Human antibodies to human tnf-like ligand 1a (tl1a)

Abstract

A fully human antibody or antigen-binding fragment of a human antibody that specifically binds and inhibits human TNF-like ligand 1A (hTL1A) is provided. The human anti-hTL1A antibodies are useful in treating diseases or disorders associated with TL1A, such as inflammatory diseases or disorders, e.g., inflammatory bowel diseases, including ulcerative colitis and Crohn's disease, rheumatoid arthritis, and the like; autoimmune diseases or disorders, such as multiple sclerosis, diabetes, and the like; and allergic reactions, such as asthma and allergic lung inflammation.

1 . A pharmaceutical composition comprising (a) an isolated human antibody or antigen-binding fragment thereof that specifically binds human TNF-like ligand 1A (hTL1A) and neutralizes hTL1A and (b) a pharmaceutically acceptable carrier. 
     
     
         2 . The composition of  claim 1 , wherein the antibody or antigen-binding fragment thereof binds to hTL1A having the amino acid sequence of SEQ ID NO:244 with an equilibrium dissociation constant (KD) of about 700 pM or less, about 300 pM or less, about 80 pM or less, or 50 pM or less. 
     
     
         3 . The composition of  claim 1 , wherein the antibody or antigen-binding fragment cross-reacts with cynomolgus monkey TL1A (MfTL1A). 
     
     
         4 . The composition of  claim 1 , wherein the antibody or antigen-binding fragment comprises a heavy and light chain CDR amino acid sequence combination selected from the group consisting of SEQ ID NOs: 4/6/8/12/14/16, 20/22/24/28/30/32, 36/38/40/44/46/48, 52/54/56/60/62/64, 68/70/72/76/78/80, 84/86/88/92/94/96, 100/102/104/108/110/112, 120/122/124/128/130/132, 140/142/144/148/150/152, 160/162/164/168/170/172, 200/202/204/208/210/212, and 220/222/224/228/230/232. 
     
     
         5 . The composition of  claim 1 , wherein the antibody or fragment cross-reacts with Fhm having the amino acid sequence of SEQ ID NO:246. 
     
     
         6 . The composition of  claim 5 , wherein the antibody or antigen-binding fragment comprises a heavy and light chain CDR amino acid sequence combination selected from the group consisting of SEQ ID NOs: 4/6/8/12/14/16, 36/38/40/44/46/48, 68/70/72/76/78/80, 84/86/88/92/94/96, 100/102/104/108/110/112, 120/122/124/128/130/132, 140/142/144/148/150/152, 160/162/164/168/170/172, 180/182/184/188/190/192, and 220/222/224/228/230/232. 
     
     
         7 . The composition of  claim 1 , wherein the antibody or fragment does not cross-react with Fhm having the amino acid sequence of SEQ ID NO: 246. 
     
     
         8 . The composition of  claim 7 , wherein the antibody or antigen-binding fragment comprises a heavy and light chain CDR amino acid sequence combination selected from the group consisting of SEQ ID NOs: 20/22/24/28/30/32, 52/54/56/60/62/64, and 200/202/204/208/210/212. 
     
     
         9 . The composition of  claim 1 , wherein the antibody or antigen-binding fragment comprises a heavy and light chain CDR amino acid sequence combination selected from the group consisting of SEQ ID NOs:4/6/8/12/14/16, 20/22/24/28/30/32, 36/38/40/44/46/48, 52/54/56/60/62/64, 68/70/72/76/78/80, 84/86/88/92/94/96, 100/102/104/108/110/112, 120/122/124/128/130/132, 140/142/144/148/150/152, 160/162/164/168/170/172, 180/182/184/188/190/192, 200/202/204/208/210/212, and 220/222/224/228/230/232. 
     
     
         10 . The composition of  claim 1 , further comprising one or more additional therapeutic agents selected from the group consisting of glucocorticoids, cyclosporin, methotrexate, interferon β (IFN-β), tacrolimus, sirolimus, azathioprine, mercaptopurine, opioids, mycophenolate, TNF-binding proteins, infliximab, eternacept, adalimumab, cytotoxic antibiotics, dactinomycin, anthracyclines, mitomycin C, bleomycin, mithramycin, antibodies targeting immune cells, anti-CD20 antibodies, anti-CD3 antibodies, corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, ibuprofen, naproxen, Cox-2 inhibitors, TNF-α antagonists, IL-1 antagonists, IL-6 antagonists, acetaminophen, morphinomimetics, antihistamines, glucocorticoids, epinephrine (adrenaline), theophylline, cromolyn sodium, anti-leukotrienes, anti-cholinergics, decongestants, and mast cell stabilizers.