IP Library › Granted Patent US 10,759,870

Granted Patent B2

US 10,759,870 · App. 16/099,341 · Granted Sep 1, 2020

Multispecific antigen-binding molecules having blood coagulation factor VIII (FVIII) cofactor function-substituting activity and pharmaceutical formulations containing such a molecule as an active ingredient

Inventors: Yuri Teranishi (Shizuoka, JP); Kazuki Kato (Shizuoka, JP); Hikaru Koga (Shizuoka, JP); Tomoyuki Igawa (Shizuoka, JP); Kazuki Yamaguchi (Shizuoka, JP); Tetsuhiro Soeda (Shizuoka, JP)

Assignee: Chugai Seiyaku Kabushiki Kaisha

C07K16/36 C07K2317/24 C07K2317/31 C07K2317/92

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Quick Facts

Patent No.: US 10,759,870
App. No.: 16/099,341
Granted: Sep 1, 2020
Kind: B2

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Abstract

Bispecific antibodies whose FIX activation-inhibiting activity is not elevated and whose FVIII cofactor function-substituting activity is elevated have been successfully discovered.

Claims (103)

1. A bispecific antibody comprising a first antibody heavy chain and a first antibody light chain that bind to blood coagulation factor IX and/or activated blood coagulation factor IX, and a second antibody heavy chain and a second antibody light chain which bind to blood coagulation factor X, wherein the bispecific antibody is any of (a) to (t) below:

(a) a bispecific antibody which comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 56, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 61, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 73, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 84;

(b) a bispecific antibody which comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 57, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 62, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 73, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 84;

(c) a bispecific antibody which comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 58, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 63, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 74, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 85;

(d) a bispecific antibody which comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 58, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 64, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 74, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 85;

(e) a bispecific antibody which comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 57, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 62, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 75, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 86;

(f) a bispecific antibody which comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 57, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 62, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 76, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 87;

(g) a bispecific antibody which comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 57, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 62, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 74, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 85;

(h) a bispecific antibody which comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 59, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 65, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 74, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 85;

(i) a bispecific antibody which comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 59, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 66, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 74, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 85;

(j) a bispecific antibody which comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 59, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 66, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 77, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 88;

(k) a bispecific antibody which comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 59, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 67, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 77, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 88;

(l) a bispecific antibody which comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 59, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 67, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 78, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 89;

(m) a bispecific antibody which comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 59, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 68, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 77, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 88;

(n) a bispecific antibody which comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 59, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 68, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 78, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 89;

(o) a bispecific antibody which comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 60, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 69, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 79, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 90;

(p) a bispecific antibody which comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 59, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 70, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 80, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 91;

(q) a bispecific antibody which comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 60, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 71, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 79, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 90;

(r) a bispecific antibody which comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 60, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 71, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 81, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 92;

(s) a bispecific antibody which comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 60, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 69, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 82, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 93;

(t) a bispecific antibody which comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 105, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 72, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 83, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 94.

2. The bispecific antibody of claim 1 , wherein the first antibody heavy chain and antibody light chain comprise constant regions comprising the amino acid sequences set forth in (1) below, and the second antibody heavy chain and antibody light chain comprise constant regions comprising the amino acid sequences set forth in (2) below:

(1) SEQ ID NO: 119 as a heavy chain constant region and SEQ ID NO: 100 as a light chain constant region;

(2) SEQ ID NO: 118 as a heavy chain constant region and SEQ ID NO: 102 as a light chain constant region.

3. A bispecific antibody comprising a first antibody heavy chain and a first antibody light chain which bind to blood coagulation factor IX and/or activated blood coagulation factor IX, and a second antibody heavy chain and a second antibody light chain which bind to blood coagulation factor X, wherein the bispecific antibody is any of (a) to (t) below:

(a) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 120, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 126, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 138, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 149;

(b) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 121, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 127, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 138, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 149;

(c) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 122, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 128, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 139, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 150;

(d) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 122, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 129, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 139, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 150;

(e) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 121, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 127, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 140, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 151;

(f) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 121, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 127, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 141, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 152;

(g) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 121, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 127, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 139, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 150;

(h) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 123, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 130, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 139, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 150;

(i) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 123, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 131, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 139, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 150;

(j) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 123, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 131, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 142, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 153;

(k) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 123, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 132, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 142, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 153;

(l) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 123, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 132, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 143, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 154;

(m) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 123, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 133, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 142, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 153;

(n) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 123, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 133, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 143, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 154;

(o) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 124, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 134, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 144, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 155;

(p) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 123, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 135, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 145, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 156;

(q) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 124, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 136, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 144, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 155;

(r) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 124, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 136, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 146, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 157;

(s) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 124, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 134, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 147, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 158;

(t) a bispecific antibody which comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 125, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 137, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 148, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 159.

