Antibody-containing preparation
The present invention relates to stable antibody-containing solution formulations in which aggregate formation of Emicizumab (ACE910) which is a bispecific antibody functionally substituting for FVIII, is suppressed. Specifically, the present invention relates to the above-mentioned antibody-containing solution formulations of pH 4.5 to 6.5 that contain the aforementioned bispecific antibody at 20 to 180 mg/mL, 10 mM to 40 mM histidine-aspartate buffer, Poloxamer 188 at 0.2 to 1 mg/mL, and 100 mM to 300 mM arginine.
1 . An antibody solution formulation consisting essentially of:
a bispecific antibody at 20 to 180 mg/mL, wherein the antibody comprises a first polypeptide and a third polypeptide that form a pair, and a second polypeptide and a fourth polypeptide that form a pair, wherein the first polypeptide comprises an H chain comprising the amino acid sequences of H-chain CDRs 1, 2, and 3 of SEQ ID NOs: 1, 2, and 3, respectively; the second polypeptide comprises an H chain comprising the amino acid sequences of H-chain CDRs 1, 2, and 3 of SEQ ID NOs: 4, 5, and 6, respectively; and the third polypeptide and the fourth polypeptide comprise a common L chain comprising the amino acid sequences of L-chain CDRs 1, 2, and 3 of SEQ ID NOs: 7, 8, and 9, respectively;
20 mM histidine/aspartate buffer, wherein aspartate is the counterion species for the buffer;
0.5 mg/mL poloxamer 188; and
150 mM arginine or a salt thereof,
wherein the formulation has a pH of 6.
2 . The antibody solution formulation of claim 1 , wherein the first polypeptide comprises an H chain comprising the amino acid sequence of SEQ ID NO: 10; the second polypeptide comprises an H chain comprising the amino acid sequence of SEQ ID NO: 11, and the third polypeptide and the fourth polypeptide comprise a common L chain of SEQ ID NO: 12.
3 . An antibody solution formulation consisting essentially of:
a bispecific antibody at 20 to 180 mg/mL, wherein the antibody comprises a first polypeptide and a third polypeptide that form a pair, and a second polypeptide and a fourth polypeptide that form a pair, wherein the first polypeptide comprises an H chain comprising the amino acid sequence of SEQ ID NO: 10, the second polypeptide comprises an H chain comprising the amino acid sequence of SEQ ID NO: 11, and the third polypeptide and the fourth polypeptide comprise a common L chain of SEQ ID NO: 12;
20 mM L-histidine/aspartate buffer, wherein aspartate is the counterion species for the buffer;
0.5 mg/mL poloxamer 188; and
150 mM L-arginine,
wherein the formulation has a pH of 6.
4 . A method for stabilizing an antibody in an antibody-containing solution formulation, the method comprising adding to an antibody-containing starting solution a histidine/aspartate buffer, poloxamer 188, and arginine, to produce an antibody-containing solution formulation of pH 6 consisting essentially of 20 to 180 mg/mL of the antibody;
20 mM histidine/aspartate buffer-for-which, wherein aspartate is the counterion species for the buffer; 0.5 mg/mL poloxamer 188; and 150 mM arginine;
wherein the antibody is emicizumab; and
wherein the antibody present in the antibody-containing solution formulation is more stable than the antibody present in the starting solution.
5 . A method for suppressing aggregate formation by an antibody in an antibody-containing solution formulation, the method comprising adding to an antibody-containing starting solution a histidine/aspartate buffer, poloxamer 188, and arginine, to produce an antibody-containing solution formulation of pH 6 consisting essentially of 20 to 180 mg/mL of the antibody; 20 mM histidine/aspartate buffer for which, wherein aspartate is the counterion species for the buffer; 0.5 mg/mL poloxamer 188; and 150 mM arginine;
wherein the antibody is emicizumab; and
wherein antibody aggregate formation is suppressed in the antibody-containing solution formulation compared to antibody aggregate formation in the starting solution.
6 . A method for suppressing formation of a component with charge heterogeneity in an antibody-containing solution formulation, the method comprising adding to an antibody-containing starting solution a histidine/aspartate buffer, poloxamer 188, and arginine, to produce an antibody-containing solution formulation of pH 6 consisting essentially of 20 to 180 mg/mL of the antibody; 20 mM histidine/aspartate buffer-for-which, wherein aspartate is the counterion species for the buffer: 0.5 mg/mL poloxamer 188; and
150 mM arginine;
wherein the antibody is emicizumab; and
wherein formation of a component with charge heterogeneity is suppressed in the antibody-containing solution formulation compared to formation of the component with charge heterogeneity in the starting solution.
7 . A method of treating a human patient in need of treatment for a condition selected from hemophilia A, hemophilia A in which an inhibitor against FVIII/FVIIIa has appeared, acquired hemophilia A, and von Willebrand's disease, the method comprising administering to the patient the antibody solution formulation of any one of claim 1, 2, or 3 .
