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CN-121987785-A - Use of cholesterol synthetases in the preparation of products for enhancing the killing function of CAR-T cells and derivatives thereof

CN121987785ACN 121987785 ACN121987785 ACN 121987785ACN-121987785-A

Abstract

The application discloses application of cholesterol synthetase in preparation of a product for enhancing killing function of CAR-T cells and derivatives thereof, wherein the cholesterol synthetase is SQLE or LSS, and the product enhances the killing function by independently knocking out SQLE or independently overexpressing LSS in the CAR-T cells and derivatives thereof. The application remarkably enhances the killing capacity of CAR-T cells and derivatives thereof by knocking out cholesterol synthesis key enzyme SQLE or over-expressing LSS.

Inventors

  • ZHANG CHAO
  • An Xueting
  • GAO XUE
  • HONG ZHANGYONG
  • WANG CHUNYANG
  • LIU YE

Assignees

  • 天津医科大学总医院

Dates

Publication Date
20260508
Application Date
20260410

Claims (7)

  1. 1. Use of cholesterol synthetases in the manufacture of a product for enhancing the killing function of CAR-T cells and derivatives thereof, characterized in that the cholesterol synthetase is SQLE or LSS, the product enhancing the killing function by knocking out SQLE alone or overexpressing LSS alone in the CAR-T cells and derivatives thereof.
  2. 2. The use according to claim 1, wherein the CAR-T cells and derivatives thereof are CAR-T cells or CAAR-T cells.
  3. 3. The use of claim 2, wherein the CAR-T cells include, but are not limited to CD19 CAR-T、BCMA CAR-T、FcRL5 CAR-T、BAFF-R CAR-T、GPRC5D CAR-T、HER2 CAR-T、EGFR CAR-T、CD38 CAR-T、CD22 CAR-T、CD20 CAR-T cells.
  4. 4. The use of claim 3, wherein the CAR-T cells are CD19 CAR-T cells.
  5. 5. The use of claim 2, wherein the CAAR-T cells include, but are not limited to AQP4 CAAR-T、MOG CAAR-T、NMDAR CAAR-T、AchR CAAR-T、MuSK CAAR-T、Dsg3 CAAR-T、LGI1 CAAR-T、GFAP CAAR-T、GAD65 CAAR-T、MBP CAAR-T cells.
  6. 6. The use according to claim 5, wherein said CAAR-T cells are AQP4 CAAR-T or MOG CAAR-T cells.
  7. 7. The use according to claim 6, wherein said AQP4 CAAR-T cell is an AQP 4M 1 CAAR-T cell or an AQP 4M 23 CAAR-T cell.

Description

Use of cholesterol synthetases in the preparation of products for enhancing the killing function of CAR-T cells and derivatives thereof Technical Field The invention relates to the technical field of biological medicine, in particular to application of cholesterol synthetase in preparation of a product for enhancing killing function of CAR-T cells and derivatives thereof. Background The core of the CAR-T cell (chimeric antigen receptor T cell) is that the Chimeric Antigen Receptor (CAR) is expressed on the cell surface by genetic engineering technology, and the receptor is composed of an antigen recognition domain (single-chain antibody scFV), a transmembrane domain and an intracellular signal domain, can bypass the restriction of MHC molecules, directly recognize specific antigens on the surface of tumor cells, quickly activate the T cell killing function and specifically remove target cells, thus being an important means for treating malignant blood tumors. However, CAR-T cells have the problems of insufficient infiltration, easy exhaustion, strong toxic and side effects and the like in solid tumors, and various optimized products including double/multi-target CAR-T cells, armored CAR-T cells, universal CAR-T cells, CAAR-T cells (chimeric autoantibody receptor T cells) and the like are derived. In the related art, the CAR-T related technology has lower killing function due to the situations of tumor microenvironment inhibition and the like. It should be noted that the information disclosed in the above background section is only for enhancing understanding of the background of the present disclosure and thus may include information that does not constitute prior art known to those of ordinary skill in the art. Disclosure of Invention The technical task of the application is to provide an application of cholesterol synthetase in preparing a product for enhancing the killing function of CAR-T cells and derivatives thereof, aiming at the defects, and the application remarkably enhances the killing capacity of the CAR-T cells by knocking out or over-expressing cholesterol synthesis key enzyme SQLE. In order to achieve the above purpose, the present application provides the following technical solutions: According to one aspect of the application there is provided the use of a cholesterol synthase, either SQLE or LSS, in the manufacture of a product for enhancing the killing function of CAR-T cells and derivatives thereof by knocking out SQLE alone or overexpressing LSS alone in the CAR-T cells and derivatives thereof. In some embodiments, the CAR-T cells and derivatives thereof are CAR-T cells or CAAR-T cells. In some embodiments, the CAR-T cells include, but are not limited to CD19 CAR-T、BCMA CAR-T、FcRL5 CAR-T、BAFF-R CAR-T、GPRC5D CAR-T、HER2 CAR-T、EGFR CAR-T、CD38 CAR-T、CD22 CAR-T、CD20 CAR-T cells. In some embodiments, the CAR-T cell is a CD19 CAR-T cell. In some embodiments, the CAAR-T cells include, but are not limited to AQP4 CAAR-T、MOG CAAR-T、NMDAR CAAR-T、AchR CAAR-T、MuSK CAAR-T、Dsg3 CAAR-T、LGI1 CAAR-T、GFAP CAAR-T、GAD65 CAAR-T、MBP CAAR-T cells. In some embodiments, the CAAR-T cells are AQP4 CAAR-T or MOG CAAR-T cells. In some embodiments, the AQP4 CAAR-T cell is an AQP 4M 1 CAAR-T cell or an AQP 4M 23 CAAR-T cell. Compared with the prior art, the application has the advantages and positive effects that: the killing capacity of the CAR-T cells is remarkably enhanced by knocking out cholesterol synthesis key enzyme SQLE or over-expressing LSS. Furthermore, the application can maintain or even improve the killing efficiency of the CAR-T cells under the condition of lower ratio of effector cells to target cells (E: T ratio), and reduce the dependence on the input of the CAR-T cells with high dosage. The dosage of the CAR-T cells in clinical treatment is reduced, so that the risk of massive release of cytokines is reduced, and clinical side effects such as cytokine storm and the like are reduced, so that the treatment safety and the patient tolerance are improved. Furthermore, the application realizes the internal enhancement of the function of the CAR-T cells under the conditions of not increasing the complexity of the CAR structure and introducing additional exogenous immune stimulation, improves the overall effectiveness and safety of the CAR-T cell treatment, and has higher clinical application value. Drawings In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings that are needed in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present application, and other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art. FIG. 1 shows the results of detection of killing efficiency of CD19 CAR-T co-incubated with Nalm6 under different treatment conditions in example 1 of the present