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Treatment and diagnosis of cancer or infectious disease using recognition mechanism of t cell receptor

Foreign code F200010135
Posted date May 22, 2020
Country EPO
Application number 17837119
Gazette No. 3494984
Date of filing Aug 4, 2017
Gazette Date Jun 12, 2019
International application number JP2017028490
International publication number WO2018026018
Date of international filing Aug 4, 2017
Date of international publication Feb 8, 2018
Priority data
  • P2016-154742 (Aug 5, 2016) JP
  • 2017JP28490 (Aug 4, 2017) WO
Title Treatment and diagnosis of cancer or infectious disease using recognition mechanism of t cell receptor
Abstract Provided is a method for treating and diagnosing cancer or an infectious disease using the recognition mechanism of a T cell receptor. An NK cell function enhancer, said NK cell function enhancer comprising as an active ingredient a T cell receptor chimeric protein which is a fused protein consisting of a variable region of a T cell receptor capable of recognizing a cancer-specific antigen or a variable region of a T cell receptor capable of recognizing an antigen specific to a pathogen causative of an infectious disease and the Fc region of immunoglobulin, which binds to an MHC molecule complex of cancer cells to induce down modulation of MHC class 1 molecule complex and thus enables NK cells to recognize the cancer cells and kill the same; and an NK cell function enhancer which imparts to NK cells an ability to recognize cancer cells expressing an MHC class 1 molecule or infected cells infected with a pathogen causative of an infectious disease and thus enables the NK cells to kill the cancer cells or the infected cells by the T cell receptor chimeric protein-dependent cytotoxicity (TDCC) activity.
Outline of related art and contending technology Background Art
As cancer treatments, surgical treatments, radiation treatments and chemotherapies are basically known and these are called as major three therapies.
In recent years, in addition to these three major therapies, immunotherapies have been getting attention as a fourth therapy. Examples of immunotherapies include: a method for activating antitumor immunity, which attacks cancer by use of immunocompetence (immune cells) originally possessed by a living body; and a method for blocking immunosuppressive reaction of cancer cells. The former treatments include immunological enhancement by cytokine, enhancement of killer T-cells or NK cells, dendritic cell vaccine therapy and peptide vaccine therapy; and the latter treatments include immune checkpoint inhibition therapy.
As described above, killer T-cells or NK cells are used as a method for activating antitumor immunity. Since NK cells can directly attack cancer, it is known that NK cells are useful in cancer treatment such as antimetastatic (see Non-Patent Literature 1).
T-cells recognize MHCs (major histocompatibility complex) and peptides. T-cells cannot recognize them if MHCs are not expressed in target cells. Meanwhile, NK cells recognize the non-existence of MHCs, and then work. NK cells cannot recognize that MHCs are expressed in target cells. Normal cell usually express MHC molecules, so they cannot become targets of NK cells.
Only NK cells, which do not target cells having an MHC expressed therein, cannot provide a sufficient immunotherapic effect on cancer; and in recent years, researches have been made on use of T-cells capable of specifically recognizing cancer and intensive researches have been made on methods for inducing killer T-cells.
In addition, researches for specifying cancer-specific antigens have been also advanced, and cancer peptide therapy or dendritic cell therapy has been developed.
T-cell receptors (TCR) perform an important role on the action of T-cells; and recent years have witnessed the development of a method for analyzing a T-cell receptor repertoire of a T-cell receptor of a patient with a certain disease and identifying a disease-specific T-cell receptor. Further, a method that uses a protein having a fragment of a T-cell receptor has been also reported (see Patent Literature 1).
As is the case with cancer, for infectious diseases, in particular, emerging/reemerging infectious diseases, for which treatments have not been established, there are expectations on immunotherapies using abilities of NK cells or T-cells for eliminating infected cells.
Citation List
Patent Literature
Patent Literature 1: JP Patent Publication (Kohyo) No. 2007-513326A
Non Patent Literature
Non Patent Literature 1: Ogasawara K. et al., Clin J Immunol; 25(6): 534-40
Scope of claims [claim1]
1. An NK cell function enhancer comprising, as an active ingredient, a T-cell receptor chimeric protein being a fusion protein of a T-cell receptor variable region capable of recognizing a cancer-specific antigen and an immunoglobulin Fc region,
wherein the T-cell receptor chimeric protein binds to an MHC molecular complex of a cancer cell to reduce the expression of an MHC class I molecular complex and the cancer cell is killed or damaged by recognition of an NK cell.

