Antibody/T-cell receptor chimeric constructs and uses thereof

Patent metadata

Field	Value
Publication number	US-10464988-B2
Application number	US-201816121475-A
Country	US
Kind code	B2
Filing date	Sep 4, 2018
Priority date	Oct 23, 2015
Publication date	Nov 5, 2019
Grant date	Nov 5, 2019

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

The invention claimed is:

1. A method of killing a target cell presenting a target antigen, comprising contacting the target cell with an effector αβ T cell comprising an antibody-T cell receptor (TCR) chimeric molecule (abTCR) that specifically binds to the target antigen, wherein the abTCR comprises:
a) a first polypeptide chain comprising a first antigen-binding domain comprising a V H antibody domain and a C H 1 antibody domain, and a first T cell receptor domain (TCRD) comprising a first transmembrane domain of a first TCR subunit, wherein the first polypeptide chain lacks variable and constant domains of the first TCR subunit; and
b) a second polypeptide chain comprising a second antigen-binding domain comprising a V L antibody domain and a C L antibody domain, and a second TCRD comprising a second transmembrane domain of a second TCR subunit, wherein the second polypeptide chain lacks variable and constant domains of the second TCR subunit,
wherein the V H domain of the first antigen-binding domain pairs with the V L domain of the second antigen-binding domain to form an antigen-binding module that specifically binds to the target antigen,
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, and
wherein the first TCR subunit is a TCR γ chain and the second TCR subunit is a TCR δ chain, or the first TCR subunit is a TCR δ chain and the second TCR subunit is a TCR γ chain.

2. The method 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 method 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 method of claim 1 , wherein the contacting is in vivo.

5. The method of claim 1 , wherein the contacting is in vitro.

6. A method of treating a target antigen-associated disease in an individual in need thereof comprising administering to the individual an effective amount of a composition comprising an effector αβ T cell comprising an abTCR that specifically binds to the target antigen, wherein the abTCR comprises:
a) a first polypeptide chain comprising a first antigen-binding domain comprising a V H antibody domain and a C H 1 antibody domain, and a first TCRD comprising a first transmembrane domain of a first TCR subunit, wherein the first polypeptide chain lacks variable and constant domains of the first TCR subunit; and
b) a second polypeptide chain comprising a second antigen-binding domain comprising a V L antibody domain and a C L antibody domain, and a second TCRD comprising a second transmembrane domain of a second TCR subunit, wherein the second polypeptide chain lacks variable and constant domains of the second TCR subunit,
wherein the V H domain of the first antigen-binding domain pairs with the V L domain of the second antigen-binding domain to form an antigen-binding module that specifically binds to the target antigen,
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, and
wherein the first TCR subunit is a TCR γ chain and the second TCR subunit is a TCR δ chain, or the first TCR subunit is a TCR δ chain and the second TCR subunit is a TCR γ chain.

7. The method of claim 6 , wherein the first TCR subunit is a TCR γ chain, and the second TCR subunit is a TCR δ chain.

8. The method of claim 6 , wherein the first TCR subunit is a TCR δ chain, and the second TCR subunit is a TCR γ chain.

9. The method of claim 6 , wherein the target antigen-associated disease is cancer.

10. The method of claim 6 , wherein the target antigen-associated disease is viral infection.

11. The method 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.

12. The method of claim 11 , wherein the TCRM comprises a disulfide bond between a residue in the first connecting peptide and a residue in the second connecting peptide.

13. The method of claim 11 , wherein:
(i) the first TCR subunit is a TCR δ chain, and the second TCR subunit is a TCR γ chain, wherein the first connecting peptide comprises the amino acid sequence of SEQ ID NO: 7, and the second connecting peptide comprises the amino acid sequence of SEQ ID NO: 8; or
(ii) the first TCR subunit is a TCR γ chain, and the second TCR subunit is a TCR δ chain, wherein the first connecting peptide comprises the amino acid sequence of SEQ ID NO: 8, and the second connecting peptide comprises the amino acid sequence of SEQ ID NO: 7.

14. The method of claim 11 , wherein:
(i) the first TCR subunit is a TCR δ chain, and the second TCR subunit is a TCR γ chain, wherein the first connecting peptide comprises the amino acid sequence of SEQ ID NO: 11, and the second connecting peptide comprises the amino acid sequence of SEQ ID NO: 12; or
(ii) the first TCR subunit is a TCR γ chain, and the second TCR subunit is a TCR δ chain, wherein the first connecting peptide comprises the amino acid sequence of SEQ ID NO: 12, and the second connecting peptide comprises the amino acid sequence of SEQ ID NO: 11.

15. The method of claim 6 , 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.

16. The method of claim 15 , wherein the TCRM comprises a disulfide bond between a residue in the first connecting peptide and a residue in the second connecting peptide.

17. The method of claim 15 , wherein:
(i) the first TCR subunit is a TCR δ chain, and the second TCR subunit is a TCR γ chain, wherein the first connecting peptide comprises the amino acid sequence of SEQ ID NO: 7, and the second connecting peptide comprises the amino acid sequence of SEQ ID NO: 8; or
(ii) the first TCR subunit is a TCR γ chain, and the second TCR subunit is a TCR δ chain, wherein the first connecting peptide comprises the amino acid sequence of SEQ ID NO: 8, and the second connecting peptide comprises the amino acid sequence of SEQ ID NO: 7.

18. The method of claim 15 , wherein:
(i) the first TCR subunit is a TCR δ chain, and the second TCR subunit is a TCR γ chain, wherein the first connecting peptide comprises the amino acid sequence of SEQ ID NO: 11, and the second connecting peptide comprises the amino acid sequence of SEQ ID NO: 12; or
(ii) the first TCR subunit is a TCR γ chain, and the second TCR subunit is a TCR δ chain, wherein the first connecting peptide comprises the amino acid sequence of SEQ ID NO: 12, and the second connecting peptide comprises the amino acid sequence of SEQ ID NO: 11.

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

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C07K14/7051 Primary

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

• C07K2319/74

  containing a fusion for binding to a cell surface receptor · CPC title

• C07K16/2809

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