CAR with GITR intracellular domain for T cell activation
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Solution Overview
Problem
Current chimeric antigen receptors (CARs) for tumor therapy have limited costimulatory molecules, leading to suboptimal T cell activation and cytotoxic activity, with some second-generation CARs exhibiting similar cytotoxic activity to first-generation CARs, necessitating the discovery of novel costimulatory molecules for enhanced efficacy.
Innovation Solution
A CAR with an intracellular domain comprising a glucocorticoid-induced tumor necrosis factor receptor (GITR) and CD3ζ, where GITR is positioned on the C-terminal side, enhancing cytotoxic activity against tumor cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional costimulatory molecules (CD28, CD137, CD134) are used in second-generation and third-generation CARs, then T cell activation is enhanced, but cytotoxic activity remains suboptimal when certain molecules are used
Solution Approach 1:
The patent changes the molecular parameter by replacing conventional costimulatory molecules with GITR (glucocorticoid-induced TNF receptor) in the CAR intracellular domain. This parameter change resolves the contradiction by achieving both strong T cell activation and enhanced cytotoxic activity, overcoming the limitation where certain conventional molecules failed to improve cytotoxic function despite enhancing activation.
Solution Approach 2:
The patent copies the intracellular domain structure of GITR and integrates it into the CAR framework. By copying this specific molecular structure and its signaling capabilities, the invention achieves reliable T cell activation while simultaneously improving cytotoxic activity against tumor cells, resolving the performance gap between activation and killing functions.
2Adaptability or versatility
If a first-generation CAR structure is used, then the CAR can recognize tumor surface antigens independently of MHC, but T cell activation ability is insufficient
Solution Approach 1:
The patent merges the MHC-independent antigen recognition capability of first-generation CARs with the enhanced T cell activation ability of GITR costimulatory signaling. By combining these two functional elements into a single CAR construct, the invention achieves both MHC-independent tumor cell recognition and strong T cell activation, resolving the contradiction between adaptability and activation reliability.
3Productivity
If novel costimulatory molecules are sought to enhance CAR function, then more molecules need to be screened and tested, but the complexity of molecular selection and optimization increases
Solution Approach 1:
The patent extracts the intracellular domain of GITR as a discrete functional element and integrates it into the CAR structure. This extraction approach simplifies the molecular selection process by focusing on a single, well-defined costimulatory domain rather than screening entire receptor molecules, thereby reducing complexity while achieving enhanced cytotoxic activity.
Data Source
Figure 1A~1B
Figure 2
Figure 3~4
AI summary
Provided are a chimeric antigen receptor comprising an extracellular domain capable of binding to an antigen, a transmembrane domain and at least one intracellular domain, the chimeric antigen receptor being characterized in that an intracellular domain of a glucocorticoid-induced tumor necrosis factor receptor (GITR) is contained as the intracellular domain; a nucleic acid encoding the chimeric antigen receptor; a cell expressing the chimeric antigen receptor; and a method for producing the cell.