Granted Patent B2

US 12,558,423 · App. 17/926,313 · Granted Feb 24, 2026

Inventors: Daisuke Kameoka (Tokyo, JP); Masaya Yasutake (Tokyo, JP); Masakazu Fukuda (Tokyo, JP); Atsushi Watanabe (Tokyo, JP); Tomoyuki Igawa (Tokyo, JP); Chifumi Imai (Tokyo, JP); Akira Hayasaka (Shizuoka, JP)

Assignee: Chugai Seiyaku Kabushiki Kaisha

A61K39/39591A61K9/08A61K9/19A61K47/10A61K47/183A61K47/22C07K16/2866A61K2039/54C07K2317/24C07K2317/565

Abstract

Claims (74)

1 . An antibody solution formulation comprising:

50 to 250 mg/mL of an antibody comprising

a heavy chain variable region that comprises a CDR1 comprising the sequence of SEQ ID NO: 1, a CDR2 comprising the sequence of SEQ ID NO: 2, and a CDR3 comprising the sequence of SEQ ID NO: 3, and

a light chain variable region that comprises a CDR1 comprising the sequence of SEQ ID NO: 4, a CDR2 comprising the sequence of SEQ ID NO: 5, and a CDR3 comprising the sequence of SEQ ID NO: 6;

10 to 100 mM of histidine-aspartate buffer or histidine-glutamate buffer;

0.2 mg/mL to 0.5 mg/mL of Poloxamer 188; and

5 mM to 300 mM of arginine,

wherein the pH of the formulation is in the range of 5.5 to 6.6.

2 . The formulation according to claim 1 , which is a solution formulation that is not a reconstituted solution of a lyophilized formulation.

3 . A lyophilized formulation that is a composition resulting from lyophilizing a solution comprising:

50 to 250 mg/mL of an antibody comprising

a heavy chain variable region that comprises a CDR1 comprising the sequence of SEQ ID NO: 1, a CDR2 comprising the sequence of SEQ ID NO: 2, and a CDR3 comprising the sequence of SEQ ID NO: 3, and

a light chain variable region that comprises a CDR1 comprising the sequence of SEQ ID NO: 4, a CDR2 comprising the sequence of SEQ ID NO: 5, and a CDR3 comprising the sequence of SEQ ID NO: 6;

10 to 100 mM of histidine-aspartate buffer or histidine-glutamate buffer;

0.2 mg/mL to 0.5 mg/mL of Poloxamer 188; and

5 mM to 300 mM of arginine,

wherein the pH of the formulation after reconstitution in water is in the range of 5.5 to 6.6.

4 . The formulation according to claim 1 , which is free of sugars.

5 . The formulation according to claim 1 , wherein antibody association is suppressed.

6 . A formulation for injection comprising:

(i) a container, and

(ii) in the container, an antibody solution formulation that comprises, per 1 mL of solution, 50 to 250 mg of an antibody comprising

a heavy chain variable region that comprises a CDR1 comprising the sequence of SEQ ID NO: 1, a CDR2 comprising the sequence of SEQ ID NO: 2, and a CDR3 comprising the sequence of SEQ ID NO: 3, and

a light chain variable region that comprises a CDR1 comprising the sequence of SEQ ID NO: 4, a CDR2 comprising the sequence of SEQ ID NO: 5, and a CDR3 comprising the sequence of SEQ ID NO: 6;

0.9 to 52.3 mg of L-arginine;

1.6 to 15.5 mg of L-histidine;

0.2 mg to 0.5 mg of Poloxamer 188; and

L-aspartic acid or L-glutamic acid,

wherein the pH of the solution formulation is in the range of 5.5 to 6.6.

7 . A formulation for injection comprising:

(i) a container, and

(ii) in the container, an antibody solution formulation that comprises, per 1 mL of solution, 60 to 200 mg of an antibody comprising

a heavy chain variable region that comprises a CDR1 comprising the sequence of SEQ ID NO: 1, a CDR2 comprising the sequence of SEQ ID NO: 2, and a CDR3 comprising the sequence of SEQ ID NO: 3, and

a light chain variable region that comprises a CDR1 comprising the sequence of SEQ ID NO: 4, a CDR2 comprising the sequence of SEQ ID NO: 5, and a CDR3 comprising the sequence of SEQ ID NO: 6;

8.7 to 26.1 mg of L-arginine;

1.6 to 6.2 mg of L-histidine;

0.2 mg to 1.0 mg of Poloxamer 188; and

L-aspartic acid or L-glutamic acid,

wherein the pH of the solution formulation is in the range of 5.5-6.3.

