ADMINISTRATION OF AGENTS FOR THE TREATMENT OF INFLAMMATION
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.
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 claim 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®.