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Application of PF543 in preparation of PD-L1/PD-1 monoclonal antibody tumor immunotherapy drug

A technology of PD-L1 and anti-tumor immunity, applied in the field of biological, PD-L1/PD-1 monoclonal antibody tumor immunotherapy, can solve the problems of complex tumor microenvironment and sexual drug resistance

Pending Publication Date: 2022-04-29
XIANGYA HOSPITAL CENT SOUTH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since PD-1 / PD-L1-related inhibitors have long-lasting anti-tumor effects, especially in some refractory malignant tumors, since 2014, multiple drugs targeting the PD-L1 / PD-1 pathway have been successively It has been approved by the FDA for the treatment of a variety of malignant tumors, and its indications are wider than that of CTLA-4 inhibitors. However, due to the different etiology and pathogenesis of various tumors, the complex tumor microenvironment, individual differences and other factors, PD-1 / PD-L1 inhibitors can only benefit some patients, and about 80% of patients develop acquired drug resistance or non-response after using the drug

Method used

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  • Application of PF543 in preparation of PD-L1/PD-1 monoclonal antibody tumor immunotherapy drug
  • Application of PF543 in preparation of PD-L1/PD-1 monoclonal antibody tumor immunotherapy drug
  • Application of PF543 in preparation of PD-L1/PD-1 monoclonal antibody tumor immunotherapy drug

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] 1. Expression and function analysis of sphingosine kinase in tumor tissue.

[0038] 1.1 Experimental method: The gene transcriptome of 33 types of cancer (including 10205 tumor samples) was obtained from the Cancer Genome Atlas (TCGA) database (http: / / gdac.broadinstitute.org / ) using the FPKM (Fragments Per Kilobase per Million) algorithm data. Use limma1.4.5 to analyze the fold change (Fold change, FC) of genes in tumors and corresponding normal tissues, and the screening threshold is |Log 2 (FC)|>0.58, using the Benjamini-Hochberg (BH) method to correct the P value of the hypothesis test probability. The Spearman correlation coefficient and its significance test were used to analyze the correlation between genes in tumor tissues, and the test level was α=0.05.

[0039] 1.2 Experimental results:

[0040] Gene set variation analysis was performed by comparing tumor and normal tissues of different cancer types in The Cancer Genome Atlas (TCGA) public database, and the ...

Embodiment 2

[0066] 1. In vitro study of SPHK1-MTA3 axis regulating the expression level of tumor PD-L1.

[0067] 1.1 Experimental methods: transcriptome sequencing, bioinformatics analysis of TCGA database, gene editing, cell gene intervention, PF543 drug intervention, Western blot, ChIP detection

[0068] The target gene siRNA Oligo sequence is shown in Table 2:

[0069]

[0070]

[0071] The specificity of the primers was judged according to the amplification curve, and the gene primers with poor specificity needed to be redesigned and synthesized. The optimized gene primer sequences are shown in Table 3 below:

[0072]

[0073] 1.2 Experimental results:

[0074] See Figure 4 A, Compared with the control group, among the 4182 significantly down-regulated genes detected in the treatment group, nine candidate transcription factors were identified according to the gene differential expression fold;

[0075] See Figure 4 B, In order to evaluate the reliability of the sequenc...

Embodiment 3

[0093] 1. In vivo study of tumor PD-L1 expression induced by SPHK1 and MTA3.

[0094] 1.1 Group settings:

[0095] CTL+IgG2α isotype control group (control group)

[0096] CTL+PD-1 monoclonal antibody group (PD-1 monoclonal antibody treatment group)

[0097] SPHK1-OE+IgG2α isotype control group (SPHK1 overexpression group)

[0098] SPHK1-OE+PD-1 monoclonal antibody group (SPHK1 overexpression PD-1 monoclonal antibody group)

[0099] MTA3-OE+IgG2α isotype control group (MTA3 overexpression group)

[0100] MTA3-OE+PD-1 monoclonal antibody group (MTA3 overexpression PD-1 monoclonal antibody group)

[0101] 1.2 Experimental process, see Image 6 A:

[0102] About 6 days before the experiment: 6-8 weeks C57BL / 6 mice were subcutaneously injected with B16F10 melanoma SPHK1 overexpression cell line and MTA3 overexpression cell line 8*10 in the right dorsal wing respectively. 5 20 mice each and the same number of CTL cell lines (empty control group).

[0103] The SPHK1 gene ove...

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Abstract

The invention belongs to the field of PD-L1 / PD-1 monoclonal antibody tumor immunotherapy, and provides a new research and development direction of PD-L1 / PD-1 monoclonal antibody tumor immunodetection or immunotherapy adjuvant drugs and a new drug combination mode. Specifically, the invention provides an application of PF543 in preparation of a PD-L1 / PD-1 monoclonal antibody tumor immune adjuvant therapy drug, the tumor is a solid tumor, and the solid tumor is further melanoma.

Description

technical field [0001] The invention relates to the field of biotechnology, in particular to the field of PD-L1 / PD-1 monoclonal antibody tumor immunotherapy. Background technique [0002] Skin tumors are the most common type of cancer among all tumors, among which skin malignant melanoma (SKCM) is a highly malignant skin tumor derived from melanocytes. Invasive melanoma accounts for only 1% of skin tumor cases but has a high mortality rate. In the past few decades, the incidence of melanoma has been on the rise. According to statistics, among the Caucasians in North America, Northern Europe, Australia and other regions, the incidence of melanoma is 4% to 6% per year. % speed climb. The latest statistics from the American Cancer Society show that the incidence of skin melanoma continues to rise. In 2020, about 100,350 new cases of melanoma will be diagnosed in the United States, and about 6,850 patients will die of melanoma. The mortality rate of cutaneous melanoma has dec...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/6886A61K45/00A61P35/00
CPCC12Q1/6886A61K45/00A61P35/00C12Q2600/158
Inventor 刘洪陈翔刘宝仪
Owner XIANGYA HOSPITAL CENT SOUTH UNIV
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