Bispecific IgG antibodies as T cell engagers

Patent metadata

Field	Value
Publication number	US-10358492-B2
Application number	US-201314040023-A
Country	US
Kind code	B2
Filing date	Sep 27, 2013
Priority date	Sep 27, 2012
Publication date	Jul 23, 2019
Grant date	Jul 23, 2019

Abstract

Bispecific IgG antibodies which bind to CLEC12A and an antigen on an immune effector cell are provided.

First claim

The invention claimed is:

1. A bispecific IgG antibody comprising
a first arm that specifically recognizes CLEC12A, wherein said first arm comprises a heavy chain CDR1 comprising the amino acid sequence SGYTFTGY (SEQ ID NO: 1), a heavy chain CDR2 comprising the amino acid sequence IINPSGGS (SEQ ID NO: 2), and a heavy chain CDR3 comprising the amino acid sequence GTTGDWFDY (SEQ ID NO: 3); and
a second arm that specifically recognizes an antigen on immune effector cells capable of recruiting such cells to an aberrant cell expressing CLEC12A.

2. The bispecific IgG antibody according to claim 1 , wherein the arm that specifically recognizes CLEC12A comprises a variable heavy chain that is at least 90% identical to the amino acid sequence:
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGIINPS GGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAKGTTGDWFDYW GQGTLVTVSS (SEQ ID NO: 4).

3. The bispecific antibody according to claim 1 , wherein said first arm that specifically recognizes CLEC12A comprises a variable heavy chain comprising the amino acid sequence:
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGIINPS GGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAKGTTGDWFDYW GQGTLVTVSS (SEQ ID NO: 4).

4. The bispecific IgG antibody according to claim 1 , wherein the variable light chain of said first arm comprises a variable light chain CDR1 comprising the amino acid sequence RASQSISSYLN (SEQ ID NO: 17), a light chain CDR2 comprising the amino acid sequence AASSLQS (SEQ ID NO: 18), and a light chain CDR3 comprising the amino acid sequence QQSYSTPPT (SEQ ID NO: 19).

5. The bispecific IgG antibody according to claim 4 , wherein the first arm comprises a variable light chain that is at least 90% identical to the amino acid sequence:
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPTFGQGTKVEIK (SEQ ID NO: 20).

6. The bispecific IgG antibody according to claim 5 , wherein the first arm comprises a variable light chain comprising the amino acid sequence:
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPTFGQGTKVEIK (SEQ ID NO: 20).

7. The bispecific IgG antibody according to claim 1 , wherein said first and second arms comprise a common light chain.

8. The bispecific IgG antibody according to claim 1 , comprising a mutated CH2 and/or lower hinge domains wherein the binding of said bispecific antibody with Fcγ receptors is significantly reduced.

9. The bispecific IgG antibody according to claim 8 , wherein said mutated CH2 and/or lower hinge domains comprise amino acid substitution L235G and/or G236R.

10. The bispecific IgG according to claim 1 , wherein said second arm specifically recognizes CD3.

11. A bispecific IgG antibody comprising
a first arm comprising a V H and a V L , wherein said first arm specifically recognizes CLEC12A and comprises a heavy chain CDR1 comprising the amino acid sequence SGYTFTSY (SEQ ID NO: 5), a heavy chain CDR2 comprising the amino acid sequence IINPSGGS (SEQ ID NO: 6), and a heavy chain CDR3 comprising the amino acid sequence GNYGDEFDY (SEQ ID NO: 7); and
a second arm comprising a V H and a V L , wherein said second arm specifically recognizes an antigen on immune effector cells capable of recruiting such cells to an aberrant cell expressing CLEC12A.

12. The bispecific IgG antibody according to claim 11 , wherein the arm that specifically recognizes CLEC12A comprises a variable heavy chain that is at least 90% identical to the amino acid sequence:
EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGIINPSG GSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGNYGDEFDYWGQ GTLVTVSS (SEQ ID NO: 8).

13. The bispecific antibody according to claim 11 , wherein said first arm that specifically recognizes CLEC12A comprises a variable heavy chain comprising the amino acid sequence:
EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGIINPSG GSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGNYGDEFDYWGQ GTLVTVSS (SEQ ID NO: 8).

14. The bispecific IgG antibody according to claim 11 , wherein the variable light chain of said first arm comprises a variable light chain CDR1 comprising the amino acid sequence RASQSISSYLN (SEQ ID NO: 17), a light chain CDR2 comprising the amino acid sequence AASSLQS (SEQ ID NO: 18), and a light chain CDR3 comprising the amino acid sequence QQSYSTPPT (SEQ ID NO: 19).

15. The bispecific IgG antibody according to claim 14 , wherein the first arm comprises a variable light chain that is at least 90% identical to the amino acid sequence:
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPTFGQGTKVEIK (SEQ ID NO: 20).

16. The bispecific IgG antibody according to claim 15 , wherein the first arm comprises a variable light chain comprising the amino acid sequence:
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPTFGQGTKVEIK (SEQ ID NO: 20).

17. The bispecific IgG antibody according to claim 11 , wherein said first and second arms comprise a common light chain.

18. The bispecific IgG antibody according to claim 11 , comprising a mutated CH2 and/or lower hinge domains wherein the binding of said bispecific antibody with Fcγ receptors is significantly reduced.

19. The bispecific IgG antibody according to claim 18 , wherein said mutated CH2 and/or lower hinge domains comprise amino acid substitution L235G and/or G236R.

20. The bispecific IgG according to claim 11 , wherein said second arm specifically recognizes CD3.

21. A bispecific IgG antibody comprising
a first arm comprising a V H and a V L , wherein said first arm specifically recognizes CLEC12A, and a heavy chain CDR1 comprising the amino acid sequence SGYTFTGY (SEQ ID NO: 9), a heavy chain CDR2 comprising the amino acid sequence WINPNSGG (SEQ ID NO: 10), and a heavy chain CDR3 comprising the amino acid sequence DGYFADAFDY (SEQ ID NO: 11); and
a second arm comprising a V H and a V L , wherein said second arm specifically recognizes an antigen on immune effector cells capable of recruiting such cells to an aberrant cell expressing CLEC12A.

22. The bispecific IgG antibody according to claim 21 , wherein the arm that specifically recognizes CLEC12A comprises a variable heavy chain that is at least 90% identical to the amino acid sequence:
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGIINPS GGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAKGTTGDWFDYW GQGTLVTVSS (SEQ ID NO: 4).

23. The bispecific antibody according to claim 21 , wherein said first arm that specifically recognizes CLEC12A comprises a variable heavy chain comprising the amino acid sequence:
QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINP NSGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDGYFADAFDY WGQGTLVTVSS (SEQ ID NO: 12).

24. The bispecific IgG antibody according to claim 21 , wherein the variable light chain of said first arm comprises a variable light chain CDR1 comprising the amino acid sequence RASQSISSYLN (SEQ ID NO: 17), a light chain CDR2 comprising the amino acid sequence AASSLQS (SEQ ID NO: 18), and a light chain CDR3 comprising the amino acid sequence QQSYSTPPT (SEQ ID NO: 19).

25. The bispecific IgG antibody according to claim 24 , wherein the first arm comprises a variable light chain that is at least 90% identical to the amino acid sequence:
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPTFGQGTKVEIK (SEQ ID NO: 20).

26. Th

Assignees

• Merus Nv

Inventors

• Bakker Alexander Berthold Hendrik
• Van Loo Pieter Fokko
• Logtenberg Ton

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07K16/3061

  Blood cells · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• C07K2317/526

  CH3 domain · CPC title