[claim2]
2. An NK cell function enhancer comprising, as an active ingredient, a T-cell receptor chimeric protein being a fusion protein of a T-cell receptor variable region capable of recognizing a cancer-specific antigen and an immunoglobulin Fc region,
wherein the enhancer is for imparting a recognition function of a cancer cell expressing an MHC class I molecule to an NK cell to kill or damage the cancer cell by TDCC (T-cell receptor chimeric protein-dependent cellular cytotoxicity) activity.

[claim3]
3. The NK cell function enhancer according to Claim 1 or 2, wherein the T-cell receptor chimeric protein comprises all of the T-cell receptor variable region and CDR3, and a J region.

[claim4]
4. The NK cell function enhancer according to any one of Claims 1 to 3, wherein the T-cell receptor variable region is an α chain and/or β chain of the T-cell receptor.

[claim5]
5. The NK cell function enhancer according to Claim 4, wherein the T-cell receptor variable region is an α chain of the T-cell receptor.

[claim6]
6. The NK cell function enhancer according to any one of Claims 1 to 5, wherein the immunoglobulin Fc region is an Fc region of IgG.

[claim7]
7. The NK cell function enhancer according to any one of Claims 1 to 6, wherein the enhancer is a dimer consisting of two fusion proteins of the T-cell receptor variable region and the immunoglobulin Fc region and the two proteins are bonded to each other by disulfide bond.

[claim8]
8. The NK cell function enhancer according to any one of Claims 1 to 7, wherein the T-cell receptor binds to an MHC class I molecule.

[claim9]
9. A method for detecting a cancer cell comprising the steps of:
bringing a labelled T-cell receptor chimeric protein, which is a T-cell receptor chimeric protein being a fusion protein of: a T-cell receptor variable region capable of recognizing a cancer-specific antigen; and an immunoglobulin Fc region, into contact with a cell collected from a biological sample of a subject; and
determining that a target cell is present in the subject when the T-cell receptor chimeric protein binds to the cell collected from the biological sample of the subject.

[claim10]
10. A reagent for cancer detection comprising a labelled T-cell receptor chimeric protein, which is a T-cell receptor chimeric protein being a fusion protein of a T-cell receptor chimeric protein capable of recognizing a cancer-specific antigen and an immunoglobulin Fc region.

[claim11]
11. A method for producing a T-cell receptor chimeric protein being a fusion protein of a T-cell receptor variable region and an immunoglobulin Fc region, the method comprising the steps of:
cloning a DNA molecule encoding a cancer antigen-specific T-cell receptor capable of recognizing a cancer-specific antigen from a T-cell collected from a cancer patient;
ligating the DNA molecule with a DNA molecule encoding the immunoglobulin Fc region and introducing the ligated product into an expression vector; and
introducing and expressing the expression vector into a host cell.

[claim12]
12. The method for producing a T-cell receptor chimeric protein being a fusion protein of a T-cell receptor variable region and an immunoglobulin Fc region according to Claim 11, the method comprising the steps of:
analyzing a repertoire of the T-cell receptor possessed by a cancer patient by use of a T-cell collected from the cancer patient;
cloning a DNA molecule encoding a T-cell receptor with a high frequency in the cancer patient as a specific T-cell receptor highly specific to the cancer;
ligating the DNA molecule with a DNA molecule encoding the immunoglobulin Fc region and introducing the ligated product into an expression vector; and
introducing and expressing the expression vector into a host cell.

[claim13]
13. A complex comprising a T-cell receptor chimeric protein capable of recognizing a cancer-specific antigen, and an NK cell receptor.

[claim14]
14. A method for producing a complex of a T-cell receptor chimeric protein and an NK cell, comprising the step of bringing a T-cell receptor chimeric protein capable of recognizing in vitro a cancer-specific antigen into contact with an NK cell.

[claim15]
15. An NK cell function enhancer comprising, as an active ingredient, a T-cell receptor chimeric protein being a fusion protein of a T-cell receptor variable region capable of recognizing an antigen specific to a pathogen causative of an infection, and an immunoglobulin Fc region,
wherein the T-cell receptor chimeric protein binds to an MHC class I molecular complex of an infected cell infected with the pathogen causative of the infection to reduce the expression of an MHC molecular complex and the infected cell is killed or damaged by recognition of an NK cell.

