Antibody/T-cell receptor chimeric constructs and uses thereof

Patent metadata

Field	Value
Publication number	US-10098951-B2
Application number	US-201715829793-A
Country	US
Kind code	B2
Filing date	Dec 1, 2017
Priority date	Oct 23, 2015
Publication date	Oct 16, 2018
Grant date	Oct 16, 2018

Abstract

The present application provides antibody-TCR chimeric constructs comprising an antibody moiety that specifically binds to a target antigen fused to a TCRM capable of recruiting at least one TCR-associated signaling module. Also provided are methods of making and using these constructs.

First claim

What is claimed is:

1. An antibody-T cell receptor (TCR) chimeric molecule (abTCR) that specifically binds to CD19, comprising:
a) a first polypeptide chain comprising a first antigen-binding domain comprising V H and C H 1 antibody domains and a first T cell receptor domain (TCRD) comprising a first transmembrane domain of a first TCR subunit; and
b) a second polypeptide chain comprising a second antigen-binding domain comprising V L and C L antibody domains and a second TCRD comprising a second transmembrane domain of a second TCR subunit,

wherein the V H and C H 1 domains of the first antigen-binding domain and the V L and C L domains of the second antigen-binding domain form an antigen-binding module that specifically binds to CD19,
wherein the first TCRD and the second TCRD form a T cell receptor module (TCRM) that is capable of recruiting at least one TCR-associated signaling module,
wherein i) the first TCR subunit is a TCR γ chain, and the second TCR subunit is a TCR δ chain, or ii) the first TCR subunit is a TCR δ chain, and the second TCR subunit is a TCR γ chain,
wherein the CH1 antibody domain comprises the amino acid sequence of SEQ ID NO: 39 and the CL antibody domain comprises the amino acid sequence of SEQ ID NO: 41,
and wherein the V H antibody domain comprises the amino acid sequence of SEQ ID NO: 59 and the V L antibody domain comprises the amino acid sequence of SEQ ID NO: 57.

2. The abTCR of claim 1 , wherein the first TCR subunit is a TCR γ chain, and the second TCR subunit is a TCR δ chain.

3. The abTCR of claim 1 , wherein the first TCR subunit is a TCR δ chain, and the second TCR subunit is a TCR γ chain.

4. The abTCR of claim 1 , wherein the first polypeptide chain further comprises a first peptide linker between the first antigen-binding domain and the first TCRD and the second polypeptide chain further comprises a second peptide linker between the second antigen-binding domain and the second TCRD.

5. The abTCR of claim 1 , wherein the first TCRD further comprises a first connecting peptide or fragment thereof of a TCR subunit N-terminal to the first transmembrane domain and the second TCRD further comprises a second connecting peptide or fragment thereof of a TCR subunit N-terminal to the second transmembrane domain.

6. The abTCR of claim 1 , wherein the transmembrane domain of a TCR δ chain comprises the amino acid sequence of SEQ ID NO: 3 and the transmembrane domain of a TCR γ chain comprises the amino acid sequence of SEQ ID NO: 4.

7. The abTCR of claim 5 , wherein the connecting peptide of the TCRD comprising a transmembrane domain of a TCR δ chain comprises the amino acid sequence of SEQ ID NO: 7 and the connecting peptide of the TCRD comprising a transmembrane domain of a TCR γ chain comprises the amino acid sequence of SEQ ID NO: 8.

8. The abTCR of claim 7 , wherein the connecting peptide of the TCRD comprising a transmembrane domain of a TCR δ chain comprises the amino acid sequence of SEQ ID NO: 11 and the connecting peptide of the TCRD comprising a transmembrane domain of a TCR γ chain comprises the amino acid sequence of SEQ ID NO: 12.

9. The abTCR of claim 7 , wherein the transmembrane domain of a TCR δ chain comprises the amino acid sequence of SEQ ID NO: 3 and the transmembrane domain of a TCR γ chain comprises the amino acid sequence of SEQ ID NO: 4.

