阅读说明：本技术 α-甲基酪氨酸或其衍生物的用途 (Use of alpha-methyl tyrosine or its derivative ) 是由 万晓春 刘茂玄 许晨光 于 2019-03-26 设计创作，主要内容包括：本发明涉及医药技术领域,尤其涉及α-甲基酪氨酸或其衍生物的用途。本发明研究表明α-甲基酪氨酸或其衍生物能够抑制CRS引起的细胞因子水平的升高,抑制因CRS引起的体温升高,维持接受过继性免疫治疗动物的体重,缓解和/或治疗CRS。与现有技术中以抗体药物只能抑制一种细胞因子的活性的方案相比,本发明的技术方案的成本更低,能够同时抑制多种细胞因子的活性,且效果显著。(The invention relates to the technical field of medicines, in particular to application of alpha-methyl tyrosine or derivatives thereof. The research of the invention shows that the alpha-methyl tyrosine or the derivative thereof can inhibit the increase of the level of cell factors caused by CRS, inhibit the increase of body temperature caused by the CRS, maintain the body weight of an animal receiving the adoptive immunotherapy, and relieve and/or treat the CRS. Compared with the scheme that only one kind of cytokine activity can be inhibited by antibody drugs in the prior art, the technical scheme of the invention has lower cost, can inhibit the activities of various cytokines simultaneously and has obvious effect.)

1. Use of alpha-methyl tyrosine or a derivative thereof for the preparation of a formulation for inhibiting the activity of a cytokine.

2. The use according to claim 1, wherein the cytokine is serum amyloid A, IL-6, IL-10 and/or TNF-a.

3. Use of alpha-methyl tyrosine or a derivative thereof for the manufacture of a medicament for the alleviation and/or treatment of CRS.

4. The use of claim 3, wherein the CRS is a CRS induced by adoptive immunotherapy.

5. The use of claim 4, wherein the adoptive immunotherapy cell is a chimeric antigen receptor T cell, a chimeric antigen receptor NK cell, a tumor antigen specific TCR transgenic T cell, a tumor infiltrating lymphocyte, a cytokine-induced killer cell or a natural killer cell.

6. The use according to claim 5, wherein in the T-cells of the chimeric antigen receptor:

the T cells are from autologous T cells, allogeneic T cells, or iPSC-induced T cells;

it targets CD19, BCMA, CD20, CD33, EGFR or Mesothelin.

7. A pharmaceutical combination comprising adoptive immunotherapy cells and α -methyl tyrosine or a derivative thereof.

8. The pharmaceutical combination according to claim 7, wherein the cells of the adoptive immunotherapy are T cells of a chimeric antigen receptor, NK cells of a chimeric antigen receptor, tumor antigen specific TCR transgenic T cells, tumor infiltrating lymphocytes, cytokine induced killer cells or natural killer cells.

9. The pharmaceutical combination according to claim 8, wherein in the T-cells of the chimeric antigen receptor:

the T cells are from autologous T cells, allogeneic T cells, or iPSC-induced T cells;

it targets CD19, BCMA, CD20, CD33, EGFR or Mesothelin.

10. Use of a pharmaceutical combination according to any one of claims 7 to 9 for the preparation of a formulation for the treatment of tumors.

Technical Field

The invention relates to the technical field of medicines, in particular to application of alpha-methyl tyrosine or derivatives thereof.

Background

The technology of T cell therapy developed in recent years for expressing a tumor-specific chimeric antigen receptor (Car) by using a genetic engineering technology has been rapidly advanced. Car T shows good killing activity, targeting property and durability in clinical and clinical tests, provides a new effective solution for treating tumors, shows huge application potential and development prospect, and is evaluated as the greatest research breakthrough in 2017 by the American clinical oncology society. The FDA approved the nova pharmaceutical kymoriah for treatment of B-cell acute lymphoblastic leukemia in relapsed or refractory children and young adults on 31/8 in 2017, and a second CAR T therapy yescata on the market on 18/10 in 2017. The marketing of these products has made Car T cell therapy attractive to the world population.

The CAR-T cell technology is designed based on the principle that T cells do not need to rely on MHC molecules and Antigen Presenting Cells (APCs), a single chain antibody (scFv) recognizing a Tumor Associated Antigen (TAA), a transmembrane costimulatory domain (such as CD28 and CD4-1BB) and an activation motif of T cells are integrated, T lymphocytes are transfected by a gene transduction method, and genetically modified T cells enhance the ability to bind to tumor cells by expressing the single chain antibody, and simultaneously activate T cells, proliferate and activate their cytotoxic activity, thereby enabling them to specifically recognize and kill tumor cells.