8 . The method of claim 7 , wherein the antibody solution formulation is subcutaneously administered to the patient.
9 . An antibody solution formulation consisting essentially of:
20-180 mg/ml emicizumab;
20 mM L-histidine/aspartate buffer, wherein aspartate is the counterion species for the buffer,
0.5 mg/mL poloxamer 188; and
150 mM L-arginine,
wherein the formulation has a pH of 6.
10 . The antibody solution formulation of claim 9 , wherein the antibody solution formulation consists essentially of:
20 mg/ml emicizumab,
20 mM L-histidine/aspartate buffer, wherein aspartate is the counterion species for the buffer;
0.5 mg/mL poloxamer 188; and
150 mM L-arginine,
wherein the formulation has a pH of 6.
11 . The antibody solution formulation of claim 9 , wherein the antibody solution formulation consists essentially of:
30 mg/ml emicizumab;
20 mM L-histidine/aspartate buffer, wherein aspartate is the counterion species for the buffer;
0.5 mg/mL poloxamer 188; and
150 mM L-arginine,
wherein the formulation has a pH of 6.
12 . The antibody solution formulation of claim 9 , wherein the antibody solution formulation consists essentially of:
40 mg/ml emicizumab;
20 mM L-histidine/aspartate buffer, wherein aspartate is the counterion species for the buffer;
0.5 mg/mL poloxamer 188; and
150 mM L-arginine,
wherein the formulation has a pH of 6.
13 . The antibody solution formulation of claim 9 , wherein the antibody solution formulation consists essentially of:
120 mg/ml emicizumab;
20 mM L-histidine/aspartate buffer, wherein aspartate is the counterion species for the buffer;
0.5 mg/mL poloxamer 188; and
150 mM L-arginine,
wherein the formulation has a pH of 6.
14 . The antibody solution formulation of claim 9 , wherein the antibody solution formulation consists essentially of:
150 mg/ml emicizumab;
20 mM L-histidine/aspartate buffer, wherein aspartate is the counterion species for the buffer;
0.5 mg/mL poloxamer 188; and
150 mM L-arginine,
wherein the formulation has a pH of 6.
15 . The antibody solution formulation of claim 9 , wherein the antibody solution formulation consists essentially of:
180 mg/ml emicizumab;
20 mM L-histidine/aspartate buffer, wherein aspartate is the counterion species for the buffer;
0.5 mg/mL poloxamer 188; and
150 mM L-arginine,
wherein the formulation has a pH of 6.
16 . A method of treating a human patient in need of treatment for a condition selected from hemophilia A, hemophilia A in which an inhibitor against FVIII/FVIIIa has appeared, acquired hemophilia A, and von Willebrand's disease, the method comprising subcutaneously administering to the patient the antibody solution formulation of claim 9 .
17 . A method of treating a human patient in need of treatment for a condition selected from hemophilia A, hemophilia A in which an inhibitor against FVIII/FVIIIa has appeared, acquired hemophilia A, and von Willebrand's disease, the method comprising subcutaneously administering to the patient the antibody solution formulation of claim 10 .
18 . A method of treating a human patient in need of treatment for a condition selected from hemophilia A, hemophilia A in which an inhibitor against FVIII/FVIIIa has appeared, acquired hemophilia A, and von Willebrand's disease, the method comprising subcutaneously administering to the patient the antibody solution formulation of claim 11 .
19 . A method of treating a human patient in need of treatment for a condition selected from hemophilia A, hemophilia A in which an inhibitor against FVIII/FVIIIa has appeared, acquired hemophilia A, and von Willebrand's disease, the method comprising subcutaneously administering to the patient the antibody solution formulation of claim 12 .
20 . A method of treating a human patient in need of treatment for a condition selected from hemophilia A, hemophilia A in which an inhibitor against FVIII/FVIIIa has appeared, acquired hemophilia A, and von Willebrand's disease, the method comprising subcutaneously administering to the patient the antibody solution formulation of claim 13 .
21 . A method of treating a human patient in need of treatment for a condition selected from hemophilia A, hemophilia A in which an inhibitor against FVIII/FVIIIa has appeared, acquired hemophilia A, and von Willebrand's disease, the method comprising subcutaneously administering to the patient the antibody solution formulation of claim 14 .
22 . A method of treating a human patient in need of treatment for a condition selected from hemophilia A, hemophilia A in which an inhibitor against FVIII/FVIIIa has appeared, acquired hemophilia A, and von Willebrand's disease, the method comprising subcutaneously administering to the patient the antibody solution formulation of claim 15 .
23 . The antibody solution formulation of claim 1 , wherein the arginine or salt thereof is arginine.
24 . The antibody solution formulation of claim 1 , wherein the arginine or salt thereof is L-arginine.
25 . The antibody solution formulation of claim 2 , wherein the arginine or salt thereof is arginine.
26 . The antibody solution formulation of claim 2 , wherein the arginine or salt thereof is L-arginine.