Bispecific binding agents binding to CLDN18.2 and CD3

Patent metadata

Field	Value
Publication number	US-12378313-B2
Application number	US-202318347361-A
Country	US
Kind code	B2
Filing date	Jul 5, 2023
Priority date	Jun 15, 2021
Publication date	Aug 5, 2025
Grant date	Aug 5, 2025

Abstract

The present invention provides binding agents comprising at least two binding domains, wherein a first binding domain has specificity for CLDN18.2 and a second binding domain has specificity for CD3, and methods of using these binding agents or nucleic acids encoding therefor for treating cancer.

First claim

The invention claimed is:

1. A bispecific binding agent that binds CLDN18.2 and CD3, the bispecific binding agent comprising:
a first heavy chain variable region (VH) and a first light chain variable region (VL) wherein said first VH and said first VL bind to CLDN18.2;
a second VH and a second VL wherein said second VH and said second VL bind to CLDN18.2;
a third VH and a third VL wherein said third VH and said third VL bind to CD3;
wherein the first and second VH each comprise a CDR1 comprising the amino acid sequence SYWIN (SEQ ID NO: 32), a CDR2 comprising the amino acid sequence NIYPSDSYTNYNQKFQG (SEQ ID NO: 33), and a CDR3 comprising the amino acid sequence SWRGNSFDY (SEQ ID NO: 34);
wherein the first and second VL each comprise a CDR1 comprising the amino acid sequence KSSQSLLNSGNQKNYLT (SEQ ID NO: 35), a CDR2 comprising the amino acid sequence WASTRES (SEQ ID NO: 36), and a CDR3 comprising the amino acid sequence QNDYSYPFT (SEQ ID NO: 37);
wherein the third VH comprises a CDR1 comprising the amino acid sequence TYAMN (SEQ ID NO: 43), a CDR2 comprising the amino acid sequence RIRSKANNYATYYADSVKG (SEQ ID NO: 50), and a CDR3 comprising the amino acid sequence HGNFGDSYVSWFAY (SEQ ID NO: 45); and
wherein the third VL comprises a CDR1 comprising the amino acid sequence GSSTGAVTTSNYAN (SEQ ID NO: 46), a CDR2 comprising the amino acid sequence GTNKRAP (SEQ ID NO: 47), and a CDR3 comprising the amino acid sequence ALWYSNHWV (SEQ ID NO: 48).

2. The bispecific binding agent of claim 1 , wherein the first VH comprises the amino acid sequence of SEQ ID NO: 39.

3. The bispecific binding agent of claim 1 , wherein the first VL comprises the amino acid sequence of SEQ ID NO: 42.

4. The bispecific binding agent of claim 1 , wherein the second VH comprises the amino acid sequence of SEQ ID NO: 39.

5. The bispecific binding agent of claim 1 , wherein the second VL comprises the amino acid sequence of SEQ ID NO: 42.

6. The bispecific binding agent of claim 1 , wherein the third VH comprises the amino acid sequence of SEQ ID NO: 58.

7. The bispecific binding agent of claim 1 , wherein the third VL comprises the amino acid sequence of SEQ ID NO: 55.

8. The bispecific binding agent of claim 1 , wherein the first and second VH each comprise the amino acid sequence of SEQ ID NO: 39, the first and second VL each comprise the amino acid sequence of SEQ ID NO: 42, the third VH comprises the amino acid sequence of SEQ ID NO: 58, and the third VL comprises the amino acid sequence of SEQ ID NO: 55.

9. One or more nucleic acid molecules encoding the bispecific binding agent of claim 1 .

10. A host cell comprising the one or more nucleic acid molecules of claim 9 .

11. A pharmaceutical composition comprising the binding agent of claim 1 .

12. A method for treating a subject having a cancer involving cancer cells expressing CLDN18.2, the method comprising administering the binding agent of claim 1 to the subject.