[claim16]
16. An NK cell function enhancer comprising, as an active ingredient, a T-cell receptor chimeric protein being a fusion protein of a T-cell receptor variable region capable of recognizing an antigen specific to a pathogen causative of an infection, and an immunoglobulin Fc region,
wherein the enhancer is for imparting a recognition function of an infected cell infected with the pathogen causative of the infection, which expresses an MHC class I molecule, to an NK cell, and killing or damaging the infected cell by TDCC (T-cell receptor chimeric protein-dependent cellular cytotoxicity) activity.

[claim17]
17. The NK cell function enhancer according to Claim 15 or 16, wherein the T-cell receptor chimeric protein comprises all of the T-cell receptor variable region and CDR3, and a J region.

[claim18]
18. The NK cell function enhancer according to any one of Claims 15 to 17, wherein the T-cell receptor variable region is an α chain and/or β chain of the T-cell receptor.

[claim19]
19. The NK cell function enhancer according to Claim 18, wherein the T-cell receptor variable region is an α chain of the T-cell receptor.

[claim20]
20. The NK cell function enhancer according to any one of Claims 15 to 19, wherein the immunoglobulin Fc region is an Fc region of IgG.

[claim21]
21. The NK cell function enhancer according to any one of Claims 15 to 20, wherein the enhancer is a dimer consisting of two fusion proteins of the T-cell receptor variable region and the immunoglobulin Fc region and the two proteins are bonded to each other by disulfide bond.

[claim22]
22. The NK cell function enhancer according to any one of Claims 15 to 21, wherein the T-cell receptor binds to an MHC class I molecule.

[claim23]
23. A method for detecting an infected cell infected with a pathogen causative of an infectious disease comprising the steps of:
bringing a labelled T-cell receptor chimeric protein, which is a T-cell receptor chimeric protein being a fusion protein of: a T-cell receptor variable region capable of recognizing an antigen specific to a pathogen causative of an infectious disease; and an immunoglobulin Fc region, into contact with a cell collected from a biological sample of a subject; and
determining that a target cell is present in the subject when the T-cell receptor chimeric protein binds to the cell collected from the biological sample of the subject.

[claim24]
24. A reagent for detecting an infected cell comprising a labelled T-cell receptor chimeric protein, which is a T-cell receptor chimeric protein being a fusion protein of a T-cell receptor chimeric protein capable of recognizing an antigen specific to a pathogen causative of an infectious disease, and an immunoglobulin Fc region.

[claim25]
25. A method for producing a T-cell receptor chimeric protein being a fusion protein of a T-cell receptor variable region and an immunoglobulin Fc region, the method comprising the steps of:
cloning a DNA molecule encoding a pathogen antigen-specific T-cell receptor capable of recognizing an antigen specific to a pathogen causative of an infection from a T-cell collected from a patient with the infectious disease;
ligating the DNA molecule with a DNA molecule encoding the immunoglobulin Fc region and introducing the ligated product into an expression vector; and
introducing and expressing the expression vector into a host cell.

[claim26]
26. The method for producing a T-cell receptor chimeric protein being a fusion protein of a T-cell receptor variable region and an immunoglobulin Fc region according to Claim 25, the method comprising the steps of:
analyzing a repertoire of the T-cell receptor possessed by the patient with the infectious disease by use of a T-cell collected from the patient with the infectious disease;
cloning a DNA molecule encoding a T-cell receptor with a high frequency in the patient with the infection as a specific T-cell receptor highly specific to the infection;
ligating the DNA molecule with a DNA molecule encoding the immunoglobulin Fc region and introducing the ligated product into an expression vector; and
introducing and expressing the expression vector into a host cell.

[claim27]
27. A complex comprising a T-cell receptor chimeric protein capable of recognizing an antigen specific to a pathogen causative of an infectious disease, and an NK cell receptor.

[claim28]
28. A method for producing a complex of a T-cell receptor chimeric protein and an NK cell, comprising the step of bringing a T-cell receptor chimeric protein capable of recognizing in vitro an antigen specific to a pathogen causative of an infection and an NK cell into contact with each other.

