converting enzyme (TACE) inhibitors; muscarinic receptor antagonists; TGF-beta antagonists; interferon gamma; perfenidone; chemotherapeutic agents, methotrexate; leflunomide; sirolimus (rapamycin) or an analog thereof, CCI-779; COX2 or cPLA2 inhibitors; NSAIDs; immunomodulators; p38 inhibitors; TPL-2, MK-2 and NFkB inhibitors; budenoside; epidermal growth factor; corticosteroids; cyclosporine; sulfasalazine; aminosalicylates; 6-mercaptopurine; azathioprine; metronidazole; lipoxygenase inhibitors; mesalamine; olsalazine; balsalazide; antioxidants; thromboxane inhibitors; IL-1 receptor antagonists; anti-IL-1β antibodies; anti-IL-6 antibodies; growth factors; elastase inhibitors; pyridinyl-imidazole compounds; antibodies or agonists of TNF, LT, IL-1β, 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; antibodies of CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or their ligands; FK506; rapamycin; mycophenolate mofetil; ibuprofen; prednisolone; phosphodiesterase inhibitors; adensosine agonists; antithrombotic agents; complement inhibitors; adrenergic agents; IRAK, NIK, IKK, p38, or MAP kinase inhibitors; IL-1β converting enzyme inhibitors; TNFα converting enzyme inhibitors; T-cell signaling inhibitors; metalloproteinase inhibitors; 6-mercaptopurines; angiotensin converting enzyme inhibitors; soluble cytokine receptors; soluble p55 TNF receptor; soluble p75 TNF receptor; sIL-1R1; sIL-1R11; sIL-6R; anti-inflammatory cytokines; IL-4; IL-10; IL-11; and TGFβ. 
     
     
         52 . The method of  claim 48  or  49 , wherein the administering step is by at least one mode of administration selected from the group consisting of parenteral, subcutaneous, intramuscular, intravenous, intrarticular, 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. 
     
     
         53 . The method of  claim 48  or  49 , wherein the variable heavy chain domain and the variable light chain domain form a pairing selected from the group consisting of: SEQ ID NO: 38 and SEQ ID NO: 44, SEQ ID NO: 40 and SEQ ID NO: 44, SEQ ID NO: 48 and SEQ ID NO: 49, SEQ ID NO: 50 and SEQ ID NO: 51, SEQ ID NO: 52 and SEQ ID NO: 53, and SEQ ID NO: 54 and SEQ ID NO: 55. 
     
     
         54 . The method of  claim 48  or  49 , wherein the antibody is selected from the group consisting of: an immunoglobulin molecule, a disulfide linked Fv, a monoclonal antibody, a scFv, a chimeric antibody, a single domain antibody, a CDR-grafted antibody, a diabody, a humanized antibody, a multispecific antibody, a Fab, a dual specific antibody, a DVD, a Fab′, a bispecific antibody, a F(ab′)2, and a Fv. 
     
     
         55 . The method of  claim 48  or  49 , wherein the antibody comprises a heavy chain immunoglobulin constant domain selected from the group consisting of: a human IgM constant domain, a human IgG4 constant domain, a human IgG1 constant domain, a human IgE constant domain, a human IgG2 constant domain, a human IgG3 constant domain, and a human IgA constant domain. 
     
     
         56 . The method of  claim 48  or  49 , wherein the antibody further comprises a heavy chain constant region comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 2 and SEQ ID NO: 3. 
     
     
         57 . The method of  claim 48  or  49 , wherein the antibody further comprises a light chain constant region comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 4 and SEQ ID NO: 5. 
     
     
         58 . The method of  claim 48  or  49 , wherein the antibody further comprises an agent selected from the group consisting of: an immunoadhension molecule, an imaging agent, a therapeutic agent, and a cytotoxic agent.