13. A bispecific binding agent that binds CLDN18.2 and CD3, the bispecific binding agent comprising:
(a) a first polypeptide chain which comprises, from N-terminus to C-terminus,
(i) a first heavy chain variable region (VH1),
(ii) a constant region 1 of a heavy chain (CH1),
(iii) a constant region 2 of a heavy chain (CH2), and
(iv) a constant region 3 of a heavy chain (CH3),

(b) a second polypeptide chain which comprises, from N-terminus to C-terminus,
(i) a first light chain variable region (VL1), and
(ii) a constant region of a light chain (CL), and

(c) a third polypeptide chain which comprises, from N-terminus to C-terminus,
(i) a second light chain variable region (VL2), and
(ii) a constant region of a light chain (CL),

(d) a fourth polypeptide chain which comprises, from N-terminus to C-terminus,
(i) a second heavy chain variable region (VH2),
(ii) a constant region 1 of a heavy chain (CH1),
(iii) a third heavy chain variable region (VH3) and a third light chain variable region (VL3), or a third light chain variable region (VL3) and a third heavy chain variable region (VH3),
(iv) a constant region 2 of a heavy chain (CH2), and
(v) a constant region 3 of a heavy chain (CH3),

wherein
VH1 and VL1 bind to CLDN18.2, VH2 and VL2 bind to CLDN18.2, and VH3 and VL3 bind to CD3;
wherein
VH1 and VH2 each comprise a CDR1 comprising the amino acid sequence SYWIN (SEQ ID NO: 32), a CDR2 comprising the amino acid sequence NIYPSDSYTNYNQKFQG (SEQ ID NO: 33), and a CDR3 comprising the amino acid sequence SWRGNSFDY (SEQ ID NO: 34), and
VL1 and VL2 each comprise a CDR1 comprising the amino acid sequence KSSQSLLNSGNQKNYLT (SEQ ID NO: 35), a CDR2 comprising the amino acid sequence WASTRES (SEQ ID NO: 36), and a CDR3 comprising the amino acid sequence QNDYSYPFT (SEQ ID NO: 37); and
wherein
VH3 comprises a CDR1 comprising the amino acid sequence TYAMN (SEQ ID NO: 43), a CDR2 comprising the amino acid sequence RIRSKANNYATYYADSVKG (SEQ ID NO: 50), and a CDR3 comprising the amino acid sequence HGNFGDSYVSWFAY (SEQ ID NO: 45), and
VL3 comprises a CDR1 comprising the amino acid sequence GSSTGAVTTSNYAN (SEQ ID NO: 46), a CDR2 comprising the amino acid sequence GTNKRAP (SEQ ID NO: 47), and a CDR3 comprising the amino acid sequence ALWYSNHWV (SEQ ID NO: 48).

14. The bispecific binding agent of claim 13 , wherein VH1 comprises the amino acid sequence of SEQ ID NO: 39.

15. The bispecific binding agent of claim 13 , wherein VL1 comprises the amino acid sequence of SEQ ID NO: 42.

16. The bispecific binding agent of claim 13 , wherein VH2 comprises the amino acid sequence of SEQ ID NO: 39.

17. The bispecific binding agent of claim 13 , wherein VL2 comprises the amino acid sequence of SEQ ID NO: 42.

18. The bispecific binding agent of claim 13 , wherein VH3 comprises the amino acid sequence of SEQ ID NO: 58.

19. The bispecific binding agent of claim 13 , wherein VL3 comprises the amino acid sequence of SEQ ID NO: 55.

20. The bispecific binding agent of claim 13 , wherein VH3 or VL3 is connected to the CH1 by a peptide linker.

21. The bispecific binding agent of claim 20 , wherein the peptide linker comprises the amino acid sequence set forth in SEQ ID NO: 2, 13, 26, 96, or 97.

22. The bispecific binding agent of claim 13 , wherein VH3 or VL3 is connected to the CH2 by a peptide linker.

23. The bispecific binding agent of claim 22 , wherein the peptide linker comprises the amino acid sequence set forth in SEQ ID NO: 2, 13, 26, 96, or 97.

24. The bispecific binding agent of claim 13 , wherein the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 73 or a variant thereof, wherein said variant of SEQ ID NO: 73 has at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 73 over the entire length of SEQ ID NO: 73.

25. The bispecific binding agent of claim 13 , wherein the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 78 or a variant thereof, wherein said variant of SEQ ID NO: 78 has at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 78 over the entire length of SEQ ID NO: 78.

26. The bispecific binding agent of claim 13 , wherein the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 78 or a variant thereof, wherein said variant of SEQ ID NO: 78 has at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 78 over the entire length of SEQ ID NO: 78.

27. The bispecific bi

Assignees

• Xencor Inc

Inventors

• Bernett Matthew
• Nisthal Alex
• Moore Gregory

Classifications

• C07K2317/92

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

• C07K2317/33

  Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity · CPC title

• C07K2317/31

  multispecific · CPC title

• C07K2317/24

  containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered · CPC title

• C07K16/2809 Primary

  against the T-cell receptor (TcR)-CD3 complex · CPC title