CAR-T Cell Hinge Region Modification for Tumor Infiltration
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Solution Overview
Problem
CAR-T cells have a short survival time in vivo and struggle to infiltrate solid tumors effectively, limiting their therapeutic efficacy in treating cancer, particularly for solid tumors where they often relapse due to immune evasion and metabolic multipotency.
Innovation Solution
A modified hinge region in the CAR-T cell structure, specifically the 7H, G4HH2H3mt, and 8H (dc) sequences, is introduced to enhance the survival time and infiltration capabilities of CAR-T cells by optimizing the flexibility and stability of the hinge region, allowing for improved antigen recognition and tumor targeting.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If conventional hinge region is used in CAR-T cell construction, then the basic CAR-T function is maintained, but the survival time of CAR-T cells in vivo is short and tumor infiltration capability is limited
Solution Approach 1:
The patent modifies the hinge region amino acid sequence by changing specific parameters (amino acid compositions at positions 15-18 and 79-82) to achieve prolonged CAR-T cell survival and enhanced tumor infiltration. The hinge region sequences are optimized with specific amino acid substitutions that improve cellular stability and function without compromising safety.
Solution Approach 2:
The invention applies local modifications to specific regions of the hinge region (positions 15-18 and 79-82) rather than changing the entire structure. This localized optimization maintains the overall CAR-T cell function while improving specific aspects such as survival time and tumor penetration capability.
2Adaptability or versatility
If conventional hinge region is used in CAR-T cell construction, then the basic CAR-T function is maintained, but the capability of CAR-T cells to infiltrate solid tumors is insufficient
Solution Approach 1:
The patent modifies the hinge region amino acid sequence by changing specific parameters (amino acid compositions at positions 15-18 and 79-82) to achieve prolonged CAR-T cell survival and enhanced tumor infiltration. The hinge region sequences are optimized with specific amino acid substitutions that improve cellular stability and function without compromising safety.
Solution Approach 2:
The invention applies local modifications to specific regions of the hinge region (positions 15-18 and 79-82) rather than changing the entire structure. This localized optimization maintains the overall CAR-T cell function while improving specific aspects such as survival time and tumor penetration capability.
3Productivity
If CAR-T cells are used to treat solid tumors, then tumor killing is achieved, but rapid death of CAR-T cells affects effectiveness and relapse occurs
Solution Approach 1:
The patent modifies the hinge region amino acid sequence by changing specific parameters (amino acid compositions at positions 15-18 and 79-82) to achieve prolonged CAR-T cell survival and enhanced tumor infiltration. The hinge region sequences are optimized with specific amino acid substitutions that improve cellular stability and function without compromising safety.
Solution Approach 2:
The modified hinge region enables continuous and sustained CAR-T cell survival and function over extended periods. The optimization ensures that CAR-T cells maintain their therapeutic activity continuously, preventing relapse and achieving long-term tumor control through persistent cellular action.
Data Source
AI summary
Provided in the present invention are an improved hinge area and the use of same in constructing CAR skeleton. The amino acid sequence of the improved hinge area is as shown in SEQ ID NO.1 or SEQ ID NO.2 or SEQ ID NO.3, and the hinge area can prolong the survival of CAR-T cells in vivo and/or improve the capability of CAR-T cells to infiltrate tumors.