CAR-T Cells Targeting MAGE-A4 Peptide via scFv
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Solution Overview
Problem
Current cancer therapies, such as TCR gene infusion therapy and CAR-T cell therapy, face challenges in effectively targeting cancer cells due to the difficulty in isolating killer T cell clones and the lack of cancer-specific antigens, particularly for intracellular molecules.
Innovation Solution
Development of an antigen-binding protein that specifically recognizes the MAGE-A4-derived peptide/HLA-A2 complex, enabling the production of CAR-T cells capable of targeting cancer cells by isolating antibodies with high affinity and constructing chimeric antigen receptors for immunotherapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If TCR gene infusion therapy is used to recognize peptide-MHC complex and kill cancer cells, then safety and effectiveness are improved, but the difficulty of isolating killer T cell clones increases
Solution Approach 1:
The patent creates a copy of the T cell receptor's antigen recognition function using a single-chain antibody fragment (scFv) that specifically recognizes the MAGE-A4 peptide/HLA-A2 complex. This copied recognition capability is then fused with the T cell's signaling and cytotoxic machinery through the CAR construct, allowing T cells to be redirected against cancer cells without requiring isolation of pre-existing killer T cell clones
Solution Approach 2:
The patent introduces an intermediary molecule (the antigen-binding protein/scFv) that mediates the recognition between T cells and the peptide-MHC complex. This intermediary carries the specificity for the cancer antigen while the T cell provides the cytotoxic function, resolving the contradiction by separating recognition and execution functions
2Adaptability or versatility
If CAR infusion therapy uses antibodies that recognize cancer antigens, then various patients can receive therapy and affinity is improved, but the availability of cancer-specific antigens deteriorates
Solution Approach 1:
The patent applies local quality by targeting intracellular antigens (MAGE-A4) that are specifically expressed in cancer cells but not in normal tissues. The CAR-T cells are engineered with specificity for this localized cancer antigen, allowing selective attack on tumor cells while sparing healthy cells, thus providing versatile therapy for various patients with MAGE-A4 positive cancers
Solution Approach 2:
Instead of trying to find cell surface antigens for CAR targeting, the patent inverts the approach by targeting intracellular antigens that are presented on the cell surface via MHC molecules. This inversion expands the available target space to include numerous intracellular cancer-specific antigens that were previously inaccessible to antibody-based therapies
3Measurement precision
If CAR-T cells are engineered to recognize peptide-MHC complex, then specificity for intracellular antigens is improved, but the complexity of constructing CAR increases
Solution Approach 1:
The patent segments the CAR construct into distinct functional modules: an extracellular antigen-binding domain (scFv) that recognizes the peptide-MHC complex, a transmembrane domain for cell membrane anchoring, and intracellular signaling domains for T cell activation. This segmentation allows systematic construction and optimization of CAR-T cells with high specificity for intracellular antigens while managing complexity through modular design
Data Source
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AI summary
[Problem] To provide CAR-T cells that can be used in CAR infusion therapy wherein a cancer-specific intracellular antigen is used. [Solution] The problem is solved by CAR-T cells for cancer therapy provided with an antibody that recognizes the MAGE-A4-derived-peptide/HLA-A2 complex, wherein the antibody has VH amino acid sequence of SEQ ID NO: 36 and VL amino acid sequence of SEQ ID NO: 38. In the case, the antibody preferably is provided with the amino acid sequence of SEQ ID NO: 32.