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Antitumor composition, expression vector for same and application of antitumor composition

An anti-tumor drug and composition technology, applied in the biological field, can solve the problem of insufficient number of local T cells in tumors, and achieve the effects of promoting anti-tumor immune response, prolonging survival, and inhibiting tumor growth

Active Publication Date: 2018-09-14
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, in actual clinical treatment, only a small number of tumor patients respond to the therapy of blocking PD-1 / PD-L1 signaling with antibodies, and most patients have no effect. This may be because the local T cells in the tumor of most patients respond to Insufficient amounts or PD-1 / PD-L1 negative signaling does not play an important role in tumor immunosuppression

Method used

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  • Antitumor composition, expression vector for same and application of antitumor composition
  • Antitumor composition, expression vector for same and application of antitumor composition
  • Antitumor composition, expression vector for same and application of antitumor composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1: Preparation and identification of recombinant vectors and transfected cell lines that stably secrete IL-36γ and sPD-1 genes

[0042] Design a fusion gene fragment containing the human CD8 signal peptide sequence and the fully active murine IL-36γ fragment (G13~S164) coding region, and design a fusion gene fragment containing the human CD8 signal peptide sequence and the mouse PD-1 extracellular functional region (G13~S164). S164) fusion gene fragments of the coding region were respectively synthesized and inserted into the eukaryotic expression vector pCDEF3 to construct recombinant expression vectors pCDEF3-IL-36γ and pCDEF3-sPD-1. The mouse melanoma cell line B16 was transfected with pCDEF3-IL-36γ and pCDEF3-sPD-1 respectively or jointly with liposomes, and was screened by G418, subcloned and identified by QRT-PCR and ELISA. 36γ, sPD-1 and gene transfected cell lines B16-IL-36γ, B16-sPD-1, B16-IL-36γ / sPD-1 ( figure 1 A and 1B). At the same time, the empty...

Embodiment 2

[0043] Example 2: IL-36γ combined with sPD-1 significantly synergistically inhibits tumor growth and prolongs the survival of tumor-bearing mice

[0044] The gene transfection cell lines B16-vec, B16-sPD-1, B16-IL-36γ and B16-IL-36γ / sPD-1 successfully constructed in Example 1 were subcutaneously inoculated into C57BL / 6 mice in the abdomen, and every 2 The tumor size of the mice was measured and the survival of the mice was observed.

[0045] The results showed that compared with the control group B16-vec, sPD-1 secreted and expressed by B16-sPD-1 did not significantly inhibit tumor growth, and IL-36γ secreted and expressed by B16-IL-36γ could significantly inhibit tumor growth. When B16-IL-36γ / sPD-1 co-expressed IL-36γ and sPD-1, tumor growth was further significantly inhibited ( figure 2 A), showing that IL-36γ combined with sPD-1 has a synergistic inhibitory effect on tumor growth. At the same time, the observation of the survival period of tumor-bearing mice showed that ...

Embodiment 3

[0046] Example 3: IL-36γ combined with sPD-1 has a synergistic effect on the anti-tumor immune response in the early tumor microenvironment

[0047] The transfected cell lines B16-vec, B16-sPD-1, B16-IL-36γ and B16-IL-36γ / sPD-1 were subcutaneously inoculated into C57BL / 6 mice in the abdomen respectively. Infiltrating lymphocytes in the microenvironment of tumors (day 25 of tumor growth) and their functions were analyzed.

[0048] (1) Compared with B16-vec, B16-sPD-1, B16-IL-36γ in the control group, in B16-IL-36γ / sPD-1 tumors: the proportion of CD4+ T cell population was significantly increased ( image 3 ); CD4 in tumor + and CD8 + T cell nuclear proliferation antigen was significantly up-regulated ( Figure 4 and Figure 5 ); CD4 in tumor + and CD8 + The function of T cells is promoted, and the expression level of IFN-γ in these two groups of T cells is significantly increased and the expression level of CD107a in CD8 + The expression level on T cells was significantl...

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Abstract

The invention relates to the field of biotechnologies, and discloses an antitumor composition, a co-expression vector for the same and application of the antitumor composition. The antitumor composition, the co-expression vector and the application have the advantages that combination of 1L-36 gamma and PD-1 (programmed death-1) / PD-L1 (programmed death-ligand 1) signal blocking agents on tumor sites is demonstrated, antitumor immune response in tumor micro-environments can be effectively promoted, and tumor growth can be obviously inhibited; the lifetime of tumor-bearing mice can be greatly prolonged, novel and effective tumor immunotherapy is created, and theoretical and method foundations can be laid for further developing corresponding tumor immunological preparations.

Description

technical field [0001] The invention relates to the field of biotechnology, in particular to an anti-tumor composition and its expression vector and application. Background technique [0002] The immune response in the tumor microenvironment is often suppressed, and the use of effective means to restore and activate the activity of tumor-infiltrating immune cells can help inhibit tumor progression. [0003] In the tumor microenvironment, the immune card control signal composed of programmed death receptor 1 (PD-1, Programmed death-1) and its ligand PD-L1 (Programmed deathligand-1) mediates the effect on T cells and NK etc. The inhibitory effect of immune cells broadly inhibits the body's anti-tumor immune response during tumorigenesis. The use of antibodies to block PD-1 / PD-L1 signaling can restore the existing T cells and other activities in the tumor microenvironment, which helps to enhance the anti-tumor immune response, which has achieved certain clinical effects. Howe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/20A61P35/00A61K48/00A61K38/17
CPCA61K38/177A61K38/20A61K48/005A61P35/00A61K2300/00
Inventor 王雪峰卢斌峰蒋敬庭朱一蓓鲁翰林申春苹陈晨宋盈莹
Owner SUZHOU UNIV
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