4. A pharmaceutical formulation which comprises the bispecific antibody of claim 1 and a pharmaceutically acceptable carrier.

5. A pharmaceutical formulation which comprises the bispecific antibody of claim 2 and a pharmaceutically acceptable carrier.

6. A pharmaceutical formulation which comprises the bispecific antibody of claim 3 and a pharmaceutically acceptable carrier.

7. The pharmaceutical formulation of claim 4 , which is for use in treatment of bleeding, a disease involving bleeding, or a disease caused by bleeding in a subject, wherein the bleeding, the disease involving bleeding, or the disease caused by bleeding is a condition which develops and/or progresses due to a decrease or deficiency in the activity of blood coagulation factor VIII and/or activated blood coagulation factor VIII.

8. The pharmaceutical formulation of claim 5 , which is for use in treatment of bleeding, a disease involving bleeding, or a disease caused by bleeding in a subject, wherein the bleeding, the disease involving bleeding, or the disease caused by bleeding is a condition which develops and/or progresses due to a decrease or deficiency in the activity of blood coagulation factor VIII and/or activated blood coagulation factor VIII.

9. The pharmaceutical formulation of claim 6 , which is for use in treatment of bleeding, a disease involving bleeding, or a disease caused by bleeding in a subject, wherein the bleeding, the disease involving bleeding, or the disease caused by bleeding is a condition which develops and/or progresses due to a decrease or deficiency in the activity of blood coagulation factor VIII and/or activated blood coagulation factor VIII.

10. The pharmaceutical formulation of claim 7 , wherein the condition which develops and/or progresses due to a decrease or deficiency in the activity of blood coagulation factor VIII and/or activated blood coagulation factor VIII is hemophilia A, acquired hemophilia, von Willebrand disease, or a disease with emergence of an inhibitor against blood coagulation factor VIII and/or activated blood coagulation factor VIII.

11. The pharmaceutical formulation of claim 8 , wherein the condition which develops and/or progresses due to a decrease or deficiency in the activity of blood coagulation factor VIII and/or activated blood coagulation factor VIII is hemophilia A, acquired hemophilia, von Willebrand disease, or a disease with emergence of an inhibitor against blood coagulation factor VIII and/or activated blood coagulation factor VIII.

12. The pharmaceutical formulation of claim 9 , wherein the condition which develops and/or progresses due to a decrease or deficiency in the activity of blood coagulation factor VIII and/or activated blood coagulation factor VIII is hemophilia A, acquired hemophilia, von Willebrand disease, or a disease with emergence of an inhibitor against blood coagulation factor VIII and/or activated blood coagulation factor VIII.

13. A method of treating or reducing the incidence of a condition that develops or progresses due to a deficiency in the activity of blood coagulation factor VIII and/or activated blood coagulation factor VIII, wherein the method comprises administering the pharmaceutical formulation of claim 4 to the subject.

14. A method of treating or reducing the incidence of a condition that develops or progresses due to a deficiency in the activity of blood coagulation factor VIII and/or activated blood coagulation factor VIII, wherein the method comprises administering the pharmaceutical formulation of claim 5 to the subject.

15. A method of treating or reducing the incidence of a condition that develops or progresses due to a deficiency in the activity of blood coagulation factor VIII and/or activated blood coagulation factor VIII, wherein the method comprises administering the pharmaceutical formulation of claim 6 to the subject.

16. The method of claim 13 , wherein the condition is hemophilia A, acquired hemophilia, von Willebrand disease, or a disease involving emergence of an inhibitor against blood coagulation factor VIII and/or activated blood coagulation factor VIII.

17. The method of claim 14 , wherein the condition is hemophilia A, acquired hemophilia, von Willebrand disease, or a disease involving emergence of an inhibitor against blood coagulation factor VIII and/or activated blood coagulation factor VIII.

18. The method of claim 15 , wherein the condition is hemophilia A, acquired hemophilia, von Willebrand disease, or a disease involving emergence of an inhibitor against blood coagulation factor VIII and/or activated blood coagulation factor VIII.

19. The bispecific antibody of claim 1 , wherein the bispecific antibody comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 56, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 61, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 73, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 84.

20. The bispecific antibody of claim 1 , wherein the bispecific antibody comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 57, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 62, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 73, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 84.

21. The bispecific antibody of claim 1 , wherein the bispecific antibody comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 58, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 63, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 74, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 85.

22. The bispecific antibody of claim 1 , wherein the bispecific antibody comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 58, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 64, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 74, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 85.

23. The bispecific antibody of claim 1 , wherein the bispecific antibody comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 57, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 62, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 75, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 86.

24. The bispecific antibody of claim 1 , wherein the bispecific antibody comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 57, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 62, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 76, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 87.

