FORMULATION FOR ANTI-ALPHA4BETA7 ANTIBODY AND METHODS OF TREATMENT
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.