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Application of CAI (Carboxyamidotriazole) and IDO1 (Indoleamine 2,3-Dioxygenase) inhibitor combination in resisting tumor

A technology of IDO1 and carboxyamine triazole, applied in the medical and pharmaceutical fields, can solve the problems of cytokine release syndrome and adverse reactions that cannot be ignored, and achieve the effects of promoting lymphocyte infiltration, no toxic side effects, and reducing expression.

Active Publication Date: 2019-04-26
GUANGDONG YINZHU PHARMACEUTICAL TECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In addition, the adverse reactions caused by tumor immunobiological therapy cannot be ignored. PD-1 antibody can cause severe liver damage and lung inflammation in some patients; CAR-T therapy may cause cytokine release syndrome and neurotoxicity, which may Risk of inflammatory and autoimmune diseases

Method used

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  • Application of CAI (Carboxyamidotriazole) and IDO1 (Indoleamine 2,3-Dioxygenase) inhibitor combination in resisting tumor
  • Application of CAI (Carboxyamidotriazole) and IDO1 (Indoleamine 2,3-Dioxygenase) inhibitor combination in resisting tumor
  • Application of CAI (Carboxyamidotriazole) and IDO1 (Indoleamine 2,3-Dioxygenase) inhibitor combination in resisting tumor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Example 1: Carboxyamidotriazole inhibits the nuclear factor NFAT2 of activated T cells from entering into the nucleus.

[0056] 1. Experimental method

[0057] CD8+ T cells were isolated from mouse splenocytes by negative sorting and activated with anti-CD3 / CD 28 microspheres for 48 hours. Then the cells were divided into CON (DMSO solvent) group, CAI (10 μM) group, ZK 756326 (1.8 μM) group, and CAI and ZK756326 group, and the cells were treated. After 24 hours, cells were fixed in 3D Matrigel, fixed, dehydrated, embedded, sectioned, and subjected to immunofluorescent staining, DAPI (blue), NFAT2 (green).

[0058] 2. Experimental results

[0059] For the results of confocal immunofluorescence images see figure 1 , where the merged image of the highlighted area shows that the localization of NFAT2 in cells differs among the groups. After CAI treatment, it can inhibit the nuclear translocation of NFAT2. ZK756326 stimulates the nuclear import of NFAT2 and reduces the ...

Embodiment 2

[0060] Example 2: Carboxytriazole reduces the percentage of PD-1+CD8+T cells

[0061] 1. Experimental method

[0062] CD8+ T cells were isolated from mouse splenocytes by negative sorting and activated with anti-CD3 / CD 28 microspheres for 48 hours. Then the cells were divided into CON (DMSO solvent) group, CAI (10 μM) group, ZK 756326 (1.8 μM) group, and CAI and ZK756326 group, and the cells were treated. After 24 hours, flow cytometry was used to evaluate the effect of CAI on the percentage of PD-1+CD8+T cells in the activated CTLs of the mouse spleen.

[0063] 2. Experimental results

[0064] PD-1+CD8+ T cell subsets were reduced by 8% to 15% after CAI treatment. However, after ZK756326 treatment, there are more PD-1 expressing cells in primary T cells, and the stimulation antagonizes the effect of CAI, see Figure 2A and 2B .

Embodiment 3

[0065] Example 3. Detection of the effects of CAI combined with AhR / IDO1 inhibitors on the apoptosis of solid tumor cells in the co-culture system of CD8+ T cells and tumor cells

[0066] 1. Experimental method

[0067] CD8+ T cells were isolated from mouse splenocytes by negative sorting, or CD8+ T cells were isolated from PBMCs of volunteers. After activation by CD3 / CD 28 microspheres for 48 hours, they were mixed with mouse melanoma cells B16 or human Co-culture of colorectal cancer cells HCT116. Ratio 20:1, co-culture for 24 hours and administer drugs: CAI (10 μM), DMF (20 mM), 1-MT (0.2 mM). Flow cytometry was used to detect tumor cell apoptosis.

[0068] 2. Experimental results

[0069] Both DMF and 1-MT have some weak anti-tumor effect when administered alone, but the effect is not as good as that of CAI. However, when CAI is administered in combination with DMF or 1-MT, the antitumor activity in the co-culture system is significantly better than that of CAI adminis...

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Abstract

The invention relates to application of a CAI (Carboxyamidotriazole) and an IDO1 (Indoleamine 2,3-Dioxygenase) inhibitor combination in resisting tumor. Specifically, the invention relates to the application of the CAI and a combination of one or multiple IDO1 inhibitors in preparing an anti-tumor drug for mammals, wherein the IDO1 inhibitors are selected from 1-MT, DMF (3',4'-Dimethoxyflavone), Epacadostat, NLG802, BMS-985205, navaximod, PF-06840003, KHK-2455-IDO1, HTI-1090 and GBV1012.

Description

technical field [0001] The present invention relates to the field of medical treatment and medicine, in particular to the use of the combination of carboxyamidotriazole and one or more IDO1 inhibitors in the preparation of anti-tumor drugs for mammals, and an anti-tumor drug composition. Background technique [0002] Malignant tumors have always been a major hidden danger to national health, bringing pain to patients and burdens and challenges to families and society. Based on the understanding of the mechanism of tumor occurrence and development, the development of effective, low-toxicity, and easy-to-obtain anti-tumor drugs is crucial to meet people's health needs. [0003] Targeting the tumor microenvironment and eradicating tumors by destroying the "soil" on which tumor cells grow has become a new anti-tumor concept. Especially tumor immunotherapy, known as the "third revolution" of anti-cancer treatment, a series of new technologies and treatment options include PD-1 / P...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4192A61K31/405A61K31/352A61K45/06A61P35/00A61P35/02
CPCA61K45/06A61P35/00A61P35/02A61K31/352A61K31/405A61K31/4192A61K2300/00
Inventor 郭磊张德昌叶菜英石婧鞠瑞
Owner GUANGDONG YINZHU PHARMACEUTICAL TECHNOLOGY CO LTD
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