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Phagocyte chimeric antigen receptor and application thereof

A chimeric antigen receptor and phagocytic cell technology, applied in the field of biomedicine, can solve problems such as tumor heterogeneity in complex immunosuppressive tumor microenvironment

Active Publication Date: 2021-01-29
NANJING HYOSKY ZHONGKE TECH DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] It is known that cell therapy faces many challenges in the treatment of solid tumors. For example, solid tumors have complex immunosuppressive tumor microenvironment and high tumor heterogeneity, so further exploration and research are still needed.

Method used

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  • Phagocyte chimeric antigen receptor and application thereof
  • Phagocyte chimeric antigen receptor and application thereof
  • Phagocyte chimeric antigen receptor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0256] Example 1 Construction and Expression of Chimeric Antigen Receptor

[0257] Construction of chimeric antigen receptor molecular machines and vectors fused with immune checkpoint PD-1.

[0258] (1) The intracellular signal transduction domain of the intracellular part of the chimeric antigen receptor (including the intracellular activation signal transduction domain as the activation element, the intracellular detection signal transduction domain as the detection element, and the Intracellular hinge domain) and extracellular target molecule binding domain, transmembrane domain and extracellular spacer domain, intracellular spacer domain (see figure 1 and figure 2 ) through genetic engineering, using Gibson Assembly seamless cloning connection for connection fusion, and finally cloned into a specific gene expression vector (such as pSIN lentiviral vector or pMSCV retroviral vector or pCAG or pCDNA3, etc.) for subsequent in vitro and in vivo Research. Among them such a...

Embodiment 2

[0261] Example 2 Detection and Characterization of Chimeric Antigen Receptors

[0262] combine Figure 1 to Figure 4 Based on the information provided, the detection and characterization schemes of various artificial molecular machines are set up, including but not limited to, the detection and characterization of the functional expression of chimeric antigen receptors in eukaryotic cells by different means, and the detection of chimeric antigen receptors in the form of purified proteins And characterize the extracellular function of chimeric antigen receptor.

[0263] in, image 3 A schematic diagram of the signal activation of a chimeric antigen receptor artificial molecular machine containing an extracellular target molecule binding domain is shown and (a) is a schematic diagram of the signal activation of the artificial molecular machine under the input of a tyrosine kinase activation signal, ( b) Schematic diagram of the signal activation of a chimeric antigen receptor ...

Embodiment 3

[0287] Example 3 Tumor cytotoxic killing experiment

[0288] Through tumor cytotoxic killing experiments, to understand the tumor killing detection of PD-L1-positive human tumor cells by human immune primary T cells modified by chimeric antigen receptors fused with immune checkpoint PD-1, the mechanism is as follows Figure 4 . Figure 4 (a) shows that the immune checkpoint receptors on the surface of endogenous innate lymphocytes, such as endogenous PD-1, recognize and bind to target molecules on the surface of tumor cells, such as PD-L1, endogenous The ability of lymphocytes to kill corresponding tumor cells is inhibited by inhibitory immune checkpoint signaling pathways. Figure 4 (b) shows that when human T lymphocytes modified and engineered based on chimeric antigen receptor fusion of immune checkpoint PD-1 recognize and bind to the target molecule PD-L1 on the surface of tumor cells, the modified T lymphocytes can effectively be activated and effectively kill the corres...

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PUM

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Abstract

The invention discloses a phagocyte chimeric antigen receptor. The phagocyte chimeric antigen receptor comprises: a) an extracellular target molecule binding motif; b) an intracellular signaling domain, which comprises at least one intracellular activation signal transduction motif, wherein activation of the intracellular activation signal transduction motif at least depends on binding of the extracellular target molecule binding domain to a target molecule, and the intracellular activation signal transduction motif contains molecules or fragments with catalytic functional groups; and c) a transmembrane domain motif, which is used for connecting the extracellular target molecule binding motif and the intracellular signal transduction motif and fixing the extracellular target molecule binding motif and the intracellular signal transduction motif on a cell membrane. The chimeric antigen receptor is combined with various means such as tumor immunology, synthetic biology, molecular cell engineering and the like, and an artificial molecular machine which is based on an immune checkpoint signal path PD-1 / PD-L1 and has a function of coding and regulating immune cells is established and applied, so a solution is provided for improving solid tumor treatment.

Description

technical field [0001] The application relates to a chimeric antigen receptor, which belongs to the field of biomedicine. Background technique [0002] Solid tumors are different from hematological tumors, for example, they have a complex dynamic ecosystem and tumor microenvironment, involving interactions between a variety of cells, such as active interactions between tumor cells and stromal cells. Tumor cells can affect the development of tumors and the response of tumors to treatment by regulating the body's adaptive immune response and innate immune response. Inflammatory cells are an important part of the tumor ecosystem, with a type of phagocyte known as tumor-associated macrophages representing one of the most abundant stromal components of the tumor microenvironment and thus a highly visible stromal target in many solid tumors cell. Tumor-associated macrophages are the most numerous leukocytes in solid tumors, and in most human tumor types, tumor-associated macroph...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K19/00C12N15/62A61K39/00A61K45/06A61K38/21A61K38/20A61K39/395A61P35/00A61P35/02A61P31/00A61P29/00A61P37/02A61P25/00
CPCC07K14/7051C07K16/2818A61P35/00C07K2319/02C07K2319/03C07K16/2827A61K39/0011A61K38/20A61K38/21A61K45/06A61P25/00A61P29/00A61P31/00A61P35/02A61P37/02C07K19/00C12N15/62C12N5/10A61K38/1774A61K38/217C12N9/12C12Y207/10001C07K14/70521C07K2319/00Y02A50/30A61K39/4631A61K39/4611A61K2239/50A61K2239/31A61K39/4636A61K2239/57A61K39/464411A61K39/3955
Inventor 李晓东
Owner NANJING HYOSKY ZHONGKE TECH DEV CO LTD
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