25. The bispecific antibody of claim 1 , wherein the bispecific antibody comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 57, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 62, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 74, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 85.

26. The bispecific antibody of claim 1 , wherein the bispecific antibody comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 59, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 65, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 74, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 85.

27. The bispecific antibody of claim 1 , wherein the bispecific antibody comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 59, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 66, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 74, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 85.

28. The bispecific antibody of claim 1 , wherein the bispecific antibody comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 59, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 66, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 77, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 88.

29. The bispecific antibody of claim 1 , wherein the bispecific antibody comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 59, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 67, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 77, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 88.

30. The bispecific antibody of claim 1 , wherein the bispecific antibody comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 59, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 67, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 78, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 89.

31. The bispecific antibody of claim 1 , wherein the bispecific antibody comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 59, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 68, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 77, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 88.

32. The bispecific antibody of claim 1 , wherein the bispecific antibody comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 59, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 68, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 78, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 89.

33. The bispecific antibody of claim 1 , wherein the bispecific antibody comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 60, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 69, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 79, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 90.

34. The bispecific antibody of claim 1 , wherein the bispecific antibody comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 59, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 70, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 80, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 91.

35. The bispecific antibody of claim 1 , wherein the bispecific antibody comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 60, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 71, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 79, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 90.

36. The bispecific antibody of claim 1 , wherein the bispecific antibody comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 60, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 71, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 81, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 92.

37. The bispecific antibody of claim 1 , wherein the bispecific antibody comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 60, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 69, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 82, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 93.

38. The bispecific antibody of claim 1 , wherein the bispecific antibody comprises a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 105, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 72, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 83, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 94.

39. The bispecific antibody of claim 3 , wherein the bispecific antibody comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 120, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 126, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 138, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 149.

40. The bispecific antibody of claim 3 , wherein the bispecific antibody comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 121, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 127, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 138, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 149.

41. The bispecific antibody of claim 3 , wherein the bispecific antibody comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 122, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 128, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 139, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 150.

42. The bispecific antibody of claim 3 , wherein the bispecific antibody comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 122, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 129, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 139, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 150.

43. The bispecific antibody of claim 3 , wherein the bispecific antibody comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 121, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 127, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 140, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 151.

44. The bispecific antibody of claim 3 , wherein the bispecific antibody comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 121, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 127, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 141, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 152.

45. The bispecific antibody of claim 3 , wherein the bispecific antibody comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 121, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 127, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 139, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 150.

46. The bispecific antibody of claim 3 , wherein the bispecific antibody comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 123, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 130, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 139, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 150.

47. The bispecific antibody of claim 3 , wherein the bispecific antibody comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 123, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 131, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 139, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 150.

48. The bispecific antibody of claim 3 , wherein the bispecific antibody comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 123, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 131, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 142, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 153.

49. The bispecific antibody of claim 3 , wherein the bispecific antibody comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 123, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 132, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 142, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 153.

50. The bispecific antibody of claim 3 , wherein the bispecific antibody comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 123, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 132, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 143, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 154.

51. The bispecific antibody of claim 3 , wherein the bispecific antibody comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 123, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 133, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 142, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 153.

52. The bispecific antibody of claim 3 , wherein the bispecific antibody comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 123, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 133, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 143, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 154.

53. The bispecific antibody of claim 3 , wherein the bispecific antibody comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 124, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 134, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 144, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 155.

54. The bispecific antibody of claim 3 , wherein the bispecific antibody comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 123, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 135, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 145, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 156.

55. The bispecific antibody of claim 3 , wherein the bispecific antibody comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 124, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 136, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 144, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 155.

56. The bispecific antibody of claim 3 , wherein the bispecific antibody comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 124, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 136, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 146, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 157.

57. The bispecific antibody of claim 3 , wherein the bispecific antibody comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 124, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 134, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 147, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 158.

58. The bispecific antibody of claim 3 , wherein the bispecific antibody comprises a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 125, a first antibody light chain comprising the amino acid sequence of SEQ ID NO: 137, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 148, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO: 159.

59. The method of claim 16 , wherein the condition is hemophilia A.

60. The method of claim 17 , wherein the condition is hemophilia A.

61. The method of claim 18 , wherein the condition is hemophilia A.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 12, 2019

From: TERANISHI, YURI; KATO, KAZUKI; KOGA, HIKARU; IGAWA, TOMOYUKI; YAMAGUCHI, KAZUKI; SOEDA, TETSUHIRO

To: CHUGAI SEIYAKU KABUSHIKI KAISHA

Reel/Frame 048306/0254 →

Priority Claims (1)

JP 2017-189647 · Sep 29, 2017 · national

Continuity (1)

Related Publication 20200223940A1 · Jul 16, 2020

Cited By (10)

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