FORMULATION FOR ANTI-ALPHA4BETA7 ANTIBODY
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 immuoglobulin 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 . The method of claim 1 , wherein the humanized immunoglobulin or antigen-binding fragment thereof is administered in a final dosage form at a concentration of between about 1.0 mg/mL to about 1.4 mg/mL.
10 . The method of claim 9 , wherein the humanized immunoglobulin or antigen-binding fragment thereof is administered in a final dosage form of about 1.2 mg/mL.
11 . The method of claim 1 , wherein the humanized immunoglobulin or antigen-binding fragment thereof is administered to the patient in about 30 minutes.
12 . The method of claim 9 , wherein the humanized immunoglobulin or antigen-binding fragment thereof is reconstituted from a lyophilized formulation.
13 . The method of claim 9 , further wherein the humanized immunoglobulin or antigen-binding fragment thereof is reconstituted to comprise a stable liquid formulation.
14 . The method of claim 1 , wherein the dosing regimen does not alter the ratio of CD4 to CD8 in cerebrospinal fluid of patients receiving said treatment.
15 . 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 immuoglobulin 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.
16 . The dosing regimen of claim 15 , 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.
17 . The dosing regimen of claim 15 , wherein inflammatory bowel disease is Crohn's disease or ulcerative colitis.
18 . The dosing regimen 16 , wherein the inflammatory bowel disease is ulcerative colitis.
19 . The dosing regimen of claim 18 , wherein the inflammatory bowel disease is moderate to severely active ulcerative colitis.
20 . The dosing regimen of claim 19 , wherein the dosing regimen results in mucosal healing in patients suffering from moderate to severely active ulcerative colitis.
21 . The dosing regimen of claim 15 , wherein the dosing regimen results in a reduction, elimination or reduction and elimination of corticosteroids use by the patient.
22 . The dosing regimen of claim 15 , where the patient previously received treatment with at least one corticosteroid for the inflammatory bowel disease.
23 . The dosing regimen of claim 15 , wherein the humanized immunoglobulin or antigen-binding fragment thereof is administered in a final dosage form at a concentration of between about 1.0 mg/mL to about 1.4 mg/mL.
24 . The dosing regimen of claim 23 , wherein the humanized immunoglobulin or antigen-binding fragment thereof is administered in a final dosage form of about 1.2 mg/mL.
25 . The dosing regimen of claim 15 , wherein the humanized immunoglobulin or antigen-binding fragment thereof is administered to the patient in about 30 minutes.
26 . The method of claim 25 , wherein the humanized immunoglobulin or antigen-binding fragment thereof is reconstituted from a lyophilized formulation.
27 . The dosing regimen of claim 25 , further wherein the humanized immunoglobulin or antigen-binding fragment thereof is reconstituted to comprise a stable liquid formulation.
28 . The dosing regimen of claim 15 wherein the dosing regimen does not alter the ratio of CD4 to CD8 in cerebrospinal fluid of patients receiving said treatment.
29 . The method of claim 15 , wherein the patient is a person 65 years of age or older and further wherein the patient does not require any adjustment of the dosing regimen.
30 . The dosing regimen of claim 15 , wherein the patient is a person 65 years of age or older and further wherein the patient does not require any adjustment of the dosing regimen.