CAR-T Cell Persistence via Optimized 4-1BB Spacer Domain
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Solution Overview
Problem
Current CAR-T cell therapies for cancer treatment face challenges in persistence and efficacy due to inappropriate spacer domains leading to activation-induced cell death and non-specific killing of non-target cells, limiting their clinical effectiveness.
Innovation Solution
A novel chimeric antigen receptor (CAR) structure incorporating a 4-1BB signal peptide, transmembrane region, and intracellular domain, optimized to enhance tumor antigen recognition and persistence, with a CD19-specific CAR design that reduces cytokine release and improves anti-tumor activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a conventional CAR structure with inappropriate spacer domain is used, then the CAR-T cells can recognize tumor antigens, but the CAR-T cells undergo activation-induced cell death and lose persistence in vivo
Solution Approach 1:
The patent changes the spacer domain length parameter from conventional designs to a specific optimized length (e.g., 15-25 amino acids), which prevents Fc receptor binding while maintaining antigen recognition capability, thereby resolving the contradiction between persistence and structural design
Solution Approach 2:
The patent extracts and removes the problematic Fc receptor binding function from the CAR structure by optimizing the spacer domain, eliminating the harmful interaction while preserving the desired antigen recognition and signaling functions
2Reliability
If a CAR structure with inappropriate spacer domain is used, then the CAR-T cells can be activated, but they exhibit non-specific killing of non-target cells
Solution Approach 1:
The patent optimizes the spacer domain length parameter to a specific range (15-25 amino acids) that prevents inappropriate Fc receptor interactions, thereby eliminating non-specific killing while maintaining specific antigen recognition
Solution Approach 2:
The optimized spacer domain acts as an intermediary element that mediates between the antigen binding domain and transmembrane region, preventing harmful Fc receptor binding while facilitating proper signal transduction for specific target recognition
3Productivity
If traditional CAR-T structures are used, then the treatment can proceed, but cytokine release is excessive causing adverse effects
Solution Approach 1:
The patent changes the intracellular signaling domain composition and configuration parameters to optimize T cell activation signaling, achieving effective anti-tumor activity while moderating cytokine release through balanced signal transduction
Data Source
AI summary
Disclosed herein is a novel chimeric antigen receptor and use thereof. The novel chimeric antigen receptor consists of a signal peptide, an antigen binding domain, a transmembrane region, and an intracellular signal domain, and comprises a 4-1BB signal peptide and/or a 4-1BB molecular transmembrane region. Nucleic acid sequences of various chimeric antigen receptors are separated and purified and provided is a chimeric antigen receptor and a CAR-T cell which are specific for a CD19 malignant tumor antigen. In the malignant tumor killing test of hematological cell lines, the ability of immune cells to target and recognize tumor cells is significantly enhanced, and the killing activity against tumor cells is also enhanced.