Application of PPAR-delta antagonist combined with PD-1 antibody in preparation of tumor immune drug

An antibody drug, PD-1 technology, applied in the direction of anti-tumor drugs, antibodies, drug combinations, etc., to achieve the effect of inhibiting growth, inhibiting tumor growth, and increasing the effect of tumor immunotherapy

Active Publication Date: 2020-03-27
JIANGSU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, whether PPARδ antagonists can enhance PD-1 antibody tumor immunotherapy is still unreported

Method used

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  • Application of PPAR-delta antagonist combined with PD-1 antibody in preparation of tumor immune drug
  • Application of PPAR-delta antagonist combined with PD-1 antibody in preparation of tumor immune drug
  • Application of PPAR-delta antagonist combined with PD-1 antibody in preparation of tumor immune drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1: PPARδ antagonists reduce PD-L1 protein levels

[0024] In this example, the effects of PPARδ antagonists GSK0660 and GSK3787 on the protein level of PD-L1 were verified. The SW480, HCT-116, and CT-26 cells were routinely cultured in DMEM complete medium containing 10% fetal bovine serum (FBS), and when they reached 80% confluence under a microscope, they were digested with 0.25% trypsin, and the cells were inoculated in a 12-well plate at 37ºC, 5% CO 2 After overnight in the incubator and when the density reached 70%-90% of the well, the cells were treated for 12 hours with dimethyl sulfoxide (DMSO) as the control group and GSK0660 and GSK3787 as the test group.

[0025] (1) Cell lysis and Western blot analysis of PD-L1 protein expression;

[0026] (2) Collect the cells by centrifugation, filter the cells with a 40 μm filter, 2x10 5 Cells were incubated with fluorescently labeled PD-L1 antibody and incubated at room temperature for 30 minutes. Cells were ...

Embodiment 2

[0029] Example 2: PPARδ antagonists inhibit PD-L1 gene expression

[0030] In this example, the effects of PPARδ antagonists GSK0660 and GSK3787 on the expression of PD-L1 gene were verified. Routinely culture SW480, HCT-116 and CT-26 cancer cells in DMEM complete medium containing 10% fetal bovine serum (FBS), and when they reach 80% confluence under a microscope, they are digested with 0.25% trypsin, and the cells are inoculated in a 12-well plate at 37ºC, 5% CO 2 After overnight in the incubator and the density reaches 70%-90% of the well, the cells are treated with DMSO (5 μM) as the control group, GSK0660 (5 μM) and GSK3787 (5 μM) as the test group.

[0031] (1) After the cells were treated for 12 hours, the cells were lysed, and the expression of PD-L1 gene was analyzed by qPCR;

[0032] (2) The cells were transfected with the PD-L1 reporter gene plasmid, and the cells were lysed 30 hours later, and the transcriptional activity of the PD-L1 gene was analyzed with a dua...

Embodiment 3

[0033] Example 3: PPARδ antagonist combined with PD-1 antibody significantly inhibits tumor growth

[0034] In this example, the effect of PPARδ antagonist GSK0660 combined with PD-1 antibody on tumor growth was verified. CT-26 cells (2 x 10 5 ) were subcutaneously inoculated into nude mice, and the inoculated mice were randomly divided into four groups: IgG (control group), PD-1, GSK0660, and PD-1+GSK0660; IgG / PD-1 antibody (200 μg / Mice), orally administered GSK0660 (20mg / kg / day) every day. Tumor volume was measured every week for a total of 4 weeks, and mice were sacrificed by neck dislocation at the end. Tumor volume calculation formula = 1 / 2 (length × width 2 ). The expression level of PD-L1 protein in tumor tissue lysates was analyzed by Western blot, in which Actin was an internal control protein.

[0035] Figure 4 It is a graph of the effect of PPARδ antagonist combined with PD-1 antibody on tumor growth; in the figure, A is a graph of tumor volume control; B is...

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Abstract

The invention relates to the field of tumor immunotherapy, in particular to an application of a PPAR-delta antagonist combined with a PD-1 antibody in the preparation of a tumor immune drug. The invention provides a new use of a PPAR-delta antagonist combined with a PD-1 antibody drug in a tumor immunotherapy drug. In the invention, a large number of experiments confirm that the PPAR-delta antagonist can significantly reduce the PD-L1 protein level and inhibit the gene expression of PD-L1, and thereby the tumor immunotherapy effect of the PD-1 antibody can be increased when a combined application of the PPAR-delta antagonist with the PD-1 antibody drug is performed, so that the tumor growth is better inhibited. Compared with single PD-1 antibody treatment, the PPAR-delta antagonist combined with the PD-1 antibody disclosed in the invention can significantly inhibit the tumor growth level in mice, and the inhibition effect is significantly higher than that of only using commonly-used antibody drugs. The PPAR-delta antagonist combined with the PD-1 antibody has significant actions on the tumor immunotherapy effect aspect.

Description

technical field [0001] The present invention relates to the field of tumor immunotherapy, in particular to the application of a PPARδ antagonist combined with PD-1 antibody in the preparation of tumor immunotherapy. Background technique [0002] The occurrence of cancer is mainly related to the loss of monitoring of tumor cells due to gene mutation and the decline of human immunity. Therefore, how to improve the body's immunity to effectively inhibit the occurrence of cancer is particularly important. The antibody drug PD-1, which acts on immune checkpoints (immune checkpoint) approved by the US FDA, can effectively treat more than 25 types of cancer. PD-1 (Programmed death-1) antibody / PD-L1 antibody is an immune checkpoint blocking drug. PD-1 is another important immunoprinted transmembrane protein expressed on the surface of T cells, a member of the CD28 superfamily, which was originally cloned from the apoptotic mouse T cell hybridoma 2B4.11. PD-1 has two ligands, PD-L1...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395A61K45/06A61P35/00A61K31/381A61K31/44
CPCA61K39/3955A61K45/06A61P35/00A61K31/381A61K31/44A61K2039/505A61K2300/00Y02A50/30
Inventor 侯永忠许慧慧苟倩史娟娟
Owner JIANGSU UNIV
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