8 . A formulation for injection, comprising:

(i) a container, and

(ii) in the container, an antibody solution formulation that comprises, per 1 mL of solution,

120 mg of an antibody comprising

a heavy chain variable region that comprises a CDR1 comprising the sequence of SEQ ID NO: 1, a CDR2 comprising the sequence of SEQ ID NO: 2, and a CDR3 comprising the sequence of SEQ ID NO: 3, and

a light chain variable region that comprises a CDR1 comprising the sequence of SEQ ID NO: 4, a CDR2 comprising the sequence of SEQ ID NO: 5, and a CDR3 comprising the sequence of SEQ ID NO: 6;

26.1 mg of L-arginine;

3.1 mg of L-histidine;

0.5 mg of Poloxamer 188; and

L-aspartic acid or L-glutamic acid,

wherein the solution formulation has a pH in the range of 5.8-6.2.

9 . The formulation according to claim 1 , wherein the antibody comprises a heavy chain comprising the sequence of SEQ ID NO: 10 and a light chain comprising the sequence of SEQ ID NO: 9.

10 . The formulation according to claim 1 , which is for subcutaneous administration.

11 . The formulation according to claim 1 , which is stable at 5° C. for at least 6 months.

12 . The formulation according to claim 1 , wherein the proportion of aggregates at 5° C. is 2.0% or less for at least 6 months.

13 . A method of suppressing antibody association and the generation of insoluble visible particles, wherein the method comprises:

adding L-aspartic acid or L-glutamic acid to a solution comprising the antibody,

adding arginine to the solution such that the arginine concentration in the solution becomes 5 mM to 300 mM, and

adding Poloxamer 188 to the solution such that the Poloxamer 188 concentration in the solution becomes 0.2 mg/mL to 2.0 mg/mL,

wherein the antibody comprises

a heavy chain variable region that comprises a CDR1 comprising the sequence of SEQ ID NO: 1, a CDR2 comprising the sequence of SEQ ID NO: 2, and a CDR3 comprising the sequence of SEQ ID NO: 3, and

a light chain variable region that comprises a CDR1 comprising the sequence of SEQ ID NO: 4, a CDR2 comprising the sequence of SEQ ID NO: 5, and a CDR3 comprising the sequence of SEQ ID NO: 6.

14 . The formulation according to claim 1 , wherein the proportion of aggregates at 5° C. is 0.8% or less for at least 30 months.

15 . The formulation according to claim 2 , which is free of sugars.

16 . The formulation according to claim 3 , which is free of sugars.

17 . The formulation according to claim 3 , wherein the antibody comprises a heavy chain comprising the sequence of SEQ ID NO: 10 and a light chain comprising the sequence of SEQ ID NO: 9.

18 . The formulation according to claim 6 , wherein the antibody comprises a heavy chain comprising the sequence of SEQ ID NO: 10 and a light chain comprising the sequence of SEQ ID NO: 9.

19 . The formulation according to claim 7 , wherein the antibody comprises a heavy chain comprising the sequence of SEQ ID NO: 10 and a light chain comprising the sequence of SEQ ID NO: 9.

20 . The formulation according to claim 8 , wherein the antibody comprises a heavy chain comprising the sequence of SEQ ID NO: 10 and a light chain comprising the sequence of SEQ ID NO: 9.

21 . The formulation according to claim 1 , wherein the formulation does not contain trehalose.

22 . The formulation of claim 1 , wherein the formulation comprises 10 to 100 mM histidine-aspartate buffer.

23 . The formulation of claim 1 , wherein the formulation comprises 20 mM histidine-aspartate buffer and 150 mM arginine, and the pH of the formulation is 6.0.

24 . The formulation of claim 1 , wherein the formulation comprises 120 mg/mL of the antibody, 20 mM histidine-aspartate buffer, and 150 mM arginine, and the pH of the formulation is 6.0.

25 . The formulation of claim 1 , wherein generation of insoluble visible particles in the formulation is decreased, as compared to in an otherwise-identical formulation that comprises polysorbate 80 instead of poloxamer 188.

26 . The formulation of claim 8 , wherein the pH of the formulation is 6.0.

Assignments (1)

Priority Claims (1)

Continuity (1)

References Cited (353)