Il-1 binding proteins

Abstract

The present invention describes IL-1β binding proteins, including chimeric, CDR-grafted, and humanized antibodies that bind IL-1β. Binding proteins of the invention have high affinity for IL-1β and neutralize IL-1β activity. A binding protein of the invention can be a full-length antibody or an IL-1β-binding portion thereof. Methods of making and methods of using the binding proteins of the invention are also described. The IL-1β binding proteins of the invention are useful for detecting IL-1β and for inhibiting IL-1β activity, including in a human subject suffering from a disease or disorder in which IL-1β activity is detrimental.

1 . (canceled) 
     
     
         2 . A binding protein that is capable of binding to IL-1β, wherein said binding protein comprises at least one complementarity determining region (CDR) comprising an amino acid sequence selected from the group consisting of residues 31-35 of SEQ ID NO:26 (CDR-H1); residues 50-65 of SEQ ID NO:26 (CDR-H2); residues 98-111 of SEQ ID NO:26 (CDR-H3); residues 24-34 of SEQ ID NO:27 (CDR-L1); residues 50-56 of SEQ ID NO:27 (CDR-L2); and residues 89-97 of SEQ ID NO:27 (CDR-L3). 
     
     
         3 - 6 . (canceled) 
     
     
         7 . The binding protein of  claim 2 , further comprising a human acceptor framework sequence. 
     
     
         8 . The binding protein of  claim 7 , wherein the human acceptor framework sequence comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:10-25. 
     
     
         9 . The binding protein of  claim 8 , wherein said human acceptor framework sequence comprises at least one amino acid substitution, wherein the amino acid sequence of the human acceptor framework sequence is at least 60% identical to an amino acid sequence of any one of SEQ ID NOs:10-25. 
     
     
         10 - 13 . (canceled) 
     
     
         14 . The binding protein of  claim 2 , wherein said binding protein has greater than 90% identity to a binding protein comprising a variable heavy chain polypeptide and a variable light chain polypeptide comprising the amino acid sequences of SEQ ID NO: 30 and SEQ ID NO: 34, respectively. 
     
     
         15 . The binding protein of  claim 2 , wherein said binding protein is selected from the group consisting of: an immunoglobulin molecule, a disulfide linked Fv, a monoclonal antibody, an scFv, a chimeric antibody, a single domain antibody, a CDR-grafted antibody, a diabody, a humanized antibody, a multispecific antibody, an Fab, a dual specific antibody, a DVD-Ig protein, a Fab′, a bispecific antibody, a F(ab′)2, and a Fv. 
     
     
         16 . The binding protein of  claim 2 , wherein said binding protein 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. 
     
     
         17 . The binding protein of  claim 2 , further comprising a heavy chain constant region having an amino acid sequence selected from the group consisting of SEQ ID NO: 2 and SEQ ID NO: 3. 
     
     
         18 . The binding protein of  claim 2 , further comprising a light chain constant region having an amino acid sequence selected from the group consisting of SEQ ID NO: 4 and SEQ ID NO: 5. 
     
     
         19 . (canceled) 
     
     
         20 . The binding protein of  claim 2 , wherein said binding protein is capable of neutralizing human IL-1β. 
     
     
         21 - 24 . (canceled) 
     
     
         25 . The binding protein of  claim 2 , wherein said binding protein further comprises an agent selected from the group consisting of: an immunoadhesion molecule, an imaging agent, a therapeutic agent, and a cytotoxic agent. 
     
     
         26 . The binding protein of  claim 25 , wherein said agent is an imaging agent selected from the group consisting of: a radiolabel, an enzyme, a fluorescent label, a luminescent label, a bioluminescent label, a magnetic label, and biotin. 
     
     
         27 . The binding protein of  claim 25 , wherein said imaging agent is a radiolabel selected from the group consisting of: 3H, 14C, 35S, 90Y, 99Tc, 111In, 125I, 131I, 177Lu, 166Ho, and 153Sm. 
     
     
         28 . The binding protein of  claim 25 , wherein said agent is a therapeutic or cytotoxic agent selected from the group consisting of: an anti-metabolite, an alkylating agent, an antibiotic, a growth factor, a cytokine, an anti-angiogenic agent, an anti-mitotic agent, an anthracycline, toxin, and an apoptotic agent. 
     
     
         29 - 53 . (canceled) 
     
     
         54 . A pharmaceutical composition comprising the binding protein of  claim 2 , and a pharmaceutically acceptable carrier. 
     
     
         55 . The pharmaceutical composition of  claim 54 , wherein said pharmaceutically acceptable carrier functions as an adjuvant useful to increase the absorption, or dispersion of said binding protein. 
     
     
         56 . The pharmaceutical composition of  claim 55 , wherein said adjuvant is hyaluronidase. 
     
     
         57 . The pharmaceutical composition of  claim 54 , further comprising at least one additional agent for treating a disorder in which IL-1β activity is detrimental. 
     
     
         58 . The pharmaceutical composition of  claim 57 , wherein said additional agent is selected from the group consisting of: a therapeutic agent; an imaging agent; a cytotoxic agent; an angiogenesis inhibitor; a kinase inhibitor; a co-stimulation molecule blocker; an adhesion molecule blocker; an anti-cytokine antibody or functional fragment thereof; methotrexate; cyclosporin; rapamycin; FK506; a detectable label or reporter; a TNF antagonist; an anti-rheumatic; a muscle relaxant; a narcotic; a non-steroid anti-inflammatory drug (NSAID); an analgesic; an anesthetic; a sedative; a local anesthetic; a neuromuscular blocker; an antimicrobial; an antipsoriatic; a corticosteroid; an anabolic steroid; an erythropoietin; an immunization; an immunoglobulin; an immunosuppressive; a growth hormone; a hormone replacement drug; a radiopharmaceutical; an antidepressant; an antipsychotic; a stimulant; an asthma medication; a beta agonist; an inhaled steroid; an oral steroid; an epinephrine or analog thereof; a cytokine; and a cytokine antagonist. 
     
     
         59 - 67 . (canceled)