IP Library › Granted Patent US 11,001,643
Granted Patent B2
US 11,001,643 · App. 15/963,221 · Granted May 11, 2021

Cytotoxicity-inducing therapeutic agent

Inventors: Junichi Nezu (Shizuoka, JP); Atsushi Narita (Shizuoka, JP); Takahiro Ishiguro (Kanagawa, JP); Mika Sakurai (Shizuoka, JP); Hirotake Shiraiwa (Shizuoka, JP); Naoka Hironiwa (Shizuoka, JP); Tomoyuki Igawa (Shizuoka, JP); Yumiko Kawai (Kanagawa, JP)
Assignee: Chugai Seiyaku Kabushiki Kaisha
C07K16/468A61K39/395C07K16/28C07K16/2809C07K16/30C07K16/303C07K16/46C12N5/10C12N15/09A61K2039/505C07K2317/24C07K2317/31C07K2317/34C07K2317/524C07K2317/526C07K2317/565C07K2317/567C07K2317/71C07K2317/73C07K2317/92C07K2317/94
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Quick Facts
Patent No.
US 11,001,643
App. No.
15/963,221
Granted
May 11, 2021
Kind
B2
Abstract

Multi specific antigen-binding molecules maintaining excellent cellular cytotoxicity and high stability, which comprise a domain that contains an antibody variable region having glypican 3-binding activity and a domain that contains an antibody variable region having T-cell receptor complex-binding activity are provided. Since the provided molecules show a strong cytotoxicity against cells and tissues expressing glypican 3, it is possible to produce pharmaceutical compositions for treating or preventing various cancers.

Claims (81)

1. A nucleic acid that encodes a bispecific antibody that binds glypican-3 and T-cell receptor complex and comprises a first and a second antibody variable domain selected from the group consisting of:

(1) a first antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:215 and a constant region having the amino acid sequence of SEQ ID NO:61; a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:424 and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:53;

(2) a first antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:215 and a constant region having the amino acid sequence of SEQ ID NO:61; a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:103 and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:53;

(3) a first antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:215 and a constant region having the amino acid sequence of SEQ ID NO:61; a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:103 and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:299;

(4) a first antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:215 and a constant region having the amino acid sequence of SEQ ID NO:61; a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:103 and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:301;

(5) a first antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:215 and a constant region having the amino acid sequence of SEQ ID NO:61; a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:103 and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:302;

(6) a first antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:215 and a constant region having the amino acid sequence of SEQ ID NO:61; a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:103 and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:304;

(7) a first antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:215 and a constant region having the amino acid sequence of SEQ ID NO:61; a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:103 and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:306;

(8) a first antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:215 and a constant region having the amino acid sequence of SEQ ID NO:61; a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:103 and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:307;

(9) a first antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:215 and a constant region having the amino acid sequence of SEQ ID NO:61; a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:103 and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:309;

(10) a first antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:215 and a constant region having the amino acid sequence of SEQ ID NO:61; a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:122 and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:53;

(11) a first antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:215 and a constant region having the amino acid sequence of SEQ ID NO:61; a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:129 and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:53;

(12) a first antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:215 and a constant region having the amino acid sequence of SEQ ID NO:61; a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:132 and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:53;

(13) a first antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:197 and a constant region having the amino acid sequence of SEQ ID NO:61; a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:128 and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:299;

(14) a first antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:197 and a constant region having the amino acid sequence of SEQ ID NO:61; a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:128 and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:310;

(15) a first antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:197 and a constant region having the amino acid sequence of SEQ ID NO:61; a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:128 and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:319;

(16) a first antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:197 and a constant region having the amino acid sequence of SEQ ID NO:61; a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:128 and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:53;

(17) a first antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:211 and a constant region having the amino acid sequence of SEQ ID NO:61; a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:142 and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:299;

(18) a first antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:211 and a constant region having the amino acid sequence of SEQ ID NO:61; a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:142 and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:223;

(19) a first antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:211 and a constant region having the amino acid sequence of SEQ ID NO:61; a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:144 and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:223;

(20) a first antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:206 and a constant region having the amino acid sequence of SEQ ID NO:61; a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:144 and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:223;

(21) a first antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:206 and a constant region having the amino acid sequence of SEQ ID NO:61; a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:142 and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:223;

(22) a first antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:206 and a constant region having the amino acid sequence of SEQ ID NO:61; a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:164 and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:223;

(23) a first antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:206 and a constant region having the amino acid sequence of SEQ ID NO:61; a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:168 and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:223;

(24) a first antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:211 and a constant region having the amino acid sequence of SEQ ID NO:61; a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:164 and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:223; and

(25) a first antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:211 and a constant region having the amino acid sequence of SEQ ID NO:61; a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:168 and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:223;

wherein the variable region of the first antibody heavy chain and the variable region of a common antibody light chain forms a first antibody variable region having glypican-3 binding activity, and the variable region of the second antibody heavy chain and the variable region of another common antibody light chain forms a second antibody variable region having T-cell receptor complex binding activity.