Although Car T cell therapy has made great progress in the field of tumor therapy, it has major side effects during the course of therapy: such as Cytokine Release Syndrome (CRS), neurotoxicity, off-target effects, and the like. Among them, CRS is currently the most common and serious side effect of immune reaction after CAR-T cell injection, and can cause significant increase in blood cytokine levels, fever, headache, diarrhea, nausea, tachycardia, hypotension, hypoxia, seizure, confusion, and the like, and in severe cases, can cause multiple organ failure and death of patients. The mechanism by which Car T causes the release of cytokines in large amounts is not well defined and may include overactivated Car-T cells, dead tumor cells, activated macrophages (and other innate immune cells) and vascular endothelial cells, among others. Currently, drugs for preventing and treating cytokine release syndrome in clinic are mainly tolizumab (tocilizumab) which is an antibody against interleukin 6(IL-6), etanercept (etanercept) which is an antibody against tumor necrosis factor alpha (TNF-alpha), and the like. However, these antibodies are expensive and have very limited effectiveness.

Alpha-methyl tyrosine is a chemically synthesized tyrosine hydroxylase small-molecule inhibitor, and the structure of the alpha-methyl tyrosine is shown as a formula I.

It can restrict the synthesis of catecholamine substances by inhibiting the activity of tyrosine hydroxylase, but no report about the influence of alpha-methyl tyrosine on CRS is found.

Disclosure of Invention

In view of the above, the technical problem to be solved by the present invention is to provide the use of α -methyl tyrosine or its derivatives, and studies show that α -methyl tyrosine or its derivatives can alleviate CRS.

The invention provides application of alpha-methyl tyrosine or derivatives thereof in preparing preparations for inhibiting cytokine activity.

In the present invention, the cytokine is serum amyloid A, IL-6, IL-10 and/or TNF-alpha.

Specifically, the cytokine activity inhibited by the alpha-methyl tyrosine provided by the invention is over-activated cytokine in CRS.

The invention also provides application of the alpha-methyl tyrosine or the derivative thereof in preparing a medicament for relieving and/or treating CRS.

In the invention, the CRS is the CRS caused by adoptive immunotherapy.

In the invention, the CRS alleviation and/or treatment comprises animal body weight maintenance, body temperature rise inhibition, serum IL-6, IL-10, TNF-alpha level inhibition, and serum amyloid A level inhibition.

In some embodiments, the adoptive immunotherapy cell is a T cell of a chimeric antigen receptor, an NK cell of a chimeric antigen receptor, a tumor antigen-specific TCR transgenic T cell, a tumor-infiltrating lymphocyte, a cytokine-induced killer cell, or a natural killer cell.

In particular embodiments, the adoptive immunotherapy is a T cell therapy technique for chimeric antigen receptors.

In some embodiments, the chimeric antigen receptor comprises a T cell:

the T cells are from autologous T cells, allogeneic T cells, or iPSC-induced T cells;

it targets CD19, BCMA, CD20, CD33, EGFR or Mesothelin.

In the present embodiment, the Car T cell is a Car T cell targeting CD 19.

The invention also provides a pharmaceutical combination comprising cells for adoptive immunotherapy and alpha-methyl tyrosine or a derivative thereof.

In the present invention, the adoptive immunotherapy cell is a T cell of a chimeric antigen receptor, an NK cell of a chimeric antigen receptor, a tumor antigen-specific TCR transgenic T cell, a tumor-infiltrating lymphocyte, a cytokine-induced killer cell or a natural killer cell.

In some embodiments, the chimeric antigen receptor comprises a T cell:

the T cells are from autologous T cells, allogeneic T cells, or iPSC-induced T cells;

it targets CD19, BCMA, CD20, CD33, EGFR or Mesothelin.

In the pharmaceutical composition of the present invention, the cells, the alpha-methyl tyrosine or its derivative and the mixture may be present independently of each other. As a medicament, both may be administered simultaneously, sequentially or in different ways. For example, the administration of the cells is injection, and the administration of α -methyltyrosine or a derivative thereof is oral, intravenous, subcutaneous, intramuscular, sublingual, nasal spray, etc.

The invention also discloses application of the pharmaceutical composition in preparing a preparation for treating tumors.

In the present invention, the tumor comprises: leukemia, multiple myeloma, malignant lymphoma, brain glioma, liver cancer, lung cancer, stomach cancer, colon cancer, pancreatic cancer or breast cancer.

The invention also provides a method for treating tumors by administering the pharmaceutical composition.

The research of the invention shows that the alpha-methyl tyrosine or the derivative thereof can inhibit the increase of the level of cell factors caused by CRS, inhibit the increase of body temperature caused by the CRS, maintain the body weight of an animal receiving the adoptive immunotherapy, and relieve and/or treat the CRS. Compared with the scheme that only one kind of cytokine activity can be inhibited by antibody drugs in the prior art, the technical scheme of the invention has lower cost, can inhibit the activities of various cytokines simultaneously and has obvious effect.