TCR for MAGE-A4 Tumor Recognition via Thymic Selection
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Solution Overview
Problem
Existing technologies face challenges in specifically recognizing and targeting MAGE-A4 antigen, a cancer-testis antigen, due to its intracellular location and the limitations of existing antibody and chimeric antigen receptor technologies, which can lead to immunotoxicity and limited clinical application in China.
Innovation Solution
Development of a natural T cell receptor (TCR) that specifically recognizes MAGE-A4 antigenic peptides, along with an expression vector and host cells, to enable targeted treatment of tumor diseases. The TCR is subjected to thymus negative selection to reduce immunotoxicity and is designed to target MAGE-A4 positive tumors, including esophageal, gastric, bladder, and laryngeal cancers, which have higher incidence rates in China.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If in vitro screening method is used to obtain TCR sequences, then TCR can recognize target antigen, but T cells may attack normal tissues causing immunotoxicity
Solution Approach 1:
The patent applies preliminary action by performing thymus negative selection in vivo before TCR-T cell construction. T cells are isolated from donors who have undergone thymic selection, ensuring autoimmunity removal occurs naturally in the thymus before the T cells are engineered and administered. This preliminary biological filtering prevents autoimmune reactions while maintaining target recognition capability.
2Measurement precision
If existing antibody technology is used, then target recognition is attempted, but MAGE-A4 cannot be specifically recognized due to intracellular location
Solution Approach 1:
The patent uses MHC molecules as intermediaries to present intracellular MAGE-A4 antigens on the tumor cell surface. The TCR recognizes the peptide-MHC complex rather than the free antigen, enabling detection of intracellular targets. This intermediary mechanism bridges the gap between intracellular antigen location and surface-based recognition systems.
3Reliability
If chimeric antigen receptor technology is used, then target targeting is attempted, but immunotoxicity occurs and clinical application is limited
Solution Approach 1:
The patent extracts only the TCR variable regions (CDR1, CDR2, CDR3) responsible for antigen recognition, separating them from the full TCR structure and associated signaling components. This extracted TCR domain is then expressed in T cells with controlled signaling, reducing off-target effects while maintaining tumor recognition capability.
Data Source
AI summary
Disclosed in the present application is a T cell receptor (TCR) capable of specifically recognizes MAGE-A4 antigenic peptide, including a TCRα Polypeptide having at least 90% identity with any one selected from a group consisting of sequences of SEQ ID No: 1 to SEQ ID No: 30 and a TCRβ polypeptide having at least 90% identity with any one selected from a group consisting of sequences of SEQ ID No: 31 to SEQ ID No: 60, in which the TCRα polypeptides are in one-to-one correspondence with the TCRβ polypeptides in order.