2. A method for producing a bispecific antibody that comprises culturing a cell comprising the nucleic acid of claim 1 and purifying the bispecific antibody.

3. A vector comprising the nucleic acid of claim 1 .

4. A cell comprising the vector of claim 3 .

5. A cell comprising the nucleic acid of claim 1 .

6. The nucleic acid of claim 1 , wherein the nucleic acid encodes a bispecific antibody that comprises:

a first antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:215 and a constant region having the amino acid sequence of SEQ ID NO:61;

a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:103 or SEQ ID NO: 424 and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and

two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:53.

7. A method for producing a bispecific antibody that comprises culturing a cell comprising the nucleic acid of claim 6 and purifying the bispecific antibody.

8. A vector comprising the nucleic acid of claim 6 .

9. A cell comprising the nucleic acid of claim 6 .

10. The nucleic acid of claim 1 , wherein the nucleic acid encodes a bispecific antibody that comprises:

a first antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:215 and a constant region having the amino acid sequence of SEQ ID NO:61;

a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO: 103 and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and

two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:53, 299, 301, 302, 304, 306, 307, or 309.

11. A method for producing a bispecific antibody that comprises culturing a cell comprising the nucleic acid of claim 10 and purifying the bispecific antibody.

12. A vector comprising the nucleic acid of claim 10 .

13. A cell comprising the vector of claim 12 .

14. A cell comprising the nucleic acid of claim 10 .

15. The nucleic acid of claim 1 , wherein the nucleic acid encodes a bispecific antibody that comprises:

a first antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:215 and a constant region having the amino acid sequence of SEQ ID NO:61;

a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO: 122, 129, or 132, and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and

two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:53.

16. A method for producing a bispecific antibody that comprises culturing a cell comprising the nucleic acid of claim 15 and purifying the bispecific antibody.

17. A vector comprising the nucleic acid of claim 15 .

18. A cell comprising the nucleic acid of claim 15 .

19. The nucleic acid of claim 1 , wherein the nucleic acid encodes a bispecific antibody that comprises:

a first antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:197 and a constant region having the amino acid sequence of SEQ ID NO:61;

a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO: 128, and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and

two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:53, 299, 310, or 319.

20. A method for producing a bispecific antibody that comprises culturing a cell comprising the nucleic acid of claim 19 and purifying the bispecific antibody.

21. A vector comprising the nucleic acid of claim 19 .

22. A cell comprising the nucleic acid of claim 19 .

23. The nucleic acid of claim 1 , wherein the nucleic acid encodes a bispecific antibody that comprises:

a first antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:211 and a constant region having the amino acid sequence of SEQ ID NO:61;

a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO: 142, 144, 164 or 168 and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and

two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:223.

24. A method for producing a bispecific antibody that comprises culturing a cell comprising the nucleic acid of claim 23 and purifying the bispecific antibody.

25. A vector comprising the nucleic acid of claim 23 .

26. A cell comprising the nucleic acid of claim 23 .

27. The nucleic acid of claim 1 , wherein the nucleic acid encodes a bispecific antibody that comprises:

a first antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO:206 and a constant region having the amino acid sequence of SEQ ID NO:61;

a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO: 142, 144, 164, or 168 and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and

two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:223.

28. A method for producing a bispecific antibody that comprises culturing a cell comprising the nucleic acid of claim 27 and purifying the bispecific antibody.

29. A vector comprising the nucleic acid of claim 27 .

30. A cell comprising the nucleic acid of claim 27 .

31. The nucleic acid of claim 1 , wherein the nucleic acid encodes a bispecific antibody that comprises:

a first antibody heavy chain that comprises variable region having the amino acid sequence of SEQ ID NO:211 and a constant region having the amino acid sequence of SEQ ID NO:61;

a second antibody heavy chain that comprises a variable region having the amino acid sequence of SEQ ID NO: 142 and a constant region having the amino acid sequence of SEQ ID NO:60 or 62; and

two common antibody light chains that comprise a variable region having the amino acid sequence of SEQ ID NO:223.

32. A method for producing a bispecific antibody that comprises culturing a cell comprising the nucleic acid of claim 31 and purifying the bispecific antibody.

33. A vector comprising the nucleic acid of claim 31 .

34. A cell comprising the nucleic acid of claim 31 .

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 11, 2020
From: NEZU, JUNICHI; NARITA, ATSUSHI; ISHIGURO, TAKAHIRO; SAKURAI, MIKA; SHIRAIWA, HIROTAKE; HIRONIWA, NAOKA; IGAWA, TOMOYUKI; KAWAI, YUMIKO
To: CHUGAI SEIYAKU KABUSHIKI KAISHA
Reel/Frame 053460/0634 →
Priority Claims (1)
JP JP2014-197315 · Sep 26, 2014 · national
Continuity (3)
Division 15467654 · Mar 23, 2017
Continuation PCTJP2015077024 · Sep 25, 2015
Related Publication 20180244805A1 · Aug 30, 2018
Cited By (5)
US 12,359,001 US 12,473,375 US 12,479,929 US 12,522,669 US 12,528,863