IP Library › Granted Patent US 9,884,075

Granted Patent B2

US 9,884,075 · App. 14/597,908 · Granted Feb 6, 2018

Domain-swap T cell receptors

Inventors: Michael T. Bethune (Pasadena, CA); Marvin H. Gee (Stanford, CA); David Baltimore (Pasadena, CA)

Assignee: California Institute of Technology

A61K35/17 C07K14/7051

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Quick Facts

Patent No.: US 9,884,075
App. No.: 14/597,908
Granted: Feb 6, 2018
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

Disclosed herein are genetically engineered T cell receptors, and methods, vectors, and genetically engineered T cells related to genetically engineered T cell receptors.

Claims (56)

1. A method of making a T cell that expresses a domain-swap T cell receptor (DS-TCR), the method comprising contacting a T cell with:

a first nucleic acid that encodes a first domain-swap chain, wherein the first domain-swap chain comprises a first chain transmembrane domain, a second chain variable domain and a second chain constant domain, but does not comprise a first chain variable domain and does not comprise a first chain constant domain; and

a second nucleic acid that encodes a second domain-swap chain, wherein the second domain-swap chain comprises a second chain transmembrane domain, a first chain variable domain and a first chain constant domain, but does not comprise a second chain variable domain and does not comprise a second chain constant domain,

wherein, the first chain variable domain comprises an alpha chain variable domain, the first chain constant domain comprises an alpha chain constant domain, the first chain transmembrane domain comprises an alpha chain transmembrane domain, the second chain variable domain comprises a beta chain variable domain, the second chain constant domain comprises a beta chain constant domain, and the second chain transmembrane domain comprises a beta chain transmembrane domain,

so as to configure the T cell to express a DS-TCR comprising the first domain-swap chain and the second domain-swap chain.

2. The method of claim 1 , wherein the first domain-swap chain further comprises a second chain connecting peptide, but does not comprise a first chain connecting peptide, and wherein the second domain-swap chain further comprises a first chain connecting peptide, but does not comprise a second chain connecting peptide,

wherein the first chain connecting peptide comprises an alpha chain connecting peptide and the second chain connecting peptide comprises a beta chain connecting peptide.

3. An expression vector or a set of expression vectors comprising:

4. The expression vector or the set of expression vectors of claim 3 , wherein the first domain-swap chain further comprises a second chain connecting peptide, but does not comprise a first chain connecting peptide, and wherein the second domain-swap chain further comprises a first chain connecting peptide, but does not comprise a second chain connecting peptide, and

wherein:

the first chain connecting peptide comprises an alpha chain connecting peptide and the second chain connecting peptide comprises a beta chain connecting peptide.

5. The expression vector or the set of expression vectors of claim 3 , wherein the first nucleic acid and the second nucleic acid are part of a same polypeptide expression vector, the vector further comprising a 2A peptide-encoding sequence flanked by the first nucleic acid and the second nucleic acid.

6. The expression vector or the set of expression vectors of claim 3 , further comprising a promoter configured to drive expression of the first nucleic acid and the second nucleic acid.

7. The expression vector or the set of expression vectors of claim 3 , wherein the first nucleic acid and the second nucleic acid are part of separate expression vectors.

8. The expression vector or the set of expression vectors of claim 3 , wherein the expression vector or the set of expression vectors comprises a lentiviral vector, retroviral vector, adenoviral vector, or adeno-associated viral vector.

9. A genetically engineered T cell, comprising:

wherein the T cell is configured to express a DS-TCR comprising the first domain-swap chain and the second domain-swap chain.

10. The genetically engineered T cell of claim 9 ,

wherein the first domain-swap chain further comprises a second chain connecting peptide, but does not comprise a first chain connecting peptide, and wherein the second domain-swap chain further comprises a first chain connecting peptide, but does not comprise a second chain connecting peptide,

wherein:

the first chain connecting peptide comprises an alpha chain connecting peptide and the second chain connecting peptide comprises a beta chain connecting peptide.

