CN111743887A - Use of alpha-methyl tyrosine or its derivative - Google Patents
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- CN111743887A CN111743887A CN201910232955.2A CN201910232955A CN111743887A CN 111743887 A CN111743887 A CN 111743887A CN 201910232955 A CN201910232955 A CN 201910232955A CN 111743887 A CN111743887 A CN 111743887A
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- NHTGHBARYWONDQ-JTQLQIEISA-N L-α-methyl-Tyrosine Chemical compound OC(=O)[C@](N)(C)CC1=CC=C(O)C=C1 NHTGHBARYWONDQ-JTQLQIEISA-N 0.000 title claims abstract description 25
- 230000000694 effects Effects 0.000 claims abstract description 14
- 102000004127 Cytokines Human genes 0.000 claims abstract description 13
- 108090000695 Cytokines Proteins 0.000 claims abstract description 13
- 238000009169 immunotherapy Methods 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 6
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 42
- 206010052015 cytokine release syndrome Diseases 0.000 claims description 20
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 claims description 14
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- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 claims description 5
- 108090001005 Interleukin-6 Proteins 0.000 claims description 5
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- 108091007433 antigens Proteins 0.000 claims description 5
- 102000036639 antigens Human genes 0.000 claims description 5
- BGFTWECWAICPDG-UHFFFAOYSA-N 2-[bis(4-chlorophenyl)methyl]-4-n-[3-[bis(4-chlorophenyl)methyl]-4-(dimethylamino)phenyl]-1-n,1-n-dimethylbenzene-1,4-diamine Chemical compound C1=C(C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C(N(C)C)=CC=C1NC(C=1)=CC=C(N(C)C)C=1C(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 BGFTWECWAICPDG-UHFFFAOYSA-N 0.000 claims description 4
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- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
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.
Description
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.
Detailed Description
The invention provides the application of alpha-methyl tyrosine or derivatives thereof, and the technical personnel can use the content to reference the content and appropriately modify the technological parameters to realize the application. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.
The test materials adopted by the invention are all common commercial products and can be purchased in the market.
The "derivatives of α -methyl tyrosine" of the present invention also include various derivatives that can be modified by simple chemical methods such as reduction, substitution, etc. on the side chain groups on the backbone by those skilled in the art, while still retaining the effect of treating CRS caused by Car T. The synthesis of these derivatives can be performed by reference to textbooks in the prior art. The derivatives of the same inch, alpha-methyl tyrosine also comprise salts, hydrates, optical isomers and the like of various acid-base forms of the derivatives.
The invention is further illustrated by the following examples:
example 1
1. Newborn (day 0-2) SGM3(NSG Tg)CMV-IL3,CSF2,KITLG1Eav/MloySzJ) sub-lethal dose (150cGy) irradiation of mice, immediate intrahepatic injection of 1 × 105Human cord blood CD34+ cells, a nhsgm 3 humanized mouse was prepared. CD19 Car T cells were prepared using nhsgm 3 humanized mouse T cells.
2. Adult (6-8 weeks) SGM3(NSG Tg)CMV-IL3,CSF2,KITLG1Eav/MloySzJ) sub-lethal dose (200cGy) irradiation of mice, immediate tail vein injection of 1 × 105Human cord blood CD34+ cells, a HuSGM3 humanized mouse was prepared.
After 3.4 weeks, tail vein injection 2 × 106CD19 Car T cells prepared from nhsgm 3 humanized mice.
4. Immediately after injection of Car T cells, 10mg/kg of alpha-methyltyrosine or an equal volume of PBS was intraperitoneally injected daily for 5 days.
5. After injecting Car T cells, the body weight of the mice was weighed every day, and the body temperature of the mice was measured; blood was taken every two days and the serum levels of human IL-6, IL-10, TNF- α and mouse serum amyloid A were measured. The CRS-related indexes are continuously detected for 21 days.
The results show that: alpha-methyl tyrosine can inhibit the activity of various cytokines and inhibit the level of serum amyloid A. Inhibiting temperature rise caused by CRS, and maintaining body weight of animals receiving adoptive immunotherapy.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that it is obvious to those skilled in the art that various modifications and improvements can be made without departing from the principle of the present invention, and these modifications and improvements should also be considered as the protection scope of the present invention.
Claims (10)
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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910232955.2A CN111743887A (en) | 2019-03-26 | 2019-03-26 | Use of alpha-methyl tyrosine or its derivative |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910232955.2A CN111743887A (en) | 2019-03-26 | 2019-03-26 | Use of alpha-methyl tyrosine or its derivative |
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| Publication Number | Publication Date |
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| CN111743887A true CN111743887A (en) | 2020-10-09 |
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| CN201910232955.2A Pending CN111743887A (en) | 2019-03-26 | 2019-03-26 | Use of alpha-methyl tyrosine or its derivative |
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| Country | Link |
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| CN (1) | CN111743887A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20170080093A1 (en) * | 2013-10-22 | 2017-03-23 | Tyme, Inc. | Tyrosine Derivatives And Compositions Comprising Them |
| WO2018102506A1 (en) * | 2016-11-30 | 2018-06-07 | Tyme, Inc. | Tyrosine derivatives and compositions comprising them |
-
2019
- 2019-03-26 CN CN201910232955.2A patent/CN111743887A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20170080093A1 (en) * | 2013-10-22 | 2017-03-23 | Tyme, Inc. | Tyrosine Derivatives And Compositions Comprising Them |
| WO2018102506A1 (en) * | 2016-11-30 | 2018-06-07 | Tyme, Inc. | Tyrosine derivatives and compositions comprising them |
Non-Patent Citations (1)
| Title |
|---|
| VERENA STAEDTKE等: "Disruption of a self-amplifying catecholamine loop reduces cytokine release syndrome", 《NATURE》 * |
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