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Hat acetylation promoters and uses of compositions thereof in promoting immunogenicity

A technology of composition and use, applied in the field of HAT acetylation promoter and its composition in promoting immunogenicity, can solve the problems of low expression of TAP, insufficient expression, lack of proteasome components, etc.

Inactive Publication Date: 2010-01-13
BIOMMUNE TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method is particularly useful in the context of tumor cells that lack proteasome components such that they express lower than normal amounts of TAP and therefore do not express sufficient MHC class I surface molecules that can be recognized by CTLs

Method used

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  • Hat acetylation promoters and uses of compositions thereof in promoting immunogenicity
  • Hat acetylation promoters and uses of compositions thereof in promoting immunogenicity
  • Hat acetylation promoters and uses of compositions thereof in promoting immunogenicity

Examples

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example 1

[0045] Using the reagents and procedures described above, it was shown that EP-1 mRNA expression correlates with its surface MHC class I expression in a mouse prostate cancer model and in an HPV-positive cancer model.

[0046] TAP-1 expression levels were demonstrated to correlate with MHC class I surface expression levels in both cell lines used (mouse prostate cancer and HPV positive cancer models). These results are shown in figure 1 middle. After transfectants become stable, expression of the luciferase gene under the control of the TAP-1 promoter generally matches endogenous TAP-1 levels. figure 1 A shows the analysis of TAP-1 and surface MHC class I expression by RT-PCR and flow cytometry, respectively. Shaded areas, thin lines and thick lines represent low (A9 or LMD), medium (D11) and high (TC-1 or PA) levels of MHC class I expression, respectively. Amplification of P-actin cDNA was used as an internal control in the RT-PCR analysis. Data are representative of th...

example 2

[0048] The role of chromatin remodeling in the regulation of TAP-1 transcription has been investigated. Previous observations by fluorescence microscopy and flow cytometry revealed that, days after transfection of several panels of TAP-expressing and TAP-deficient cell lines with a reporter construct containing the EGFP gene driven by the TAP-1 promoter, TAP-deficient Multiple cells in the TAP-expressing group expressed similar or even higher levels of EGFP relative to the majority of cells in the TAP-expressing group (data not shown), whereas EGFP expression levels in stable transfectants matched the endogenous TAP-1 expression profile (Setiadi et al., Cancer Res, 65, 7485-7492). In this experiment, a luciferase reporter construct was generated by cloning the mouse TAP-1 promoter (pTAP1-luc) upstream of the luc gene in the pGL4.14[luc2 / Hygro] vector and transfected into cells Department. Based on previous observations of EGFP levels, expression levels of the luc gene were f...

example 3

[0050] Example 3 Evidence that histone H3 acetylation is lower at the TAP-1 promoter in MHC class I-deficient carcinoma.

[0051] This experiment investigates the level of histone H3 acetylation at the TAP-1 promoter in murine prostate and cervical cancer cell lines to determine the role of histone H3 acetylation in the regulation of TAP-1 transcription. Although histone H3 is not the only class of core histones whose modifications have been shown elsewhere to have a role in the expression of various genes, since the association between histone H3 tail acetylation and the activation of various genes has been extensively studied and is now has been widely accepted [9, 10, 11], so this experiment studies its acetylation status.

[0052] According to the RNA pol II level in the TAP-1 promoter and the TAP-1 transcription level ( figure 1 and 2), it was found that the level of acetyl-histone H3 was lower in the TAP-1 promoter in cells expressing lower TAP-1 levels (Figure 2). ...

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Abstract

The invention provides processes and compositions for enhancing the immunogenicity of TAP-I expression-deficient cells by increasing the presentation of MHC Class I surface molecules for detection by cytotoxic T-lymphocyte cells through increased TAP-I expression, which comprises administering to the TAP-I expression-deficient cells a TAP-I expression increasing amount of a bio-acceptable substance that promotes transcription of TAP-I gene in the cells to cause enhanced MHC Class I surface expression of the cells. The bio-acceptable substance may be a histone H3 deacetylase inhibitor such as trichostatin A, a transcriptional co-activator having intrinsic histone acetyl transferase activity or a histone acetyl transferase comprising at least one member of the CBP / p300 protein family. The process and compositions increase the immunogenicity of the target cells, e.g. tumor cells, to enhance their destruction by cytotoxic lymphocytes.

Description

technical field [0001] The present invention relates to pharmaceutical compositions and their use in medical therapy. More specifically, it relates to compositions and medical treatments that enhance the immunogenicity of selected cells in a patient, thereby rendering the cells more susceptible to recognition and elimination by the body's immune system. Background technique [0002] Cytotoxic T-lymphocyte (CTL) responses are a major component of the immune system and play a role in immune surveillance and immune destruction of infected or malignant cells and invading organisms expressing foreign antigens on their surfaces. The ligand of antigen-specific T-cell receptor is a complex composed of exogenous antigen peptide fragments combined with major histocompatibility complex (MHC) molecules. Cytotoxic T lymphocytes recognize peptides bound to MHC class I molecules, which are normally expressed on the cell surface as a ternary complex including a peptide moiety. Ternary com...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/45A61K31/165A61K39/00A61P31/00A61P35/00A61P37/04
CPCA61K38/45A61K31/165A61P31/00A61P31/04A61P31/12A61P35/00A61P37/02A61P37/04A61P43/00Y02A50/30
Inventor 阿尔韦里娜·F·赛蒂亚迪米里埃尔·D·戴维罗宾·P·塞普珍妮弗·哈尔蒂凯琳雷沙德·戈保罗威尔弗雷德·A·杰弗里斯
Owner BIOMMUNE TECH
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