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Application of PPAR delta inhibitor combined immunotherapy drug in preparation of antitumor drugs

A technology of immunotherapy drugs and anti-tumor drugs, which is applied in the field of biomedicine to achieve strong targeting, avoid toxic and side effects, and enhance anti-tumor effects

Pending Publication Date: 2021-06-18
JILIN UNIV FIRST HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Therefore, larger doses of anti-CD40 agonists or combined use with other immunostimulators tend to cause greater side effects due to the overall activation of the immune system, thus limiting its clinical application. How to reduce the toxicity caused by the application of high-dose CD40 agonists Not affecting or even increasing its anti-tumor activity is the key problem to be solved in the clinical application of CD40 agonists in anti-tumor

Method used

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  • Application of PPAR delta inhibitor combined immunotherapy drug in preparation of antitumor drugs
  • Application of PPAR delta inhibitor combined immunotherapy drug in preparation of antitumor drugs
  • Application of PPAR delta inhibitor combined immunotherapy drug in preparation of antitumor drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] Example 1 The anti-CD40 agonistic antibody has dose-dependent anti-tumor effect, but high dose can cause obvious liver toxicity.

[0074] Anti-CD40 agonistic antibodies can promote the transformation of cold tumors into hot tumors, and have moderate anti-tumor effects on some tumors, but their effective dose range is narrow and they are toxic to the liver and other tissues. Toxic effects have been reported to be attenuated by intratissue injection and slow release of anti-CD40 agonist antibodies into tumor-draining areas.

[0075] First, we examined whether peritumoral injections of anti-CD40 agonistic antibodies had significant toxicity.

[0076] We used a well-studied and immunogenic mouse B16 melanoma model (C57BL / 6B16 tumor-bearing mouse model): C57BL / 6 mice (8-10 weeks, n=5 / group) were inoculated subcutaneously for 7 ×10 5 For B16 tumor cells (mouse melanoma cells), an anti-CD40 agonist antibody was administered when the tumor was palpable about 8 days after tumo...

Embodiment 2

[0083] Example 2 PPARδ inhibitors can enhance the therapeutic effect of small doses of anti-CD40 agonist antibodies without significant liver toxicity, while PPARγ inhibitors have no such effect.

[0084] It has been reported that PPARγ or PPARδ are sensors of fatty acids and are necessary for the maturation of macrophages of the M2 type (a suppressive phenotype), and blocking the PPARγ or PPARδ pathway can promote the polarization of macrophages to the M1 state. In the tumor microenvironment, macrophages are one of the major populations of infiltrating lymphocytes with an M2-like phenotype, which promote tumor progression and resistance to immunotherapy or chemotherapy. Reversing its polarization to the M1 state is considered to be an important anticancer immunotherapeutic strategy. Given its ability to switch tumor-infiltrating macrophages (TAMs) to a predominantly M1 phenotype, we utilized the B16 tumor-bearing mouse model of Example 1 and a treatment regimen of low-dose FG...

Embodiment 3

[0094] Example 3 Combination therapy of FGK45.5 and PPARδ inhibitors can effectively increase the depth of CD8 T cells infiltrating tumors.

[0095] Immune effector cells in tumors treated with FGK45.5 alone, low-dose FGK45.5 combined with a PPARδ inhibitor, and controls were quantified by flow cytometry and immunocytostaining of tissue sections.

[0096] The result is as image 3 As shown, though, compared with the FGK45.5 alone treatment group, intratumoral CD8 + T cells account for CD45 + The proportion of cells was only slightly increased, showing no statistically significant difference, but CD8+ cytotoxic T cells accounted for CD45 + The proportion of cells increased significantly. Tumor CD45 in FGK45.5 combined with PPARδ inhibitor treatment group + CD8 + The proportion of T cells increased to about 25%, about 15% in the FGK45.5 treatment group alone, and only 10% in the control group. In contrast, CD4 + T cells, B cells, and myeloid-derived suppressor cells (MDSC...

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Abstract

The invention relates to application of a PPAR delta inhibitor combined immunotherapy drug in preparation of antitumor drugs. The immunotherapy drug is an immune agonist or an immune checkpoint inhibitor. The tumors are preferably melanoma, breast cancer, ovarian cancer, pancreatic cancer, lung cancer, liver cancer, esophageal cancer, colorectal cancer, colon cancer, lymphoma, brain tumor, sarcoma, cervical cancer, prostate cancer, bladder cancer, osteosarcoma, head and neck cancer, renal cell cancer or gastric cancer. The medicine disclosed by the invention is remarkable in anti-tumor effect, high in targeting property and very small in side effect.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to the application of a PPARδ inhibitor combined with an immunotherapy drug in the preparation of an anti-tumor drug and an anti-tumor drug composition. Background technique [0002] In recent years, tumors have become a serious disease that threatens people's health. In addition to traditional surgery, radiotherapy and chemotherapy, immunotherapy can mobilize the body's immune system to specifically kill tumors. Compared with traditional treatment methods, immunotherapy has fewer side effects Small size, good therapeutic effect and long-lasting effect are attracting more and more attention. Immunotherapy can be used not only alone but also in combination with radiotherapy and chemotherapy, and different immunotherapies can also be used in combination to enhance the effect of treating tumors. [0003] The goal of immunotherapy is to establish a new or promote an existing anti-tu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/06A61K31/44A61K39/395A61P35/00
CPCA61K45/06A61K31/44A61K39/3955A61P35/00A61K2300/00C07K16/2878C07K16/2818C07K2317/75A61K2039/505A61K2039/545A61K39/395A61K9/0019
Inventor 刘文涛杨永广陈晨
Owner JILIN UNIV FIRST HOSPITAL
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