Administration of agents for the treatment of inflammation

Abstract

A method of chronically reducing a patient's pathological inflammation via the administration of an agent that specifically binds to an alpha-4 integrin or a dimer comprising an alpha-4 integrin is disclosed. The agent provided must have a binding affinity such that administration is sufficient to suppress pathological inflammation, and the agent is administered chronically to provide long-term suppression of pathological inflammation.

We claim: 
     
         1 . A method of chronically reducing pathological inflammation in a patient in need thereof comprising chronically administering an agent to the patient that inhibits alpha-4 integrin or inhibits a dimer comprising alpha-4 integrin in a therapeutically effective amount. 
     
     
         2 . The method of  claim 1 , wherein the chronic administration is for a period of at least 6 months. 
     
     
         3 . The method of  claim 2 , wherein the chronic administration is for a period of at least 12 months. 
     
     
         4 . The method of  claim 1 , wherein the agent is administered repeatedly in a manner to bind to alpha-4 integrin or a dimer comprising alpha-4 integrin, and wherein the administration maintains alpha-4 integrin receptor saturation at a level sufficient to chronically suppress pathological inflammation in the patient. 
     
     
         5 . The method of  claim 4 , wherein the agent is administered repeatedly to the patient such that alpha-4 integrin receptor saturation is about at least 65% to about 100% in the patient. 
     
     
         6 . The method of  claim 5 , wherein the saturation is at least 75%. 
     
     
         7 . The method of  claim 5 , wherein the saturation is at least 80%. 
     
     
         8 . The method of  claim 1 , wherein the agent binds to alpha-4 integrin dimers. 
     
     
         9 . The method of  claim 1 , wherein the agent is a monoclonal antibody or an immunogically active fragment thereof. 
     
     
         10 . The method of  claim 9 , wherein the monoclonal antibody is natalizumab. 
     
     
         11 . The method of  claim 1 , wherein the alpha-4 integrin dimer is alpha-4 beta-1. 
     
     
         12 . The method of  claim 4 , wherein the agent is administered in amount sufficient to saturate at least one alpha-4 integrin dimer receptor thereby inhibiting pathological inflammation. 
     
     
         13 . The method of  claim 12 , wherein the dimer receptors are alpha-4 beta-1 or alpha-4 beta-7, and the pathological inflammation is caused by multiple sclerosis. 
     
     
         14 . The method of  claim 12 , wherein the dimers receptors are alpha-4 beta-1 or alpha-4 beta-7, and the pathological inflammation is caused by an inflammatory disease of the gastrointestinal tract. 
     
     
         15 . The method of  claim 14 , wherein the inflammatory disease of the gastrointestinal tract is Crohn's Disease, ulcerative colitis or inflammatory bowel disease. 
     
     
         16 . The method of  claim 1 , wherein the pathological inflammation is caused by an inflammatory disease of the gastrointestinal tract. 
     
     
         17 . The method of  claim 16 , wherein the inflammatory disease of the gastrointestinal tract is Crohn's disease, ulcerative colitis, or inflammatory bowel disease. 
     
     
         18 . The method of  claim 1 , wherein the pathological inflammation is caused by multiple sclerosis. 
     
     
         19 . A method of determining the efficacy of a chronic administration regime for treating pathological inflammation in a subject, wherein the pathological inflammation is modulated by an alpha-4 integrin comprising measuring saturation of the alpha-4 integrin or a dimer comprising alpha-4 integrin. 
     
     
         20 . The method of  claim 19 , wherein the alpha-4 integrin dimer is alpha-4 beta-1 or alpha-4 beta-7. 
     
     
         21 . The method of  claim 19 , wherein the pathological inflammation is caused by Crohn's Disease, and measurement of the C-reactive protein and/or CDAI in the patient measures saturation of alpha-4 integrin. 
     
     
         22 . The method of clam 19, wherein the pathological inflammation is caused by multiple sclerosis. 
     
     
         23 . The method of  claim 1 , wherein the pathological inflammation is an inflammatory disease of the gastrointestinal tract and comprises chronically administering a therapeutically effective dose of natalizumab or an immunologically active fragment thereof to a patient in need thereof sufficient to treat or ameliorate the inflammatory disease of the gastrointestinal tract in the patient. 
     
     
         24 . The method of  claim 23 , wherein the disease of the gastrointestinal tract is inflammatory bowel disease, Crohn's disease or ulcerative colitis. 
     
     
         25 . The method of  claim 23 , wherein natalizumab is administered by infusion every four weeks for at least 6 months in an amount of about 1 mg/kg patient to about 20 mg/kg patient. 
     
     
         26 . The method of  claim 25 , wherein the infusions are administered for at least 12 months. 
     
     
         27 . The method of  claim 1 , wherein the pathological inflammation is multiple sclerosis and comprises chronically administrating a therapeutically effective dose of natalizumab or an immunologically active fragment thereof, to a patient in need thereof sufficient to relieve symptoms of multiple sclerosis. 
     
     
         28 . The method of  claim 27 , wherein natalizumab is administered by infusion every four weeks for at least 6 months in an amount of about 1 mg/kg patient to about 20 mg/kg patient. 
     
     
         29 . The method of  claim 28 , wherein the infusions are administered for at least 12 months. 
     
     
         30 . A composition for chronic treatment of pathological inflammation in a patient comprising an agent in an amount sufficient to relieve symptoms of the pathological inflammation in the patient in need thereof. 
     
     
         31 . The composition of  claim 30 , wherein the agent inhibits alpha-4 integrin activity and/or alpha-4 integrin dimer activity. 
     
     
         32 . The composition of  claim 30 , wherein the composition further comprises a stabilizer, a carrier and/or an excipient. 
     
     
         33 . The composition of  claim 30 , wherein the agent is natalizumab. 
     
     
         34 . The composition of  claim 33 , wherein natalizumab is formulated for intravenous infusion in the amount of about 1 mg/kg patient to about 20 mg/kg patient for administration every 4 weeks for at least 6 months. 
     
     
         35 . The composition of  claim 33 , wherein the pathological inflammation is caused by multiple sclerosis. 
     
     
         36 . The composition of  claim 33 , wherein the pathological inflammation is caused by an inflammatory disease of the gastrointestinal tract. 
     
     
         37 . The composition of  claim 36 , wherein the inflammatory disease of the gastrointestinal tract is Crohn's disease, ulcerative colitis or inflammatory bowel disease. 
     
     
         38 . A combination therapy for the chronic treatment of pathological inflammation in a patient, wherein the combination therapy comprises a composition of  claim 30  and a compound that ameliorates the pathological inflammation. 
     
     
         39 . The combination therapy of  claim 38 , wherein the pathological inflammation is caused by an inflammatory disease of the gastrointestinal tract. 
     
     
         40 . The combination therapy of  claim 39 , wherein the inflammatory disease of the gastrointestinal tract is ulcerative colitis, inflammatory bowel disease or Crohn's disease, and the compound is a 5-aminosalicylate, a glucocorticoid, a thioguanine derivative, methotrexate, a cyclosporine, a monoclonal antibody that binds to TNF, or an antibiotic. 
     
     
         41 . The combination therapy of  claim 38 , wherein the pathological inflammation is caused by multiple sclerosis. 
     
     
         42 . The combination therapy of  claim 41 , wherein the compound is infliximab, interferon beta-1b, interferon beta-1a, copaxone®, a non-steroidal anti-inflammatory drug, or Novantrone®.