10. A composition comprising nucleic acid(s) encoding the first and second polypeptide chains of the abTCR of claim 1 .

11. A complex comprising the abTCR of claim 1 and at least one TCR-associated signaling module selected from the group consisting of CD3δε, CD3γε, and ζζ.

12. An effector cell presenting on its surface the abTCR of claim 1 .

13. An effector cell comprising the nucleic acid(s) of the composition of claim 10 .

14. The effector cell of claim 12 , wherein the effector cell does not express TCRγ and/or TCRδ.

15. The effector cell of claim 14 , wherein the effector cell is an αβ T cell.

16. The effector cell of claim 12 , wherein the effector cell is modified to block or decrease the expression of a first endogenous TCR subunit and/or a second endogenous TCR subunit.

17. The effector cell of claim 12 , wherein the effector cell is selected from the group consisting of a cytotoxic T cell, a helper T cell, a natural killer T cell, and a suppressor T cell.

18. The effector cell of claim 12 , comprising a vector comprising a first nucleic acid sequence encoding the first polypeptide chain of the abTCR and a second nucleic acid sequence encoding the second polypeptide chain of the abTCR.

19. A pharmaceutical composition comprising the effector cell of claim 12 .

20. A method of treating a CD19-associated disease in an individual in need thereof comprising administering to the individual an effective amount of the pharmaceutical composition of claim 19 .

21. The method of claim 20 , wherein the CD19-associated disease is cancer.

22. The method of claim 21 , wherein the cancer is lymphoma, or leukemia.

23. The abTCR of claim 1 , wherein the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 56, and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 54.

24. An antibody-T cell receptor (TCR) chimeric molecule (abTCR) that specifically binds to a complex comprising an AFP peptide and a major histocompatibility complex (MHC) protein, comprising:
a) a first polypeptide chain comprising a first antigen-binding domain comprising Vu and C H 1 antibody domains and a first T cell receptor domain (TCRD) comprising a first transmembrane domain of a first TCR subunit; and
b) a second polypeptide chain comprising a second antigen-binding domain comprising V L and C L antibody domains and a second TCRD comprising a second transmembrane domain of a second TCR subunit,

wherein the V H and C H 1 domains of the first antigen-binding domain and the V L and C L domains of the second antigen-binding domain form an antigen-binding module that specifically binds to the complex comprising the AFP peptide and the MHC protein,
wherein the first TCRD and the second TCRD form a T cell receptor module (TCRM) that is capable of recruiting at least one TCR-associated signaling module,
wherein i) the first TCR subunit is a TCR γ chain, and the second TCR subunit is a TCR δ chain, or ii) the first TCR subunit is a TCR δ chain, and the second TCR subunit is a TCR γ chain, wherein the CH1 antibody domain comprises the amino acid sequence of SEQ ID NO: 39 and the CL antibody domain comprises the amino acid sequence of SEQ ID NO: 41,
and wherein the V H antibody domain comprises the amino acid sequence of SEQ ID NO: 38 and the V L antibody domain comprises the amino acid sequence of SEQ ID NO: 40.

25. The abTCR of claim 24 , wherein the first TCR subunit is a TCR γ chain, and the second TCR subunit is a TCR δ chain.

26. The abTCR of claim 24 , wherein the first TCR subunit is a TCR δ chain, and the second TCR subunit is a TCR γ chain.

27. The abTCR of claim 24 , wherein the first polypeptide chain further comprises a first peptide linker between the first antigen-binding domain and the first TCRD and the second polypeptide chain further comprises a second peptide linker between the second antigen-binding domain and the second TCRD.

28. The abTCR of claim 24 , wherein the first TCR

Assignees

• Eureka Therapeutics Inc

Inventors

• Lu Jingwei
• Yang Zhiyuan
• Liu Cheng
• Liu Hong
• Xu Yiyang
• Yan Su
• Chan Vivien Wai-Fan
• Horan Lucas

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07K2317/55

  Fab or Fab' · CPC title

• C07K2319/03

  containing a transmembrane segment · CPC title

• C07K2319/00

  Fusion polypeptide · CPC title

• A61K2039/505

  comprising antibodies · CPC title