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New application of phenothiazine or compound with similar structure in pharmacy

A technology of phenothiazines and compounds, which is applied in the combined application of PD-1 antibody, combined application of phenothiazines and adoptive cell therapy, to achieve the effect of improving killing effect, high patient compliance and improving function

Active Publication Date: 2021-03-02
GUANGZHOU VIROTECH PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is still a lack of effective drugs to treat cancer clinically, so providing a drug that can effectively treat cancer has important clinical significance

Method used

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  • New application of phenothiazine or compound with similar structure in pharmacy
  • New application of phenothiazine or compound with similar structure in pharmacy
  • New application of phenothiazine or compound with similar structure in pharmacy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0114] Example 1. MTC improves the function of human T cells

[0115] 1. Experimental method:

[0116](1) Jurkat cells were used to construct a stable cell line with high expression of PD-1. The pCAGin-PD-1 plasmid was electrotransfected into Jurkat cells, then screened with 900 μg / mL G418 antibiotics, and single clones were sorted by flow cytometry. A DNA fragment, which controls the gene for luciferase from the NFAT binding site (denoted as NFAT-LUC), was then electrotransferred in Jurkat-PD-1 cells. Then, a single clone was selected by flow cytometry and named as clone No. 5. Using this cell, the expression level of IL-2 can be reflected by measuring the activity of luciferase. Raji cells stably expressing PD-L1 were constructed, and the pCDNA-PD-L1 plasmid was electrotransfected into Raji cells, screened for resistance with 2 μg / mL puromycin, and then the single clone was sorted by flow cytometry and named as clone 1.

[0117] (2) Raji cells stably expressing PD-L1 are...

Embodiment 2

[0125] Example 2. MTC is able to promote the division and secretion of effector molecules in OT-1 cells

[0126] CD8+ T cells from OT-1 transgenic mice express a TCR that recognizes the SIINFEKL-H-2Kb complex of chicken ovalbumin. Therefore, when the spleen cells of OT-1 mice were cultured in vitro, under the stimulation of SIINFEKL peptide, the CD8+ T cells in the spleen could be activated and expanded dramatically, which we call CTL cells.

[0127] 1. Experimental method:

[0128] (1) Preparation of CTL cells: take the spleen of OT1 mice, grind and add red blood cell lysate to lyse red blood cells to make a single cell suspension. The cell density is about 2-4 million / mL, add 10 nM OVA257-264, 37℃, 5%CO 2 The cells were cultured in an incubator, and from the day of CTL preparation, they were stained with FITC-labeled PD-1 antibody every day, and then the changes of PD-1 expression on the cell surface were detected by flow cytometry.

[0129] (2) The above CTL cells were l...

Embodiment 3

[0135] Example 3. MTC is able to restore OT-1 T cell killing of target cells

[0136] 1. Experimental method:

[0137] (1) See Example 2 for the preparation of CTL cells.

[0138] (2) EG-7-PD-L1 cells were labeled with 5 nM CFSE, then CTL cells were mixed with EG-7-PD-L1 at a ratio of 5:1, and then treated with 1 μM, 5 μM, and 10 μM MTC After 4 hours of treatment, stain with 10 μg / mL PI to detect the apoptosis of target cells EG-7-PD-L1 by flow cytometry, and then judge the killing ability of CTL cells on target cells.

[0139] (3) Melanoma cells B16-OVA (B16 cells expressing OVA gene) were treated with 10 μg / mL IFN-γ for 24 hours, mixed with CTL cells at a ratio of 1:5 and cultured for 4 hours, and MTC (1 μM) treatment, B16-OVA cells treated with DMSO and MTC without IFN-γ treatment were used as controls. The apoptosis of B16-OVA was observed under a microscope, and then the killing ability of CTL cells on target cells was judged.

[0140](4) Melanoma cells B16-OVA (B16 c...

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Abstract

The invention relates to a new application of phenothiazine compounds in pharmacy, wherein the phenothiazine compounds are selected from a compound represented by a formula (I), hydrates, solvates orreduced forms thereof; the invention particularly provides the application in preparation of a PD-1 signal transduction inhibitor. The phenothiazine compounds provided by the invention can inhibit thefunction of PD-1 and hinders the signal transduction of PD-1, so that the phenothiazine compounds can be used as a PD-1 signal transduction inhibitor. In-vitro experiments find that the compounds canrecover the functions of immune cells inhibited by PD-1, so that the functions of secreting cytokines and killing target cells of immune cells such as CTL and the like are improved, the immune function of an organism can be improved, and tumors can be effectively treated.

Description

technical field [0001] The invention relates to the technical field of medicines, in particular to a new application of a phenothiazine or a compound with a similar structure, a hydrate, a solvate or a reduced form thereof in pharmacy. Another aspect of the present invention relates to the combined application of phenothiazine compounds and adoptive cell therapy. Another aspect of the present invention relates to the combined application of phenothiazine compounds and tumor immunochemotherapy agents, especially PD-1 antibodies. Background technique [0002] Adoptive cell therapy (Adoptive cell therapy) is a treatment method that includes collecting one or more different types of immune cells from mammals, culturing and / or manipulating the collected immune cells ex vivo, and treating The cultured and / or manipulated immune cells are returned to the mammal. Ex vivo manipulation of harvested immune cells includes introducing recombinant nucleic acid into the immune cells. Ado...

Claims

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Application Information

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IPC IPC(8): A61K39/00A61K31/5415A61K45/06A61P35/00
CPCA61K31/5415A61P35/00A61K39/0011A61K35/17A61K2039/5156A61K2300/00C07K16/2818C07K2317/76C07K16/2815A61K39/395C07K2317/21A61K2039/505Y02A50/30A61K39/4644A61K2239/31A61K39/4611A61K2239/48A61K2239/38A61K39/3955
Inventor 陈良范真真贺嵩敏陈婕思马克斯·桑德尔龚守芳杨晓志林子青
Owner GUANGZHOU VIROTECH PHARMA
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