Chimeric antigen receptor and application thereof

A chimeric antigen receptor and binding domain technology, applied in the field of biomedicine, can solve the problems of complex immunosuppressive tumor microenvironment, tumor heterogeneity, etc.

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

Data released in 2017 showed that patients receiving this therapy could achieve an overall remission rate of up to 83%, which is unprecedented
[0007] Although CAR-T cell therapy has achieved exciting results in the treatment of blood cancers, CAR-T cell therapy in the treatment of solid tumors faces many challenges, such as solid tumors have a complex immunosuppressive tumor microenvironment and a high degree of Tumor heterogeneity, etc., still need to be further explored and studied

Method used

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  • Chimeric antigen receptor and application thereof
  • Chimeric antigen receptor and application thereof
  • Chimeric antigen receptor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0275] Example 1 Construction and Expression of Chimeric Antigen Receptor

[0276] Construction of chimeric antigen receptor molecular machines and vectors fused with immune checkpoint PD-1.

[0277] (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 ) 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 as figure 1 (h)...

Embodiment 2

[0280] Example 2 Detection and Characterization of Chimeric Antigen Receptors

[0281] combine figure 1 and figure 2 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.

[0282] in, figure 2 A schematic diagram of the signal activation of the chimeric antigen receptor artificial molecular machine containing the 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 rec...

Embodiment 3

[0319] Example 3 Tumor cytotoxic killing experiment

[0320] Through tumor cytotoxic killing experiments, to understand the mechanism of tumor killing detection of PD-L1 positive human tumor cells by human immune primary T lymphocytes modified by Chimeric Antigen Receptor fused with immune checkpoint PD-1 like image 3 . image 3 (a) shows that the immune checkpoint receptors (such as endogenous PD-1) on the surface of endogenous innate lymphocytes recognize and bind to the target molecules (such as PD-L1) on the surface of tumor cells endogenous The ability of lymphocytes to kill corresponding tumor cells is inhibited by inhibitory immune checkpoint signaling pathways. image 3 (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 correspo...

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Abstract

The invention discloses a chimeric antigen receptor. The chimeric antigen receptor comprises: a) an extracellular target molecule binding motif; b) an intracellular signal transduction motif, which comprises at least one intracellular activation signal transduction motif, wherein the activation of the intracellular activation signal transduction motif at least depends on binding of the extracellular target molecule binding motif to a target molecule, and the intracellular activation signal transduction motif contains molecules or fragments with catalytic functional groups; and c) a transmembrane region motif for linking the extracellular target molecule binding motif and the intracellular signal transduction motif. The chimeric antigen receptor is combined with various means such as tumorimmunology, synthetic biology, molecular cell engineering and the like, 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, and the chimeric antigen receptor has the same advantages as both an immune checkpoint inhibitor and CART cell therapy and provides a solution 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] Cancer is one of the most important public health burdens in the world, accounting for about 1 in every 6 deaths worldwide, and most cancer types, especially malignant tumors with low survival rates, frequently occur in the elderly population (World Health Organization, WHO report on cancer, 2020). For example, in the United States, cancer was the second leading cause of death in 2019, after heart disease, with more than a hundred types of cancer due to many different causes, and a disproportionately high proportion of cancer diagnoses in people over the age of 55 80% (Siegel RL et al., CA: a cancer journal forclinicians. 2020 Jan; 70(1):7-30.). In China, with the aging of the Chinese population, the acceleration of industrial urbanization, and the widespread prevalence of unhealthy lifestyles, more public health problems h...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K19/00C12N15/62A61K39/00A61P35/00
CPCC07K14/7051C07K16/2818A61P35/00C07K2319/02C07K2319/03C07K16/2827A61K39/0011A61K38/20A61K38/21A61K39/00A61K45/06A61P25/00A61P29/00A61P31/00A61P35/02A61P37/02C07K19/00C12N15/62C12N5/10A61K35/17A61K38/1774A61K38/217C12N9/12C12Y207/10001A61K2039/5156C07K14/70521C07K2319/00Y02A50/30A61K39/3955
Inventor 李晓东
Owner NANJING HYOSKY ZHONGKE TECH DEV CO LTD
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