[claim29]
29. An MHC molecular complex down-modulating agent comprising, as an active ingredient, a T-cell receptor chimeric protein being a fusion protein of a T-cell receptor variable region and an immunoglobulin Fc region, wherein the agent binds to an MHC molecular complex of a target cell to reduce the expression of an MHC class I molecular complex.

[claim30]
30. The MHC molecular complex down-modulating agent according to Claim 29, wherein the T-cell receptor chimeric protein comprises all of the T-cell receptor variable region and CDR3, and a J region.

[claim31]
31. The MHC molecular complex down-modulating agent according to Claim 29 or 30, wherein the T-cell receptor variable region is an α chain and/or β chain of the T-cell receptor.

[claim32]
32. The MHC molecular complex down-modulating agent according to Claim 31, wherein the T-cell receptor variable region is an α chain of the T-cell receptor.

[claim33]
33. The MHC molecular complex down-modulating agent according to any one of Claims 29 to 32, wherein the immunoglobulin Fc region is an Fc region of IgG.

[claim34]
34. The MHC molecular complex down-modulating agent according to any one of Claims 29 to 33, wherein the agent is a dimer of two fusion proteins of the T-cell receptor variable region and the immunoglobulin Fc region and the two proteins are bonded to each other by disulfide bond.

[claim35]
35. The MHC molecular complex down-modulating agent according to any one of Claims 29 to 34, wherein the T-cell receptor binds to an MHC class I molecule.

[claim36]
36. The MHC molecular complex down-modulating agent according to any one of Claims 29 to 35, wherein the target cell is a cancer cell or an infected cell infected with a pathogen causative of an infection.

[claim37]
37. A method for specifying a cancer-specific T-cell receptor α chain variable region, the method comprising the steps of:
identifying a repertoire of a T-cell receptor α chain variable region of a lymphocyte in a cancer tissue of a cancer patient and a repertoire of a T-cell receptor α chain of a lymphocyte in peripheral blood of the cancer patient; and
determining, as a cancer-specific T-cell receptor α chain variable region, a T-cell receptor α chain variable region that is present in the lymphocyte in the cancer tissue two-fold or more in abundance than in the lymphocyte in the peripheral blood.

[claim38]
38. The method for specifying a cancer-specific T-cell receptor α chain variable region according to Claim 37, the method comprising the steps of:
specifying a cancer-specific T-cell receptor α chain variable region in a plurality of cancer patients; and
determining, as a cancer-specific human common T-cell receptor α chain variable region, a T-cell receptor α chain variable region that is present in a lymphocyte in a cancer tissue two-fold or more in abundance than in a lymphocyte in peripheral blood.

[claim39]
39. A method for specifying a cancer-specific T-cell receptor α chain variable region, the method comprising the steps of:
identifying a repertoire of a T-cell receptor α chain variable region of a lymphocyte in a cancer tissue of a cancer patient and a repertoire of a T-cell receptor α chain of a lymphocyte in peripheral blood of a healthy subject; and
determining, as a cancer-specific T-cell receptor α chain variable region, a T-cell receptor α chain variable region that is present in the lymphocyte in the cancer tissue two-fold or more in abundance than in the lymphocyte in peripheral blood of the healthy subject.

[claim40]
40. The method for specifying a cancer-specific T-cell receptor α chain variable region according to Claim 39, wherein the method uses a mixture of lymphocytes in cancer tissues of a plurality of cancer patients and a mixture of lymphocytes in peripheral blood of a plurality of healthy subjects to determine, as a cancer-specific human common T-cell receptor α chain variable region, a T-cell receptor α chain variable region that is present in the lymphocytes in the cancer tissues two-fold or more in abundance than in the lymphocytes in peripheral blood of the healthy subjects.

[claim41]
41. A method for specifying a cancer-specific T-cell receptor α chain variable region, comprising determining, as a cancer-specific human common T-cell receptor α chain variable region, both of a cancer-specific T-cell receptor α chain variable region specified by the method of Claim 38 and a cancer-specific T-cell receptor α chain variable region specified by the method of Claim 40.

[claim42]
42. The method for specifying a cancer-specific T-cell receptor α chain variable region according to any one of Claims 37 to 41, wherein the cancer is squamous cancer.

[claim43]
43. The method for specifying a cancer-specific T-cell α chain variable region according to any one of Claims 37 to 41, wherein the cancer is cervical cancer or lung cancer.