11. The genetically engineered T cell of claim 9 , wherein the T genetically engineered T cell is configured to express the first domain-swap chain as a first polypeptide and the second domain-swap chain as second polypeptide, and

wherein the first domain-swap chain and second domain-swap chain are separate molecules.

12. The genetically engineered T cell of claim 9 , wherein expression of an endogenous TCR is repressed or eliminated.

13. A method of inducing an immune response in a subject, the method comprising:

configuring an isolated T cell to express:

a first domain-swap chain, wherein the first domain-swap chain comprises a first chain transmembrane domain, a second chain variable domain and a second chain constant domain, but does not comprise a first chain variable domain and does not comprise a first chain constant domain; and

a second domain-swap chain, wherein the second domain-swap chain comprises a second chain transmembrane domain, a first chain variable domain and a first chain constant domain, but does not comprise a second chain variable domain and does not comprise a second chain constant domain,

thereby producing a genetically engineered T cell configured to express a domain-swap T cell receptor (DS-TCR) comprising the first domain-swap chain and the second domain-swap chain; and

administering the genetically engineered T cell to the subject.

14. The method of claim 13 , wherein the first domain-swap chain further comprises a second chain connecting peptide, but does not comprise a first chain connecting peptide, and wherein the second domain-swap chain further comprises a first chain connecting peptide, but does not comprise a second chain connecting peptide,

wherein:

the first chain connecting peptide comprises an alpha chain connecting peptide and the second chain connecting peptide comprises a beta chain connecting peptide.

15. The method of claim 13 , wherein the T cell comprises an autologous cell of the subject.

16. The method of claim 13 , wherein the T cell comprises a donor cell that is allogeneic to the subject.

17. The method of claim 13 , wherein the T cell comprises a CD4 T cell, or a CD8 T cell or a regulatory T cell.

18. The method of claim 13 , wherein the genetically engineered T cell is co-administered with a second genetically engineered T cell population.

19. The method of claim 13 , wherein the subject has at least one of: a tumor or a cancer, an infectious disease, an autoimmune disease, or diminished or ineffective or exhausted T cells, and is in need of treatment therefor.

20. The method of claim 13 , wherein the T cell is induced to express a plurality of DS-TCR against an array of antigens.

21. The method of claim 13 , wherein administering to the subject comprises at least one of intravenous injection, or intraperitoneal injection.

22. The method of claim 13 , further comprising monitoring the administered T cell over time.

23. The method of claim 13 , wherein the method is repeated.

24. A domain-swap T cell receptor (DS-TCR) comprising: a first domain-swap chain, wherein the first domain-swap chain comprises a first chain transmembrane domain, a second chain variable domain and a second chain constant domain, but does not comprise a first chain variable domain and does not comprise a first chain constant domain; and

25. The domain-swap T cell receptor of claim 24 , wherein the first domain-swap chain further comprises a second chain connecting peptide, but does not comprise a first chain connecting peptide, and wherein the second domain-swap chain further comprises a first chain connecting peptide, but does not comprise a second chain connecting peptide, and

wherein the first chain connecting peptide comprises an alpha chain connecting peptide and the second chain connecting peptide comprises a beta chain connecting peptide.

26. The domain-swap T cell receptor of claim 24 , wherein the first domain-swap chain and the second domain-swap chain are expressed by a single expression vector.

27. The domain-swap T cell receptor of claim 24 , wherein the first domain-swap chain and the second domain-swap chain are expressed by separate expression vectors.

Assignments (2)

CONFIRMATORY LICENSE Recorded Mar 20, 2015

From: CALIFORNIA INSTITUTE OF TECHNOLOGY

To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT

Reel/Frame 035243/0525 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 23, 2015

From: BETHUNE, MICHAEL T.; GEE, MARVIN H.; BALTIMORE, DAVID

To: CALIFORNIA INSTITUTE OF TECHNOLOGY

Reel/Frame 034801/0304 →

Continuity (2)

Provisional Application 61928142 · Jan 16, 2014

Related Publication 20150197771A1 · Jul 16, 2015