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Application of p62/SQSTM1 in preparation of PD-L1/PD-1 monoclonal antibody tumor immunotherapy drug

A PD-L1, anti-tumor immunity technology, used in PD-L1/PD-1 monoclonal anti-tumor immunotherapy drugs, biomedicine, and can solve problems such as unclear mechanism

Active Publication Date: 2020-12-01
XIANGYA HOSPITAL CENT SOUTH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The overall response rate of PD-1 monoclonal antibody therapy for melanoma is less than 40%, and the mechanism is still unclear
At present, there is no relevant literature report on the regulation of PD-L1 by sunitinib. Therefore, in-depth research on the mechanism of sunitinib down-regulating the protein level of PD-L1 in melanoma will help to develop new immunotherapy models for clinical treatment. Treatment Offers New Strategies

Method used

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  • Application of p62/SQSTM1 in preparation of PD-L1/PD-1 monoclonal antibody tumor immunotherapy drug
  • Application of p62/SQSTM1 in preparation of PD-L1/PD-1 monoclonal antibody tumor immunotherapy drug
  • Application of p62/SQSTM1 in preparation of PD-L1/PD-1 monoclonal antibody tumor immunotherapy drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] 1. Retrospective clinical observation of the correlation between tumor PD-L1 and p62 expression levels in NSCLC patients treated with PD-1 monoclonal antibody (nivolumab).

[0029] The experimental results are shown in Table 1. In NSCLC patients treated with PD-1 monoclonal antibody, there was a significant negative correlation between the expression levels of tumor PD-L1 and p62, and there was a statistical difference, P<0.05.

[0030]

[0031] Description of attached table 1: Table 1 shows the expression levels of tumor PD-L1 and p62 marked by immunofluorescent staining on paraffin sections of tumor tissue samples from NSCLC patients treated with PD-1 monoclonal antibody. Table 1 summarizes the number of patients in each category. According to these Data, the significance of the correlation between the two was assessed by Fisher's exact test (two-sided test).

[0032] 2. Retrospective clinical observation of the correlation between tumor PD-L1 and p62 expression an...

Embodiment 2

[0044] 6. In vivo study on the proliferation of xenograft tumors (melanoma, non-small cell lung cancer) in mice combined with sunitinib (Sunitinib) combined with CTLA-4 monoclonal antibody.

[0045] 6.1 Group settings:

[0046] Vehicle+IgG2b (control group)

[0047] Sunitinib+IgG2b (sunitinib single drug group)

[0048] Vehicle+CTLA-4 mAb (CTLA-4 mAb treatment group)

[0049] Sunitinib+CTLA-4 mAb (joint intervention group)

[0050] 6.2 Experimental process, see Figure 4 A. 5A:

[0051] About 6 days before the experiment: 6-8 weeks C57BL / 6 mice were subcutaneously injected with B16F10 melanoma 5*10 in the right dorsal wing 5 Individual or LLC non-small cell lung cancer 1*10 6 wild-type cell lines, 40 mice each.

[0052] Day 0 of the experiment: record the body weight and tumor volume of the mice, when the tumor volume grows to about 100mm 3 At the beginning of time, the inoculated mice were divided into four groups, which were given Sunitinib 20 mg / kg / day, intraperiton...

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Abstract

The invention provides application of p62 / SQSTM1 as a biomarker and a target site detection reagent as well as application of an inhibitor of p62 / SQSTM1 in PD-L1 / PD-1 monoclonal antibody tumor immunotherapy Drug, and also discloses application of combination of sunitinib and CTLA-4 monoclonal antibody drugs in preparation of tumor immunotherapy adjuvant drugs, wherein the tumor is preferably melanoma or lung cancer. The invention provides a new research and development direction of PD-L1 / PD-1 monoclonal antibody tumor immunodetection or immunotherapy adjuvant drugs, and develops a new drug combination mode.

Description

technical field [0001] The invention relates to the field of biomedicine technology, in particular to the field of PD-L1 / PD-1 monoclonal antibody tumor immunotherapy drugs. Background technique [0002] Sunitinib is a multi-target small molecule inhibitor acting on the tyrosine kinase receptor (Receptor tyrosine kinase, RTK), which has been approved by the FDA for the treatment of advanced renal cell carcinoma, imatinib-resistant or intolerable gastrointestinal stromal tumors (GISTS) and advanced pancreatic neuroendocrine tumors. Current studies have found that sunitinib can effectively treat small cell lung cancer and colon cancer. Literature reports and the applicant's previous research have found that sunitinib can significantly inhibit the proliferation of melanoma. Sunitinib can block downstream MAPK, PI3K-AKT, NF-κB and other signaling pathways, thereby inhibiting tumor proliferation and promoting tumor apoptosis. At the same time, it can also inhibit tumor angiogen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N33/574A61K45/00A61K31/404A61K39/395A61P35/00
CPCG01N33/57484A61K45/00A61K31/404A61K39/39558A61P35/00A61K2300/00
Inventor 匡欣薇刘洪陈翔刘静
Owner XIANGYA HOSPITAL CENT SOUTH UNIV
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