Application of PCSK9 inhibitor in malignant tumor immunotherapy

An inhibitor, tumor technology, used in anti-tumor drugs, blood/immune system cells, allergic diseases, etc., can solve problems such as anemia

Active Publication Date: 2018-08-14
HEPATOBILIARY SURGERY HOSPITAL SECOND MILITARY MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although those skilled in the art are committed to anti-tumor research and have developed a variety of tumor immunotherapy methods, there are still many technical difficulties. For example, there are still some problems in immune checkpoint drugs: due to PD-1 / PD- The L1 signaling pathway only acts on the effector phase of T cells. The effect of anti-PD-1 / PD-L1 drugs requires the presentation of tumor antigens. Clinically, about 70% of tumors with low immunogenicity are often ineffective. Chemotherapy, radiotherapy and other drugs are used in combination; in addition, cancer cells sometimes achieve immune escape through different or multiple ways, and simply blocking the PD-1 / PD-L1 pathway may have no effect on the immune escape of some cancer cells
Antibodies targeting CD47 have functions such as activating macrophages and enhancing T cell antigen presentation, and are functionally complementary to anti-PD-1 / PD-L1. However, the expression of CD47 is not strictly tumor-specific. Using CD47 in vivo Antibodies often cause adverse reactions such as anemia

Method used

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  • Application of PCSK9 inhibitor in malignant tumor immunotherapy
  • Application of PCSK9 inhibitor in malignant tumor immunotherapy
  • Application of PCSK9 inhibitor in malignant tumor immunotherapy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Example 1: Establishment of mouse tumor-bearing model

[0068]First, in the tumor-bearing experiment of mice in the PCSK9 antibody (purchased from BPS Bioscience) group, 20 male C57BL / 6J mice aged 6-8 weeks were selected, and each mouse was inoculated with 2×10 mice by subcutaneous injection. 6 A melanoma B16F10 cell, liver cancer cell Hepa1-6, lung cancer cell LLC, and prostate cancer cell RM-1 (purchased from the Chinese Academy of Sciences) were observed for tumor formation after 8 days. Sixteen mice with similar tumor sizes were selected, and then they were divided into a control group (8 mice) and a PCSK9 antibody group (8 mice).

[0069] Secondly, in the tumor-bearing experiment of mice in the PCSK9 antibody group, 30 male C57BL / 6J mice aged 6 to 8 weeks were selected, and each mouse was inoculated with 2×10 6 A melanoma B16F10 cell or a lung cancer cell LLC, and the tumor formation was observed after 8 days. Select 24 mice with similar tumor size, and then divi...

Embodiment 2

[0070] Example 2: Effects of PCSK9 inhibitors on tumor growth in mice

[0071] 1. Effect of PCSK9 antibody on tumor growth in mice

[0072] After the mice were grouped, the mice in the control group were given isotype control IgG, and the mice in the experimental group were given PCSK9 antibody (dissolved in saline), 10 mg / Kg, once every 3 days, intraperitoneal injection, or PD-1 antibody, every time 200μg (about 10mg / Kg) per mouse, once every 3 days, intraperitoneal injection, or a combination of the two. After the administration, the subcutaneous tumor size of mice in each group was measured every week, and the tumor volume was calculated (tumor volume=long diameter of tumor×short diameter of tumor) 2 / 2). The largest mouse tumor volume reached 2cm 3 When left and right, the mice in each group were sacrificed, the subcutaneous tumors were taken out, and the tumor growth curves were drawn.

[0073] Such as figure 1 , 2, 3 showed that the subcutaneous tumors in the contro...

Embodiment 3

[0080] Example 3: Detection of blood cholesterol-related indicators in mice

[0081] Before the mice in each group were sacrificed, the blood was collected with anticoagulant tubes, and the supernatant was collected after centrifugation to detect the total blood cholesterol content and low-density lipoprotein cholesterol content.

[0082] Such as Figure 5 As shown, the total blood cholesterol and low-density lipoprotein cholesterol levels in mice injected with PCSK9 antibody were significantly reduced, while triglyceride and high-density lipoprotein cholesterol had no significant changes, which was consistent with the medicinal effect of PCSK9 antibody.

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Abstract

The invention relates to an application of a PCSK9 inhibitor in malignant tumor immunotherapy. The PCSK9 inhibitor can effectively inhibit tumour. Through increasing of expression of an immunocyte activation related gene, the immunocyte activity can be enhanced by the PCSK9 inhibitor, and the tumour can be inhibited. The invention also reveals obvious effect of combined application of the PCSK9 inhibitor and a PD-1 inhibitor for increasing immunocyte activity and tumour inhibition.

Description

technical field [0001] The invention relates to the field of chemical medicines, more specifically, the invention relates to the application of PCSK9 inhibitors in anti-tumor immunotherapy. Background technique [0002] Tumor immunotherapy is the most promising new therapy that has emerged in recent years. This therapy can enhance the response ability of the immune system and stimulate specific immune responses, so as to delay tumor progression, inhibit tumor recurrence and metastasis, and even completely cure tumors. [0003] At present, tumor immunotherapy can be divided into the following categories: (1) Non-specific immunotherapy, which refers to the application of some immunomodulators to non-specifically enhance the body's immune function and activate the body's anti-tumor immune response to achieve the purpose of treating tumors . Currently, cytokines (1L-2, IFN, TNF, etc.), microorganisms and their products, vitamin K, heat shock protein (HSP), etc. are used in tumo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61K45/06C12N5/0783A61P35/00A61P37/04
CPCA61K45/00A61K45/06C12N5/0636C12N5/0646C12N2501/734
Inventor 王红阳付静秦文昊杨知时陈瑶
Owner HEPATOBILIARY SURGERY HOSPITAL SECOND MILITARY MEDICAL UNIV
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