Formulation for anti-alpha4beta7 antibody and methods of treatment

Abstract

Antibody formulations are described comprising a mixture of a non-reducing sugar, an anti-α4β7 antibody and at least one amino acid. The disclosed formulations have improved stability, reduced aggregate formation, and may retard degradation of the anti-α4β7 antibody therein or exhibit any combinations thereof. The present invention further provides a safe dosing regimen of these antibody formulations that is easy to follow, and which results in a therapeutically effective amount of the anti-α4β7 antibody in vivo.

1 . A method for treating a human patient suffering from inflammatory bowel disease, wherein the method comprises the step of:
 administering to a patient suffering from inflammatory bowel disease, a humanized immunoglobulin or antigen-binding fragment thereof having binding specificity for human .α4β7 integrin,   wherein the humanized immunoglobulin or antigen-binding fragment thereof is administered to the patient according to the following dosing regimen:
 a. an initial dose of 300 mg of the humanized immunoglobulin or antigen-binding fragment thereof as an intravenous infusion; 
 b. followed by a second subsequent dose of 300 mg of the humanized immunoglobulin or antigen-binding fragment thereof as an intravenous infusion at about two weeks after the initial dose; 
 c. followed by a third subsequent dose of 300 mg of the humanized immunoglobulin or antigen-binding fragment thereof as an intravenous infusion at about six weeks after the initial dose; 
 d. followed by a fourth and subsequent doses of 300 mg of the humanized immunoglobulin or antigen-binding fragment thereof as an intravenous infusion every four weeks or every eight weeks after the third subsequent dose of the humanized antibody as needed; 
 wherein the dosing regimen induces a clinical response and clinical remission in the inflammatory bowel disease of the patient; and 
 further wherein the humanized immunoglobulin or antigen-binding fragment comprises an antigen binding region of nonhuman origin and at least a portion of an antibody of human origin, wherein the humanized immunoglobulin or antigen-binding fragment has binding specificity for the α4β7 complex, wherein the antigen-binding region comprises the CDRs: 
 Light chain: CDR1 SEQ ID NO:9
 CDR2 SEQ ID NO:10 
 CDR3 SEQ ID NO:11 
 
 Heavy chain: CDR1 SEQ ID NO:12
 CDR2 SEQ ID NO:13 
 CDR3 SEQ ID NO:14. 
 
   
     
     
         2 . The method of  claim 1 , wherein the patient had a lack of an adequate response with, loss response to, or was intolerant to treatment with at least one of an immunomodulator, a tumor necrosis factor-alpha antagonist or combinations thereof. 
     
     
         3 . The method of  claim 1 , wherein inflammatory bowel disease is Crohn's disease or ulcerative colitis. 
     
     
         4 . The method of  claim 3 , wherein the inflammatory bowel disease is ulcerative colitis. 
     
     
         5 . The method of  claim 3 , wherein the inflammatory bowel disease is moderate to severely active ulcerative colitis. 
     
     
         6 . The method of  claim 5 , wherein the dosing regimen results in mucosal healing in patients suffering from moderate to severely active ulcerative colitis. 
     
     
         7 . The method of  claim 1 , wherein the dosing regimen results in a reduction, elimination or reduction and elimination of corticosteroids use by the patient. 
     
     
         8 . The method of  claim 1 , where the patient previously received treatment with at least one corticosteroid for the inflammatory bowel disease. 
     
     
         9 . A dosing regimen for the therapeutic treatment of inflammatory bowel disease, wherein the method comprises the step of: administering to a patient suffering from inflammatory bowel disease, a humanized immunoglobulin or antigen-binding fragment thereof having binding specificity for human α4β7 integrin, wherein the humanized immunoglobulin or antigen-binding fragment thereof is administered to the patient according to the following dosing regimen:
 a. an initial dose of 300 mg of the humanized immunoglobulin or antigen-binding fragment thereof as an intravenous infusion; 
 b. followed by a second subsequent dose of 300 mg of the humanized immunoglobulin or antigen-binding fragment thereof as an intravenous infusion at about two weeks after the initial dose; 
 c. followed by a third subsequent dose of 300 mg of the humanized immunoglobulin or antigen-binding fragment thereof as an intravenous infusion at about six weeks after the initial dose; 
 d. followed by a fourth and subsequent doses of 300 mg of the humanized immunoglobulin or antigen-binding fragment thereof as an intravenous infusion every four weeks or every eight weeks after the third subsequent dose of the humanized antibody as needed; 
 wherein the dosing regimen induces a clinical response and clinical remission in the inflammatory bowel disease of the patient; and 
 further wherein the humanized immunoglobulin or antigen-binding fragment comprises an antigen binding region of nonhuman origin and at least a portion of an antibody of human origin, wherein the humanized immunoglobulin or antigen-binding fragment has binding specificity for the α4β7 complex, 
 wherein the antigen-binding region comprises the complementarity determining regions (CDRs) set forth below:
 Light chain: CDR1 SEQ ID NO:9
 CDR2 SEQ ID NO:10 
 CDR3 SEQ ID NO: 11 
 
 Heavy chain: CDR1 SEQ ID NO:12
 CDR2 SEQ ID NO:13 
 CDR3 SEQ ID NO:14. 
 
 
 
     
     
         10 . The dosing regimen of  claim 9 , wherein the patient had a lack of an adequate response with, loss response to, or was intolerant to treatment with at least one of an immunomodulator, a tumor necrosis factor-alpha antagonist or combinations thereof. 
     
     
         11 . The dosing regimen of  claim 9 , wherein inflammatory bowel disease is Crohn's disease or ulcerative colitis. 
     
     
         12 . The dosing regimen 11, wherein the inflammatory bowel disease is ulcerative colitis. 
     
     
         13 . The dosing regimen of  claim 12 , wherein the inflammatory bowel disease is moderate to severely active ulcerative colitis. 
     
     
         14 . The dosing regimen of  claim 13 , wherein the dosing regimen results in mucosal healing in patients suffering from moderate to severely active ulcerative colitis. 
     
     
         15 . The dosing regimen of  claim 9 , wherein the dosing regimen results in a reduction, elimination or reduction and elimination of corticosteroids use by the patient. 
     
     
         16 . The dosing regimen of  claim 9 , where the patient previously received treatment with at least one corticosteroid for the inflammatory bowel disease. 
     
     
         17 . A stable formulation comprising a mixture of a non-reducing sugar, an anti-α4β7 antibody and at least one free amino acid, wherein the formulation is in solid form, and the molar ratio of non-reducing sugar to anti-α4β7 antibody (mole:mole) is greater than 600:1, wherein the free amino acid to antibody molar ratio is at least 250:1. 
     
     
         18 . The formulation of  claim 1 , wherein said formulation further comprises a buffering agent. 
     
     
         19 . The formulation of  claim 1 , wherein said non-reducing sugar is selected from the group consisting of mannitol, sorbitol, sucrose, trehalose and combinations thereof. 
     
     
         20 . The formulation of  claim 1 , wherein said free amino acid is selected from the group consisting of histidine, alanine, arginine, glycine, glutamic acid and combinations thereof. 
     
     
         21 . The formulation of  claim 1 , wherein said formulation further comprises a surfactant.