High-affinity DMF5 T cell receptor (TCR) variants

Patent metadata

Field	Value
Publication number	US-9717758-B2
Application number	US-201414280308-A
Country	US
Kind code	B2
Filing date	May 16, 2014
Priority date	May 17, 2013
Publication date	Aug 1, 2017
Grant date	Aug 1, 2017

Abstract

High-affinity variants of the DMF5 TCR, and methods of use thereof for the treatment and imaging of cancer in a patient.

First claim

What is claimed is:

1. A high-affinity DMF5 T cell receptor variant α chain, wherein the aspartic amino acid at position 27 or 49 is a Y (αD27Y or αD49Y) or W (αD27W or αD49W).

2. A high-affinity DMF5 T cell receptor variant β chain, wherein the leucine amino acid at position 95, 96 or 114 is a W (βL95W, βL96W βL114W).

3. A high-affinity DMF5 T cell receptor variant comprising:
a high-affinity DMF5 T cell receptor variant α chain, wherein the aspartic amino acid at
position 27 or 49 is a Y (αD27Y or αD49Y) or W (αD27W or αD49W), and
a high-affinity DMF5 T cell receptor variant β chain, wherein the leucine amino acid at position 95, 96 or 114 is a W (βL95W, βL96W βL114W).

4. A fusion protein comprising the high-affinity DMF5 T cell receptor variant of claim 3 linked to a non-TCR sequence.

5. A therapeutic composition comprising:
a therapeutic agent linked to
the high-affinity DMF5 T cell receptor variant of claim 3 , optionally linked to a non-TCR sequence.

6. The therapeutic composition of claim 5 , wherein the therapeutic agent is a radioisotope; an anticancer drug; or a cytotoxic moiety.

7. A composition comprising:
a detectable moiety linked to
the high-affinity DMF5 T cell receptor variant of claim 3 , optionally linked to a non-TCR sequence.

8. The composition of claim 7 , wherein the detectable moiety is a contrast agent.

9. The composition of claim 8 , wherein the contrast agent is selected from the group consisting of gold, gadolinium, iron oxides, manganese chelates, barium sulfate, iodinated contrast media, microbubbles, and perfluorocarbons.

10. A nucleic acid encoding:
the high-affinity DMF5 T cell receptor variant of claim 3 , optionally linked to a non-TCR sequence.

11. A vector comprising the nucleic acid of claim 10 .

12. The vector of claim 11 , which is a retroviral vector.

13. A host cell expressing:
the high-affinity DMF5 T cell receptor variant of claim 3 , optionally linked to a non-TCR sequence.

14. A host cell comprising the nucleic acid of claim 10 .

15. The host cell of claim 14 , wherein the cell is a peripheral blood lymphocyte (PBL).

16. A method of treating a subject who has melanoma, the method comprising administering to the subject a therapeutically effective amount of the therapeutic composition of claim 5 .

17. A method of treating a subject who has melanoma, the method comprising administering to the subject a therapeutically effective amount of the host cells of claim 14 .

18. The method of claim 17 , wherein the host cells are autologous to the subject.

19. A method of treating a subject who has melanoma, the method comprising:
obtaining cells from the subject;
transducing the cells with a vector expressing:
the high-affinity DMF5 T cell receptor variant of claim 3 , optionally linked to a non-TCR sequence;
optionally maintaining the cells in culture for a time sufficient for the cells to express the variant or fusion protein and/or to proliferate; and
administering a therapeutically effective amount of the cells to the subject thereafter.

20. The method of claim 19 , wherein the cells are PBLs.

Assignees

• Univ Massachusetts
• Univ Notre Dame Du Lac

Inventors

• Pierce Brian G
• Weng Zhiping
• Baker Brian M

Classifications

• A61K35/17 Primary

  Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes (when activated by a specific antigen A61K39/00) · CPC title

• C07K14/705 Primary

  Receptors; Cell surface antigens; Cell surface determinants {(tumour specific antigens C07K14/4748)} · CPC title

• A61K40/4272

  Melan-A/MART · CPC title

• A61K40/32

  T-cell receptors [TCR] · CPC title

• A61K40/11

  T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells · CPC title