[claim44]
44. A cancer-specific human common T-cell receptor α chain variable region of cervical cancer comprising a T-cell receptor α chain variable region coded by any of T-cell receptor α chain variable region gene selected from the group consisting of TRAV1-1-01, TRAV1-1-02, TRAV21-02, TRAV22-01, TRAVI-2-01, TRAV12-2-03, TRAV39-01, TRAV2-01, TRAV21-01, TRAV12-1-01, TRAV1-2-01 and TRAV38-2/DV8-01.

[claim45]
45. A cancer-specific human common T-cell receptor α chain variable region of cervical cancer comprising a T-cell receptor α chain variable region having a CDR3 region having a consensus frame represented by AVR---(x=1 to 6)--G-(x=1 to 3)--KL(I)/(T).

[claim46]
46. A cancer-specific human common T-cell receptor α chain variable region of lung cancer comprising a T-cell receptor α chain variable region coded by any of T-cell receptor α chain variable region gene selected from the group consisting of TRAV12-1-01, TRAV16-01, TRAV19-01, TRAV22-01, TRAV35-02, TRAV17-01, TRAV9-2-02 and TRAV13-1-01.

[claim47]
47. The NK cell function enhancer according to any of Claims 1 to 8 and 15 to 22, wherein the T-cell receptor variable region is a T-cell receptor variable region specified by the method of any one of Claims 37 to 42.

[claim48]
48. The NK cell function enhancer according to Claim 47, wherein the T-cell receptor variable region is a cancer-specific human common T-cell receptor α chain variable region for cervical cancer coded by any of T-cell receptor α chain variable region gene selected from the group consisting of TRAV1-1-01, TRAV1-1-02, TRAV21-02, TRAV22-01, TRAV1-2-01, TRAV12-2-03, TRAV39-01, TRAV2-01, TRAV21-01, TRAV12-1-01, TRAV1-2-01 and TRAV38-2/DV8-01.

[claim49]
49. The NK cell function enhancer according to Claim 47 or 48, wherein the T-cell receptor variable region is a cancer-specific human common T-cell receptor α chain variable region for cervical cancer having a CDR3 region having a consensus frame represented by AVR---(x=1 to 6)--G-(x=1 to 3)--KL(I)/(T).

[claim50]
50. The NK cell function enhancer according to Claim 47, wherein the T-cell receptor variable region is a cancer-specific human common T-cell receptor α chain variable region for lung cancer coded by any of T-cell receptor α chain variable region gene selected from the group consisting of TRAV12-1-01, TRAV16-01, TRAV19-01, TRAV22-01, TRAV35-02, TRAV17-01, TRAV9-2-02 and TRAV13-1-01.

[claim51]
51. The MHC molecular complex down-modulating agent according to any of Claims 29 to 36, wherein the T-cell receptor variable region is a T-cell receptor variable region specified by the method according to any one of Claims 37 to 43.

[claim52]
52. The MHC molecular complex down-modulating agent according to Claim 51, wherein the T-cell receptor variable region is a cancer-specific human common T-cell receptor α chain variable region for cervical cancer coded by any of T-cell receptor α chain variable region gene selected from the group consisting of TRAV1-1-01, TRAV1-1-02, TRAV21-02, TRAV22-01, TRAV1-2-01, TRAV12-2-03, TRAV39-01, TRAV2-01, TRAV21-01, TRAV12-1-01, TRAV1-2-01 and TRAV38-2/DV8-01.

[claim53]
53. The MHC molecular complex down-modulating agent according to Claims 51 or 52, wherein the T-cell receptor variable region is a cancer-specific human common T-cell receptor α chain variable region for cervical cancer having a CDR3 region having a consensus frame represented by AVR---(x=1 to 6)--G-(x=1 to 3)--KL(I)/(T).

[claim54]
54. The MHC molecular complex down-modulating agent according to Claim 51, wherein the T-cell receptor variable region is a cancer-specific human common T-cell receptor α chain variable region for lung cancer coded by any of T-cell receptor α chain variable region gene selected from the group consisting of TRAV12-1-01, TRAV16-01, TRAV19-01, TRAV22-01, TRAV35-02, TRAV17-01, TRAV9-2-02 and TRAV13-1-01.
  • Applicant
  • TOHOKU UNIVERSITY
  • Inventor
  • OGASAWARA KOETSU
IPC(International Patent Classification)
Specified countries Contracting States: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
Extension States: BA ME
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