Il-23 antibodies and methods of using the same

Abstract

The present invention relates to antagonizing the activity of IL-17A, IL-17F and IL-23 using bispecific antibodies that comprise a binding entity that is cross-reactive for IL-17A and IL-17F and a binding entity that binds IL-23p19. The present invention relates to novel bispecific antibody formats and methods of using the same.

What is claimed is: 
     
         1 . An isolated monoclonal antibody that specifically binds to IL-23p19 (SEQ ID NO:6) comprising a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises a CDR1 having the amino acid sequence of SEQ ID NO:19, a CDR2 having the amino acid sequence of SEQ ID NO:20 and a CDR3 having the amino acid sequence of SEQ ID NO:21, and wherein the light chain variable domain comprises a CDR1 having the amino acid sequence of SEQ ID NO:22, a CDR2 having the amino acid sequence of SEQ ID NO:23 and a CDR3 having the amino acid sequence of SEQ ID NO:24. 
     
     
         2 . The isolated monoclonal antibody of  claim 1 , wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:7. 
     
     
         3 . The isolated monoclonal antibody of  claim 2 , wherein the light chain variable domain comprises the amino acid sequence of SEQ ID NO:9. 
     
     
         4 . The isolated monoclonal antibody of  claim 3 , wherein the antibody comprises a human constant region. 
     
     
         5 . The isolated monoclonal antibody of  claim 4 , wherein the isotype of the heavy chain is IgG1, IgG2, IgG3 or IgG4. 
     
     
         6 . The isolated monoclonal antibody of  claim 5 , wherein the IgG4 heavy chain has a Serine to Proline mutation at position 241 according to Kabat. 
     
     
         7 . The isolated monoclonal antibody of  claim 4 , wherein the heavy chain constant domain comprises the amino acid sequence of SEQ ID NO:8 or SEQ ID NO:11. 
     
     
         8 . The isolated monoclonal antibody of  claim 7 , wherein the light chain comprises the amino acid sequence of SEQ ID NO:17. 
     
     
         9 . An isolated nucleic acid encoding the heavy chain and/or the light chain of the antibody according to  claim 1 . 
     
     
         10 . An expression vector comprising the following operably linked elements:
 a transcription promoter;   a polycleotide encoding the heavy chain of the antibody of  claim 1 ; and   a transcription terminator.   
     
     
         11 . An expression vector comprising the following operably linked elements:
 a transcription promoter;   a polycleotide encoding the light chain of the antibody of  claim 1 ; and   a transcription terminator.   
     
     
         12 . A recombinant host cell comprising the expression vector of  claim 10 , wherein the cell expresses the heavy chain. 
     
     
         13 . The recombinant host cell of  claim 12 , further comprising an expression vector comprising the following operably linked elements:
 a transcription promoter;   a polynucleotide encoding a light chain comprising a light chain variable domain which comprises a CDR1 having the amino acid sequence of SEQ ID NO:22, a CDR2 having the amino acid sequence of SEQ ID NO:23 and a CDR3 having the amino acid sequence of SEQ ID NO:24, wherein the cell expresses the heavy chain and the light chain.   
     
     
         14 . An expression vector comprising the following operably linked elements:
 a transcription promoter;   a first polynucleotide encoding the heavy chain of the antibody of  claim 1 ;   a second polynucleotide encoding the light chain of the antibody of  claim 1 ; and   a transcription terminator.   
     
     
         15 . A recombinant host cell comprising the expression vector of  claim 14 , wherein the cell expresses the heavy chain and light chain. 
     
     
         16 . An expression vector comprising the following operably linked elements:
 a first transcription promoter;   a first polynucleotide encoding the heavy chain of the antibody of  claim 1 ; and   a first transcription terminator; and   a second transcription promoter;   a second polynucleotide encoding the light chain of the antibody of  claim 1 ; and   a second transcription terminator.   
     
     
         17 . A recombinant host cell comprising the expression vector of  claim 16 , wherein the cell expresses the heavy chain and light chain. 
     
     
         18 . A method of producing a monoclonal antibody that specifically binds to IL-23p19 (SEQ ID NO:6), the method comprising:
 culturing the cell according to  claim 13 ; and   isolating the antibody produced by the cell.   
     
     
         19 . A method of producing a monoclonal antibody that specifically binds to IL-23p19 (SEQ ID NO:6), the method comprising:
 culturing the cell according to  claim 15 ; and   isolating the antibody produced by the cell.   
     
     
         20 . A method of producing a monoclonal antibody that specifically binds to IL-23p19 (SEQ ID NO:6), the method comprising:
 culturing the cell according to  claim 17 ; and   isolating the antibody produced by the cell.   
     
     
         21 . A composition comprising the monoclonal antibody according  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         22 . A method of treating a disease characterized by elevated expression of IL-23 in a mammal in need of such treatment comprising administering a therapeutically effective amount of the monoclonal antibody according to  claim 1  or the composition of  claim 21  to said mammal. 
     
     
         23 . The method of  claim 22 , wherein the disease is irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, atopic dermatitis, contact dermatitis, systemic sclerosis, systemic lupus erythematosus (SLE), antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), giant cell arteritis, multiple sclerosis (MS), relapsing-remitting multiple sclerosis, secondary-progressive multiple sclerosis, primary-progressive multiple sclerosis and/or progressive-relapsing multiple sclerosis, colitis, endotoxemia, arthritis, rheumatoid arthritis (RA), osteoarthritis, Sjögren's syndrome, psoriasis, psoriatic arthritis, adult respiratory disease (ARD), septic shock, multiple organ failure, idiopathic pulmonary fibrosis, asthma, chronic obstructive pulmonary disease (COPD), airway hyper-responsiveness, chronic bronchitis, allergic asthma, eczema,  Helicobacter pylori  infection, intraabdominal adhesions and/or abscesses as results of peritoneal inflammation, idiopathic demyelinating polyneuropathy, Guillain-Barre syndrome, organ allograft rejection, graft vs. host disease (GVHD), lupus nephritis, IgA nephropathy, diabetic kidney disease, minimal change disease (lipoid nephrosis), focal segmental glomerulosclerosis (FSGS), nephrogenic systemic fibrosis (NSF), nephrogenic fibrosing dermopathy, fibrosing cholestatic hepatitis, eosinophilic fasciitis (Shulman's syndrome), scleromyxedema (popular mucinosis), scleroderma, lichen sclerosusetatrophicus, POEMs syndrome (Crow-Fukase syndrome, Takatsuki disease or PEP syndrome), nephrotic syndrome, lytic bone disease, multiple myeloma-induced lytic bone disease, cystic fibrosis, age-related macular degeneration (AMD; wet AMD and dry AMD), liver fibrosis, pulmonary fibrosis, atherosclerosis, cardiac ischemia/reperfusion injury, heart failure, myocarditis, cardiac fibrosis, adverse myocardial remodeling, transplant rejection, streptococcal cell wall (SCW)-induced arthritis, gingivitis/periodontitis, herpetic stromal keratitis, gluten-sensitive enteropathy restenosis, Kawasaki disease, or an immune mediated renal disease.