MAGE-A4 Specific TCR for Reducing Immunotoxicity
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Solution Overview
Problem
Current T cell receptor (TCR) technologies for recognizing MAGE-A4 antigen face challenges in specificity, as they may not undergo thymus negative selection, leading to immunotoxicity and are primarily indicated for sarcoma, which constitutes a low proportion of tumors in China, limiting their clinical application.
Innovation Solution
Development of a T cell receptor (TCR) specifically recognizing MAGE-A4 antigenic peptides with high identity sequences, subjected to thymus negative selection, and an expression vector for targeting esophageal, gastric, bladder, and laryngeal cancers, expanding the application scope by identifying TCR sequences from tumor tissues using immunohistochemistry and single-cell omics.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If TCR sequences are screened through in vitro stimulation of naive T cells, then T cells can identify specific targets and pass functional verification, but the T cells are not subjected to thymus negative selection, leading to immunotoxicity and attack on normal tissues
Solution Approach 1:
The patent applies preliminary action by obtaining T cells from tumor-infiltrating lymphocytes (TILs) that have already undergone natural thymus negative selection in vivo, rather than generating T cells through in vitro stimulation. This pre-selection process eliminates autoreactive T cells before they can cause immunotoxicity, while preserving target-specific T cells that survived natural selection.
Solution Approach 2:
The patent extracts T cells directly from the tumor microenvironment (tumor-infiltrating lymphocytes) rather than generating them through in vitro methods. This extraction approach obtains T cells that have naturally selected against self-antigens in the thymus, thereby removing the harmful autoreactive component while retaining target-specific functionality.
2Reliability
If TCR-T technology primarily targets sarcoma, then specific treatment can be provided, but sarcoma accounts for an extremely low proportion in tumor patients in China, limiting clinical application scope
Solution Approach 1:
The patent achieves universality by identifying MAGE-A4 as a pan-cancer antigen expressed across multiple tumor types including esophageal cancer, gastric cancer, bladder cancer, and laryngeal cancer in addition to sarcoma. The TCR constructed against MAGE-A4 can therefore be applied universally across these different cancer indications, expanding clinical utility beyond the limited sarcoma indication.
Solution Approach 2:
The patent applies parameter changes by shifting the target antigen selection from sarcoma-specific markers to MAGE-A4, a cancer-testis antigen with broad expression across multiple tumor types. This parameter change in target selection enables the TCR-T therapy to treat a wider range of cancers that are more prevalent in the Chinese population.
3Ease of operation
If existing antibody technology and chimeric antigen receptor technology are used, then treatment can be provided, but they cannot specifically recognize intracellular cancer antigens presented on tumor cell surface
Solution Approach 1:
The patent uses MHC molecules as intermediaries to present intracellular cancer antigens (such as MAGE-A4 peptides) on the tumor cell surface. The TCR is designed to recognize the peptide-MHC complex rather than the free antigen or surface proteins, enabling detection of intracellular antigens through this intermediary presentation mechanism that bridges intracellular and extracellular recognition.
Data Source
Figure 1A~1B
Figure 1C~1D
Figure 2~3A
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.